Présentation des travaux de thèse des doctorants de l

Transcription

19&20 mai 2016
Amphithéâtre Ponte
Campus St Jérôme
Av Escadrille Niémen
13013 Marseille
http://www.univ-amu/recherche
(cliquer sur ED250)
Présentation des travaux de thèse des doctorants
de l’école doctorale des Sciences Chimiques
i8h30
8 a v r I l 2 0 1 4Accueil
9h00
Ouverture
9h15
Myrial Dekhil
ISM2
Session 1 - Communications orales. Modérateur : Thierry Constantieux, directeur de l’ED
NMR Crystallography: Internuclear distance measurement on powder samples using solidstate NMR. Directeur de thèse : Stéphane Viel
Fabien Perez
ISM2
Organocatalysis by iminium activation. Directeur de thèse : Yoann Coquerel
Sébastien Lemouzy
ISM2
Protecting group strategy in the stereospecific synthesis of phosphorus-borane compounds: a
straightforward access to new ligands for asymmetric catalysis.
Directeur de thèse : Gérard Buono
Adèle Ferrand
ICR
Synthesis of new single-ion copolymer electrolytes for lithium-metal batteries.
Directeur de thèse : Didier Gigmes
Yohan Dudognon
ISM2
Synthesis and use of original 1,3-dicarbonyls in enantioselective organocatalysis.
Directeur de thèse : Thierry Constantieux
Frédéric Brunel
CINaM
Antibacterial activities of fluorescent nanoparticles derived from triphenylamine phosphonium
ionic liquid. Directeur de thèse : Michel Camplo
10h30
Pause
10h45
Conférence 1
Mickaël Antoni, professeur au Madirel (Matériaux Divisés, Interfaces, Réactivité,
Electrochimie). Titre : « Chemical properties of interfaces in dispersed materials" »
11h45
Pause déjeuner - Libre
13h10
Association Modocc : renouvellement du bureau et présentation des activités.
13h15
Salle des Actes
Séance « posters » des doctorants en 2
année.
Présentation en 3 minutes des travaux de thèse !
14h45
Paulin Nkolo
ICR
Session 2 - Communications orales. Modérateur : Xavier Bugaut, MCF
Synthesis and Evaluation of new nitroxides and alkoxyamines for diagnostic probes and
polymer chemistry. Directeur de thèse : Gérard Audran
ème
Romuald Eto Ekomo Influence of co-solvents to understand enantiorecognition mechanisms: Alcohol induced
ISM2
reversa of elution order in chiral chromatography. Directeur de these : Christian Roussel
Hongguang Jin
ISM2
Biomimetic Self-assembling Acylphthalocyanines.
Directeur de these : Theodor Silvius Balaban
Cyril Borie
ICR
Perfluorinated Enediynes: New Anticancer Molecules for Theranostics.
Directeur de thèse : Malek Nechab
Julia Rendon
BIP
Local structures of the molybdenum cofactor in Nitrate Reductase probed by advanced EPR
spectroscopy. Directeur de thèse : Bruno Gugliarelli
15h45
Pause
16h00
Intervention 1
Pierre Carron de l’Association OTECI (Office Technique d’Études et de Coopération
Internationale). « Réseaux sociaux : une opportunité. Pourquoi ? Comment ? »
16h30
Karen Monsalve
BIP
Session 3 - Communications orales. Modérateur : Yoann Coquerel, DR
A hydrogen biofuel cell to feed a wireless communication device.
Directeur de thèse : Elisabeth Lojou
Cyrielle Dol
ICR
Nanoconfinement Effect on Phenoxyl Radical Lifetime in Nanostructured Silica.
Directeur de thèse : Stéphane Gastaldi
Tatiana Straistari
ISM2
N2S2 based molecular systems for electrocatalytic proton reduction.
Directeur de thèse : Marius Réglier
Aurélien Stutzmann
TMCD2
Phenothiazine derivatives as a solution for antibiotic-resistant Gram-negative bacteria.
Directeur de thèse : Gérard Boyer
8h45
Accueil
9h15 Amphi Ponte
Session 4 - Communications orales Modérateur : Sandrine Alibert, MCF
Olesea Cuzan
ISM2
Synthesis and study of new copper coordination compounds containing 2-(2H-benzotriazol2-yl)-4,6-ditert-pentylphenol ligand. Directeur de these : Michel Maffei
Jessica Hernandez
TMCD2
Design & Synthesis of Quinolone Analogues to Block Antibiotic Efflux in Gram-negative
Bacteria. Directeur de thèse : Gérard Boyer
Alexander Zoller
ICR
Simulation and decomposition kinetics of “cold” free radical polymerization (FRP) with a
peroxide/amine initiation system. Directeur de thése : Didier Gigmes
Mylène Roudier
ISM2
Triple iron/copper/iminium activation for the efficient redox neutral catalytic enantioselective
functionalization of allylic alcohols. Directeur de thèse : Jean Rodriguez
Nicolas Zivic
ICR
Synthesis and study of naphthalimide chromophores as photoinitiators.
Directeur de thèse : Didier Gigmes
10h15
Pause
10h30
Marie Bénédicte Fonanarava, Chargée de mission relations extérieures et partenariats Incubateur inter-universitaire Impulse. « De l’idée au projet … du projet à l’entreprise ».
10h50
Conférence 2
and
Mathieu Sollogoub, professeur à l’Université Pierre et Marie Curie.
Titre : Synthesis of site-specifically modified Cyclodextrins for supramolecular assemblies
catalysis ».
11h50
Buffet – Salle des Actes
13h15
Salle des Actes
Séance « posters » des doctorants en 2
année.
Présentation en 3 minutes des travaux de thèse !
14h20
Amphi Ponte
Ophélie Quinonero
ISM2
Session 5 - Communications orales. Modérateur : Rémy Fortrie, MCF
Enantioselective synthesis of 4-arylpyridine atropisomers by central-to-axial chirality
conversion. Directeur de thèse : Cyril Bressy
Aurélien Fresneau
PIIM
A la recherche de l'origine de la matière organique des comètes.
Directeur de thèse : Thierry Chiavassa
Christophe Chendo
ICR
Mass Spectrometry of Poly(4-vinylpyridine) synthesized by Nitroxide-Mediated
Polymerization : a case of reactive MALDI. Directeur de thèse : Laurence Charles
15h00 En visioconférence
Intervention 3
Christophe Allais - Docteur de l’Ecole Doctorale Sciences Chimiques.
Principal Scientist at Pfizer (Etats-Unis) : « Témoignage d’un parcours professionnel ».
15h30
Amphi Ponte
Maria Kafentzy
ISM2
Session 6 - Communications orales. Modérateur : Grégoire Danger, MCF
Electrochemical hydroxylation of nonreactive C-H bonds of aminoindane substrates mediated
by copper complexes. Directeur de thèse : Jalila Simaann
Kawtar Mouhat
ICR
Two-dimensional Covalent Organic Frameworks on surface.
Directeur de thése : Didier Gigmes
Laura Sams
EIPL
Constitutive expression of recombinant human gastric lipase and some clones in Pichia
pastoris. Directeur de thèse : Frédéric Carrière.
ème
Mot de clôture des 6èmes Rencontres Scientifiques
16h15
Sigles des
laboratoires et
équipes de recherche
AFMB
BIP
CINaM
EIPL
ICR
ISM2
LISA
PIIM
TMCD2
Architecture et Fonction des Macromolécules Biologiques
Bioénergétique et Ingénierie des Protéines
Centre Interdisciplinaire de Nanosciences de Marseille
Enzymologie Interfaciale et de Physiologie de la Lipolyse
Institut Chimie Radicalaire
Institut des Sciences Moléculaires de Marseille
Laboratoire d'Instrumentation et Sciences Analytiques
Physique des Interactions Ioniques et Moléculaires
Transporteurs Membranaires, Chimiorésistance et Drug-Design
Comité d’organisation
Doctorants de l’école doctorale des Sciences chimiques
Aurélien STUTZMANN
3ème Année – TMCD2
Marion DELORME
1ère année – ISM2
Florian LAGARDE
Magalie DELECLUSE
Clara AUPIC
ère
1
année – ISM2
Vincent BELOT
2ème année – ISM2
Hugo LINGUA
année – ISM2
ème
2
Teddy BUTSCHER
2ème année - PIIM
-
Conférences
Jeudi 19 mai à 10h45 – Amphi Ponte
Mickaël Antoni
« Chemical properties of interfaces
in dispersed materials"
Vendredi 20 mai à 10h50 – Amphi Ponte
Matthieu Sollogoub
Synthesis of site-specifically modified Cyclodextrins
for supramolecular assemblies and catalysis
Vendredi 20 mai 2016 à 10h50
Conférence
Matthieu Sollogoub
Sorbonne Universités, UPMC Univ Paris 06, Institut Parisien de Chimie Moléculaire (UMR CNRS
8232), Paris, France ([email protected])
Synthesis of site-specifically modified Cyclodextrins for supramolecular assemblies
and catalysis
Site-selective functionalization of complex molecules, which consists in targeting only one
position out of many similar ones, is a particularly demanding challenge. Concave molecules
such as cyclodextrins desperately need efficient and regioselective poly heterofunctionalization methods to expand their field of applications, but this task is highly difficult
because of their high symmetry. As an illustration there are 7826 ways to arrange six
functions on the primary rim of α-cyclodextrin. Based on the discovery of a regioselective
debenzylation reaction of sugars, and the understanding of its mechanism, 1 we delineated
several strategies to access poly-hetero-functionalized cyclodextrins2 and reached the Grail
of cyclodextrin functionalization: the hexadifferentiation.3 The access to such complex
structures allows applications in a wide range of areas including hierarchical
supramolecular assemblies,4 catalysis5 that will be illustrated.
References:
1. Chem. Eur. J. 2004, 10, 2960.
2. Chem. Commun. 2006, 1112; Chem. Eur. J. 2007, 13, 9757; J. Org. Chem. 2008, 73,
2819; Angew. Chem., Int. Ed. 2008, 47, 7060; Angew. Chem., Int. Ed. 2013, 52, 639.
3. Nature Comms. 2014, 5, 5354
4. Chem. Eur. J. 2007, 13, 8847; Chem. Commun. 2010, 46, 2238; Angew. Chem. Int. Ed.
2012, 51, 487; Angew. Chem. Int. Ed. 2014, 53, 7238.
5. Angew. Chem. Int. Ed. 2010, 49, 2314; Chem. Commun. 2011, 47, 9206; Angew. Chem.
Int. Ed. 2013, 52, 7213.
NMR Crystallography: Internuclear distance measurement on powder
samples using solid-state NMR
Myriam Dekhila, Giulia Mollicaa, Fabio Ziarellib, Pierre Thureaua, Stéphane Viela
a
b
Aix-Marseille Université, CNRS, ICR UMR 7273, 13397 Marseille, France;
Aix-Marseille Université, Centrale Marseille, CNRS, Fédération des sciences
Email: [email protected]
Since structure and properties of solids are related, structural characterization is one of the
major issues for modern chemistry. While X-ray diffraction remains the method of choice to
characterize single crystals, structural determination of powder samples represents an
important challenge. In fact, X-ray diffraction is inadequate when single crystals of sufficient
size or quality are not available. In this context, solid-state NMR is an effective tool to study
molecular structure on powders. Internuclear distances, and from these, the geometry and
conformation of molecules, can be obtained on powders.
During my doctoral work, we developed two methodologies that permit short-range as well as
long-range distance measurements in powder samples. Our first technique applies to
uniformly enriched samples by modifying magic angle spinning (MAS) and using frequencyselective pulses to isolate specific distances1. Our second methodology is based on the
dramatic increase in sensitivity provided by dynamic nuclear polarization (DNP)2 in order to
record 2D 13C-13C INADEQUATE spectra which depend on internuclear distances in natural
isotopic abundance powder samples. In particular, we focused on natural abundance
theophylline powder sample. Theophylline is a pharmaceutical compound representative of
the current challenges found in structure determination: it has several polymorphic forms,
and, although it may form crystals suitable for X-ray diffraction, its crystallization is far from
straightforward. We demonstrated that the so-obtained distances are sensitive to both
molecular conformation and crystal packing of theophylline as a powder.
a)
6 7
4
1
23
6 7
a)b)
4
1
23
5
5
∗∗ ∗ ∗
∗∗ ∗ ∗
DQ chemical shift
7
1
4
2-6&72
3
6
13
5
DQ chemical shift
ppm
ppm
3-6&7
ppm
C chemical shift
6-7
6-7
Figure : INADEQUATE spectrum of theophylline
5-6&7
powder sample
at natural abundance. The
3-6&7
spectrum depends
on internuclear distances and
1-6&in
7 7 hours.
5-5recorded
was
5-6&7
2-6&7
3-6&&77
3-6
1-6&7
3-5
1-5
b)
5-5
2-5
1-2
1-3
2-3
2-5
3-5
3-5
1-5
1-5
1-2
ppm
C chemical shift
13
2-6&7
1-6&&77
1-6
1-3
2-3
3-5
1-5
ppm
C chemical shift
13
1
G. Mollica, M. Dekhil, F. Ziarelli, P. Thureau and S. Viel, Solid State Nuclear Magnetic Resonance 2015, 65,
114-121
2
G. Mollica, M. Dekhil, F. Ziarelli, P. Thureau and S. Viel, Angewandte Chemie International Edition 2015,
127, 6126-6129
Organocatalysis by iminium activation
Fabien PEREZa, Jean RODRIGUEZ*a, Yoann COQUEREL*a
a
Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313
Web site: http://ism2.univ-amu.fr/
Iminium activation is one of the most popular organocatalytic activation methods. As nicely
presented by MacMillan,1 “it is based on the capacity of chiral amines to function as
enantioselective catalysts for several transformations that traditionally use Lewis acid
catalysts. The concept was funded on a mechanistic hypothesis that the reversible formation
of iminium ions from ,-unsaturated aldehydes and chiral amines might emulate the
equilibrium dynamics and -orbital electronics that are inherent to Lewis acid catalysis (that
is, lowest-unoccupied molecular orbital (LUMO)-lowering activation.” The mechanistic
considerations of iminium activation have recently been reviewed in detail.2
Despite the enormous understanding, rationalization and progresses in iminium activation
since 2000, the currently available organocatalysts still required relatively high catalyst
loadings (5-20 mol%) and/or long reaction times (hours to days).
In this communication, our progresses on the use of “super-active” organocatalysts for
iminium activation will be discussed.
Scheme 1: iminium activation
1
D. W. C. MacMillan, Nature, 2008, 455, 304-308.
M. Nielsen, D. Worgull, T. Zweifel, B. Gschwend, S. Bertelsen, K. A. Jørgensen, Chem. Commun. 2011, 47,
632-649
2
Protecting group strategy in the stereospecific synthesis of
phosphorus-borane compounds: a straightforward access to new
ligands for asymmetric catalysis
Sébastien LEMOUZYa, Romain MEMBRAT, Marion JEAN, Laurent
GIORDANO, Damien HERAULT*, Gérard BUONO*
a
ISM2 Equipe Chirosciences, UMR 7313, Aix-Marseille Université, France.
Web site: http://ism2.univ-amu.fr/
The tailoring of chiral phosphorus molecules has emerged as a powerful tool in asymmetric
catalysis, especially using transition-metal catalysts1. Although chiral-group substituted
phosphorus compounds have been extensively investigated, and represent the vast majority of
these ligands, the ones bearing the chirality at the phosphorus atom (P-stereogenic) have been
overlooked the scientific community, mostly due to synthetic reasons. In this context, the
development of synthetic methodologies allowing the access to such P-chiral molecules
remains a challenging area of research, as it opens new horizons for the development of chiral
ligands in asymmetric catalysis2.
Recently, our group has developed new methods which allow the stereospecific,
chemodivergent synthesis of enantiopure phosphorus-borane compounds via a protectinggroup approach, starting from Adamantyl H-phosphinates3. Indeed, hydroxylakyl moiety was
found to be a suitable surrogate of hydrogen atom, allowing the in situ generation of unstable
species, such as phosphido-boranes and halo-phosphines-boranes4.
1
Phosphorus ligands in asymmetric catalysis; Börner, A., Ed.; Wiley-VCH: Weinheim, Germany, 2008.
For recent methodologies employing P-chiral ligands, see: (a) Jin, M.; Adak, L.; Nakamura, M. J. Am. Chem.
Soc. 2015, 137, 7128. (b) You, W.; Brown, M.K. J. Am. Chem. Soc. 2015, 137, 14578.
3
Gatineau, D.; Nguyen, D.-H.; Hérault, D.; Vanthuyne, N.; Leclaire, J.; Giordano, L.; Buono, G. J. Org. Chem.,
2015, 80, 4132.
4
(a) Lemouzy, S.; Jean, M.; Giordano, L.; Hérault, D.; Buono, G. Org. Lett. 2016, 18, 140. (b) Manuscript in
preparation.
2
Synthesis of new single-ion copolymer electrolytes for lithiummetal batteries
Adèle FERRANDa, Trang N.T.PHANa, Sébastien MARIAa, Renaud
BOUCHETb, Didier GIGMESa
a
Institut de Chimie Radicalaire, CROPS, UMR 7273, Aix-Marseille Université
b
LEPMI, UMR 5279, Université Grenoble Alpes
Alternative mode of transportation such as fully-electric or hybrid vehicles are a
matter of primary importance for a sustainable long-term development. In line with this
societal context, the elaboration of cheap and safe batteries with high specific energy suitable
for the mass-market of electric vehicles has been stimulating the scientific community for
many years. Among different battery technologies, Lithium-Metal Batteries are very wellpositioned1 thanks to the high energy density of lithium. However, this technology presents
several issues such as the use of liquid-based electrolytes that can lead to undesired leaks. But,
the main concern of this technology is related to a possible lithium dendritic growth during
charge/discharge cycles causing internal short-circuits possibly followed by dramatic
explosion and fire. To overcome these drawbacks, solid polymer electrolytes (SPE)
combining both high conductivity and suitable mechanical properties to prevent dendritic
growth are perfect candidates. Recently, we demonstrated the remarkable potential of
multifunctional single-ion block copolymers based on polystyrene derivatives and
poly(ethylene oxide) as SPE for Lithium-Metal battery technology.2-3 In order to constantly
improve the SPE properties and to get a better insight of their mode of action, we present in
this study the synthesis of new series of single-ion copolymer electrolytes based on anionic
poly(meth)acrylate derivatives. (Fig.1)
R = H or CH3
R’= alkyl group
Fig.1: Structure of single-ion block copolymer electrolyte
Various block copolymers with different compositions were synthesised using the
Nitroxide-Mediated Polymerization technique. Their performance as SPE for ionic
conduction was evaluated by electrochemical impedance spectroscopy.
1 M. Armand, J-M. Tarascon, Nature. 451 2008 652–657.
2 R. Bouchet, S. Maria, R. Meziane, A. Aboulaich, L. Lienafa, J-P. Bonnet, T.N.T. Phan, D. Bertin, D. Gigmes,
D. Devaux, R. Denoyel, M. Armand, Nature Materials. 12 2013 452-457.
3 R. Bouchet, T.N.T. Phan, E. Beaudoin, D. Devaux, P. Davidson, D. Bertin, R. Denoyel, Macromolecules. 47
2014 2659-2665.
Synthesis and use of original 1,3-dicarbonyls in
enantioselective organocatalysis
Y. Dudognona, X. Bugauta, T. Constantieuxa, J. Rodrigueza
a
iSm2, Stéréo Team, UMR 7313, Aix-Marseille Université
Web site: http://ism2.univ-amu.fr/equipes/Stereo_1.htm
Email: [email protected], [email protected]
1,3-Dicarbonyl compounds, with their numerous electrophilic and nucleophilic positions, are interesting
substrates for organocatalyzed transformations. Using β-ketoamides, we have developed the first
organocatalyzed multicomponent synthesis of enantioenriched polycyclic 1,2,3,4-tetrahydropyridine derivatives
under iminium activation.[1] Those tetrahydropyridines, in which four new bonds are created and three
stereogenic centers are forged, were prepared with moderate yields, very good enantioselectivities, fixed
kinetically by the catalyst, as well as complete regioselectivities and high diastereoselectivities, under
thermodynamic substrate control. Using tosylated secondary amides, bridge polycyclic structures could also be
obtained.[2]
Despite the interesting features of those β-ketoamides, it is still a necessity to synthesize new substrates
to access new reactivities and products. In this context, we have developed the first addition of silylated
nucleophiles to α-oxoketenes generated by microwave-assisted Wolff rearrangement of 2-diazo-1,3-dicarbonylcompounds to create interesting building blocks, which are hard or impossible to access by others existing
methods.[3] This methodology is a rapid, efficient and easy-to-handle way to prepare original scaffolds and
intermediates that can be either post-functionalized or used in organocatalytic reactions.
References
[1]
Y. Dudognon, H. Du, J. Rodriguez, X. Bugaut, T. Constantieux, Chem. Commun. 2015, 51, 1980.
Y. Dudognon, H. Du, M. M. Sanchez Duque, S. Goudedranche, J. Rodriguez, X. Bugaut, T. Constantieux, manuscript in
preparation.
[3]
Y. Dudognon, M. Presset, J. Rodriguez, Y. Coquerel, X. Bugaut, T. Constantieux, Chem. Commun., 2016, 52, 3010.
[2]
Antibacterial activities of fluorescent nanoparticles derived from
triphenylamine phosphonium ionic liquid
Frédéric BRUNEL,1 Christelle LAUTARD,2 Frédéric GARZINO,1 Suzanne
GIORGIO,1 Jean-M RAIMUNDO,1 Jean-M BOLLA,2 Michel CAMPLO*,1
1
2
Aix-Marseille Université CINaM (CNRS UMR 7325), Marseille, France;
Aix-Marseille Université IRBA TMCD2 (CNRS UMR-MD1), Marseille, France
Email: [email protected] ; [email protected]
Staphylococcus aureus, a Gram positive coccal bacterium is a major cause of nosocomial
infection. We report the synthesis of new triphenylamine phosphonium ionic liquids which
are able to self-assemble into multiwall nanoparticles and to reveal a strong bactericidal
activity (MIC = 0.5mg/L) for Gram + bacteria (including resistant strains) comparable to that
of standard antibiotics. Time kill, metabolism and fluorescence studies show a quasiinstantaneously penetration of the nanoparticles inside the bacteria resulting of a rapid
blocking (30 min) of their proliferation. As confirmed by rezasurin reduction monitoring,
these compounds strongly affect the bacterial metabolism and a Gram + versus Gram selectivity is clearly observed. These fluorescent phosphonium ionic liquid might constitute a
useful tool for both translocation studies and to tackle infectious diseases related to the field
of implantology.
Fig. 1: Graphic abstract
[1]. O’Toole, G.A.; Wathier, M.; Zegans, M.E.; Shanks, R.M.Q.; Kowalski, R.; Grinstaff, M.W. Cornea.
2012, 31(7), 810-816.
[2]. Ling, L.L.; Schneider, T.; Peoples, A.J.; Spoering, A.L.; Engels, I.; Conlon, B.P.; Mueller; A.;
Schäberle, T.F.; Hughes, D.E., Epstein; S. (2015). Nature. 2015, 517, 455–459.
6ème edition des Rencontres Scientifiques des Doctorants en Chimie de Marseille.
Synthesis and Evaluation of new nitroxides and alkoxyamines for
diagnostic probes and polymer chemistry.
Gérard Audran,a Raphaël Bikanga,b Paul Brémond,a Jean-Bernard Bongui,b
Sylvain R. A. Marque,a Paulin Nkoloa
CRAB, ICR UMR 7273, Aix-Marseille Université
This work focuses on the synthesis and charactzrization of novel nitroxides and
alkoxyamines. The physico-chemical analysis of alkoxyamines and the effect of solvents on
the nitroxides .
The solvent effect on the nitroxide is a chemical investigation methods to better understand
the phenomenon of delocalition of single electron on the N-O bond and angle , given by the
Heller- McConnel equation : ap = B0 + B1cos2 (  ), allows insight into conformation
of the nitroxide .
Radical initiators (alkoxyamines) belong to a class of chemical species finding a broad range
of applications in organic chemistry and material sciences. Among various possibilities the
generation of these species is mainly obtained from the thermolysis or photolysis of peroxy
compounds including alkyperoxides, dialkyperesters, hyroperoxides, alkyl peracid,
diacylperoxides, percarbonates or azo derivatives. In material science, these compounds are
particularly useful as polymerization initiators, crosslinking agents or for the chemical
modification of the polymer backbone.
Therefore, to meet the requirements of the chemical, polymer and coating industries, a safe
alternative to peroxides has then been developed. Then, we propose the synthesis of new
alkoxyamines which are:
- higher efficiency in initiation stage than the conventional initiators (azo
compounds and peroxide derivatives);
- more ecological, i.e., less side-product issued from the decomposition of the
initiator.
Influence of co-solvents to understand enantiorecognition mechanisms :
Alcohol induced reversal of elution order in chiral chromatography
Doctorant Romuald ETO EKOMO- PrChristian ROUSSEL
Equipe chiroscience/Ism2, UMU
Website: http://ism2.univ-amu.fr/pages-bleues/index2.htm
When we separate a compound in chiral chromatography using different
solvents, what we expected is a modification of the retention time, but what we
observed after to do a screening of a lot of chiral compounds on our columns
with stationary phase coated (CHIRALPAK AD-H, OD-H…) and stationary
phase immobilized (CHIRALPAK IA, IB….), is a reversal of elution order and
others unusual behaviour.
Separation of enantiomers in chiral chromatography is done via interaction
between chiral selector ( amylose, cellulose and molecular) and the enantiomer
by various mechanisms of interactions such as: π, steric, hydrophobic… to give
labile diastereomers and enantiomer wich forms more the more stable
diastereomer will be more retained in column.
Separation needs also mobile phase which is liquid such as: alcohol in our case
and others, and the results we obtained indicate that solvent haves not only the
objective to elute the compound but could bring an other unknown in
enantiorecognition mechanism which is responsible of unusual behaviours.
The using of solvents and their mixture could help us to understand their
responsibility in the change of enantiorecognition mechanism.
Example:
Biomimetic Self-assembling Acylphthalocyanines
Hong-Guang Jin, Mihaela Carmen Balaban, Sabine Chevallier-Michaud,
Michel Righezza and Teodor Silviu Balaban
Aix-Marseille Université, CNRS UMR 7313, Centrale Marseille,Chirosciences, Service 442,
Avenue Escadrille Normandie-Niemen, F-13013 Marseille, France
E-mail: [email protected]
Highly ordered self-assembling functional dyes with efficient energy utilization are
desirable for materials science.1 Compared to traditional covalent bonds, the supramolecular
self-assembly based on noncovalent interactions is a powerful approach to reach this goal.
Green photosynthetic bacteria can capture light efficiently even at 100 m under water surface 2
thanks to their special organelles, called chlorosomes, which agglomerate homologues of
bacteriochlorophylls (BChl’s) c, d, e. Our group has mimicked3 and extended4 the selfassembly algorithm by employing different recognition motifs as well as various solubilizing
groups grafted onto porphyrins or chlorins which self-assemble in the same way as the natural
BChl’s. Here, we synthesized a series of biomimetic self-assembling phthalocyanines (Pc’s)5
equipped with carbonyl groups as recognition motifs, a central zinc atoms and diverse
solubilizing alkyl chains mimicked the natural BChl’s. Upon self-assembly a very broad and
red-shifted Q-band absorption extending to over 900 nm is put into evidence.
Acknowledgements: H.-G. Jin gratefully acknowledges his PhD fellowship from China Scholarship Council.
REFERENCES
1. (a) J.-M.Lehn, Science, 2002, 295, 2400; (b) P. Kambhampati, Acc. Chem; Res., 2011, 44, 1; (c) J. Rawson,
A. C. Stuart, W. You, M. J. Therien, J. Am. Chem. Soc., 2014, 136, 17561.
2. (a) J. Overmann, H. Cypionka, N. Pfennig, Limnol. Oceanogr., 1992, 37, 150; (b) A. K. Manske, J. Glaeser,
M. M. M. Kuypers, J. Overmann, J. Appl. Environ. Mircrobiol., 2005, 71, 8049.
3. (a) T. S. Balaban, A. D. Bhise, M. Fischer, M. Linke-Schaetzel, C. Roussel, N. Vanthuyne, Angew. Chem. Int.
Ed., 2003, 42, 2140; (b) T. S. Balaban, M. Linke-Schaetzel, A. D. Bhise, N. Vanthuyne, C. Roussel, Eur. J.
Org. Chem., 2004, 3919.
4. (a) M. C. Balaban, T. S. Balaban, J. Porphyrins Phthalocyanines, 2007, 11, 277; (b) J. Szmytkowski, J.
Conradt, H. Kuhn, C. M. Reddy, M. C. Balaban, T. S. Balaban, H. Kalt, J. Phys. Chem. C, 2011, 115, 8832.
5. H.-G. Jin, M. C. Balaban, S. Chevallier-Michaud, M. Righezza, T. S. Balaban, Chem. Commun., 2015, 51,
11884.
Perfluorinated Enediynes:
New Anticancer Molecules for Theranostics
Cyril Borie * (1), Tanzeel Arif (1), Manon Briand (1), Daniel Olive (2), Malek Nechab* (1)
(1) Aix-Marseille Université, CNRS, Institut de Chimie Radicalaire UMR 7273, 13390 Marseille, France
(2) Inserm 1068, Centre de Recherche en Cancérologie de Marseille, 13273 Marseille Cedex 09, France
In the last decades, the enediynes derived from natural products, such as
calicheamicins[1], have been used as anticancer drug candidates. Their biological activity
stems from cyclization of the enediyne moiety (Bergman reaction) to a highly reactive 1,4benzenoid diradical (Scheme 1). The latter is able to abstract hydrogen atoms from the sugar
phosphate backbone of adjacent strands of DNA causing scission.
Unfortunately, the extreme cytotoxicity of enediynes and the lack of antitumor
selectivity results in a very high general toxicity. For this reason Mylotarg®, a calicheamicin
derivative developed by Pfizer, has been withdrawn from clinical trial.
Scheme 1: Calicheamicin derivative (Mylotarg®) and general enediyne reactivity
We have been interested in the Photo Dynamic Therapy (PDT) strategy by designing a
new family of polyfluorinated enediynes that could be candidates for this application. Photopromoted cycloaromatization would be an effective way to control DNA damage since the
biradical formation is generated upon photo-activation, thus avoiding secondary effects.
We also wanted a molecule bearing a perfluorinated moiety, enabling 19F MRI
technique to be used, to associate diagnosis to therapeutic effects, in a theranostic strategy.
Scheme 2: Typical synthesized molecule
Several derivatives were synthesized in 5 to 6 steps (Scheme 2); interestingly two
molecules showed a very promising biological activity on DNA plasmids as well as on
cancerous cell lines.
[1] a) Maiese, W. M. et al., The Journal of Antibiotics, 1989, 42, No. 4, 558-563 ; b) Lee, M. D. et al., The
Journal of Antibiotics, 1989, 42, No. 7, 1070-1087; c) K. C. Nicolaou et al,. Science, 1992, 256, 1172-1178; d) J.
Ahlert, et al. Science, 2002, 297, 1173-1176
*
contact : [email protected] ; [email protected]
Local structures of the molybdenum cofactor in Nitrate Reductase
probed by advanced EPR spectroscopy
Julia Rendona, Frédéric Biasoa, Pierre Ceccaldia, René Tocib, Léa Sylvib,
Guillaume Gerbauda, Axel Magalonb, Bruno Guigliarellia, Stéphane Grimaldia
a
Bioénergetique et Ingénierie des Protéines, UMR 7281 CNRS and Aix-Marseille
University, 13009 Marseille, France
b
Laboratoire de Chimie Bactérienne, UMR 7283 CNRS and Aix-Marseille University,
13009 Marseille, France
Molybdenum enzymes having a single Mo atom at the active site are widespread in living
organisms. They mainly catalyse two-electron redox
reactions and are often associated with oxygen transfer
reactions. Many of them are involved in bioenergetic
processes [1]. An example is provided by Nitrate reductase
A (NarGHI) from Escherichia coli, a respiratory enzyme
that catalyzes the two electron reduction of nitrate into
nitrite. Its molybdenum-containing active site exhibits two
main paramagnetic MoV EPR signals from the so-called
high-pH (hpH) and low-pH species [2] according to the pH
conditions in which they are predominant. The catalytic
Figure 1 - Crystallographic structure of
relevance of both species has been previously discussed
NarGH obtained by X-ray diffraction
[3,4]. In contrast to the hpH species, the lpH MoV EPR
signature has been shown to be sensitive to the presence of the substrate (NO3-), raising the
question of its mode of interaction to the Mo center [5]. In this work, we aim at resolving the
local structure of the hpH and lpH species as well as the structural changes induced upon
substrate binding through the detection of 14N and 15N magnetic interactions to the Mo(V)
ions using advanced EPR (HYSCORE) spectroscopy. DFT calculations have been performed
to understand the origin of the detected hyperfine couplings and to propose structural models
for the Mo(V) intermediates which account for available spectroscopic data. Our results lay
the foundation for in-depth understanding of the structure of the MoV catalytic intermediates
in NarGHI.
1. Grimaldi S., Schoepp-Cothenet B., Ceccaldi P., Guigliarelli B., Magalon A., Biochim. Biophys. Acta –
Bioenergetics, 2013, 1827, 1048-1085
2. Vincent, S.P. and Bray, R.C., Biochem J, 1978, 171, 639-47
3. Magalon, A., Asso, M., Guigliarelli, B., Rothery, R.A., Bertrand, P., Giordano, G. and Blasco, F.,
Biochemistry, 1998, 37, 7363-70
4. Ceccaldi, P., Rendon, J., Leger, C., Toci, R., Guigliarelli, B., Magalon, A., Grimaldi, S., Fourmond, V.,
Biochim. Biophys. Acta – Bioenergetics, 2015, 1847, 1055-63
5. George, G.N., Turner, N. A., Bray, R.C., Morpeth, F.F., Boxer, D.H., and Cramer, S.P., Biochem J., 1989,
259, 693-700
A hydrogen biofuel cell to feed a wireless
communication device.
Monsalve Karen,a Le Goff Alan,b Giudici-Orticoni Marie
Thérèse,a Lojou Elisabetha
[email protected]
a
b
BIP, UMR 7281, CNRS-AMU, Marseille, France
Univ. Grenoble Alpes, DCM, UMR 5250 Grenoble, France
Enzymatic H2/O2 biofuel cells (BFC) recently emerged as attractive
devices for small power applications [1]. In this “green” fuel cell,
biocatalysts would replace chemical catalysts. However, BFCs need
to achieve higher performances and stability in order to become a
self-sufficiency source of energy. H2/O2 BFC based on
nanomaterials proved that three main key challenges on enzyme
immobilization have to be overcome: 1- Nanomaterial film stability
on planar electrodes; 2- Substrate transport limitation; and 3Stability of the bio hybrid over time [2-3]. We present in this work,
a strategy based on enzymes entrapped in carbon felt-based
materials which act as enzyme host matrices with no need of
additional electron collector. Microscopy and electrochemical
probes experiments were carried out to characterize the carbon
support. Catalytic oxidation of H2 and reduction of O2 are analyzed
using electrochemistry in terms of enzyme grafting, influence of
carbon material modification with different nano-materials. Finally,
we develop a H2/O2 BFC demonstrator with the power cell
efficiency required to feed a wireless electronic device for over 7
hours [4].
References
(1) A. de Poulpiquet et al., ChemElectroChem, 2014, 1, 1724-1750
(2) A. de Poulpiquet et al., Electrochem.Commun., 2014, 42, 72-74
(3) K. Monsalve et al., Bioelectrochem. 2015, 106, 47-55
(4) K.Monsalve et al., Electrochem.Commun. 2015, 60, 216-220
Nanoconfinement Effect on Phenoxyl Radical Lifetime
in Nanostructured Silica
Cyrielle DOLa, Eric BESSONa, Stéphane GASTALDIa
a
Aix-Marseille Université, CNRS, Institut de Chimie Radicalaire UMR 7273,
13397 Cedex 20, Marseille, France
Web site: http://icr-amu.cnrs.fr/
Organic radicals and materials have already a long common history. Organic radical
precursors have been adsorbed in zeolites, grafted onto silicas and onto nanostructured silicas.
In these previous studies the organic radical precursor was introduced in the material
by simple adsorption or by post-grafting, in other words with no means to control the
distribution of the radical precursor in the inorganic material.
Recently, our group focused his attention on the effect of nano-structuration on the
behavior of transient radical. 1,2.
In this study, we report the effect of nanoconfinement on phenoxyl radical properties
when a radical precursor was wittingly located in the wall or in the pores of a nanostructured
silica. Several phenoxyl radical precursors3 were considered as well as various substitution.
This nanoconfinement enables to a transient phenoxyl radical to become persistent and
thus facilitates the determination of spectroscopic properties. The influence of the radical
precursor and the substitution on the radical lifetime will be presented.
Figure 1 : Influence of nanoconfinement on radical lifetime
1
F. Vibert, S. R. A. Marque, E. Bloch, S. Queyroy, M. P. Bertrand, S. Gastaldi, E. Besson, Chem. Sci., 2014, 5,
4716
2
F. Vibert, S. R. A. Marque, E. Bloch, S. Queyroy, M. P. Bertrand, S. Gastaldi, E. Besson, J. Phys. Chem. C,
2015, 119, 5434
3
C. Dol, M. P. Bertrand, S. Gastaldi, E. Besson, Tetrahedron, 2016, 72, DOI: 10.1016/j.tet.2016.02.010
N2S2 BASED MOLECULAR SYSTEMS FOR
ELECTROCATALYTIC PROTON REDUCTION
Tatiana STRAISTARIa,b, Marius REGLIERa Constantin TURTAb, ||
a
Aix Marseille Université, ISM2, UMR CNRS 7313, Av. Escadrille Normandie Niemen, 13397
Marseille, cedex 20, France
b
Institute of Chemistry of the Academy of Sciences of Moldova, Academiei str. 3, MD-2028
Chishinau, Moldova
||
Deceased March, 23, 2015
The N2S2 molecular systems with nd metal, are well known for a long time1. Many
potential applications were proposed, including antitumor activity2, however few reports can
be found in the literature describing the use of MN2S2 based thiocarbazones as electrocatalysts
for protons reduction.
The petformed cyclic voltammetry experiments showed electrocatalytic response for
H2 evolution in DMF with increasing current response as concentration of trifluoroacetic acid
was raised. These promising results and the easiness to tune the system’s electrochemical
behaviour by varying the ligand/metal could provide access to a new class of molecular
catalysts for hydrogen evolution.
Continuous flow rig with in-line GC analysis was used to detect the produced H2. It
was found that applying a potential of -1.2 V vs Ag/AgCl/KCl electrode at mercury working
electrode results in formation of molecular hydrogen. Comparing this value with the charge
consumed during the electrolysis, converted to the theoretical amount of hydrogen, the
Faradaic yield of the process was calculated.
b
c
NiL
Co2L2(SCN)2
Molecular structure of the Ni(II) and Co(III) compound with (2,4–{bis (4–(p–
methoxyphenyl)–thiosemicarbazone)}–butane (H2L)
The best results in the catalytic hydrogen production were shown by the compounds of
Co and Ni, characterized by Faradaic yield in the range of 80-93 % and TON value between
21-43.
1
2
D. Palanimuthu, S. V. Shinde, K. Somasundaram, A. G. Samuelson / J. Med. Chem., 2013, 56 (3), pp 722–734
L. J. Ackerman et al. / Polyhedron 18 (1999) 2759 –2767
Phenothiazine derivatives as a solution for antibiotic-resistant
Gram-negative bacteria
Aurélien STUTZMANNa, Arnaud CACLARDa, Fabrice BIOTa, Eric VALADEa,
Sandrine ALIBERTa, Gérard BOYERa, Jean-Michel BOLLAa, Jean-Marie PAGESa
a
TMCD2, UMR-MD1, Aix-Marseille Université / IRBA
Web site: http://pharmacie.univ-amu.fr/umr-md1
Antimicrobial drugs have been crucial tools of health for decades due to their
effectiveness in control of bacterial infections. However, soon after their discovery, some
pathogens rapidly developed Multi-Drug Resistance (MDR) to antibiotics1. The overexpression
of efflux mechanisms contributes widely to the MDR phenotype of Gram negative bacteria
(Figure 1). During the recent years, investigation of inhibition of MDR attracted world-wide2.
By a medicinal chemistry approach, phenothiazine derivatives were synthesized in order
to be tested as adjuvants of usual antibiotics on Burkholderia thailandensis, a Gram-negative
bacteria specie3. The activity of N-substituted phenothiazines was determined with various
functional groups (Figure 2), using Epsilometer test method; they appear to have no direct
activity on bacteria but can potentiate the activity of diverse classes of antibiotics or have an
effect on efflux pumps expression.
TolC
Outer membrane channel
AcrA
Membrane fusion protein
linker between TolC and AcrB
AcrB
Multiple resistance antiporter
driver by proton motrice
force
Figure 2 : Design strategy for new
phenothiazine derivatives
Figure 1 : Structure of the tripartite efflux pump
AcrAB-TolC from E. coli
1
Wong, K.; Ma, J.; Rothnie, A.; Biggin, P.C.; Kerr; I.D. Trends Biochem. Sci. 2014, 39(1), 8.
Bolla, J.M.; Alibert-Franco, S.; Handzlik, J.; Chevalier, J.; Mahamoud, A.; Boyer, G.; Kieć-Kononowicz, K.;
Pagès, J.M. FEBS Lett. 2011, 585(11), 1682.
3
Biot, F.; Lopez, M.; Poyot, T.; Neulat-Ripoll, F.; Lignon, S.; Caclard, A.; Thibault, F.; Peinnequin, A.; Pagès,
J.M.; Valade, E. PLoS One 2013, 8(12):e84068.
2
Synthesis and study of new copper coordination compounds
containing 2-(2H-benzotriazol-2-yl)-4,6-ditert-pentylphenol ligand
Olesea CUZANa,b, Michel MAFFEIa, Marius REGLIERa, Constantin TURTAb,†
a
ISM2, UMR CNRS 7313, Aix-Marseille Université, Av. Escadrille Normandie Niemen, 13397
Marseille, cedex 20, France
b
Institute of Chemistry of the Academy of Sciences of Moldova, Academiei str. 3, MD-2028
Chishinau, Moldova
† Deceased March, 23, 2015
Having as a goal the synthesis of new bioinspired model of GOase we realised the reactions
between 2-(2H-benzotriazol-2-yl)-4,6-ditert-pentylphenol ligand and copper (II) salts into
formation of 4 copper coordination compounds: [Cu(L)2] (1), [Cu(L)2(DMF)0.5] (2),
[Cu(L)2(DMA)0.5] (3), [Cu(L)2(DMSO)0.33] (4), where L = 2-(2H-benzotriazol-2-yl)-4,6ditert-pentylphenolate, DMF = N,N-diméthylformamide, DMA = dimethylacetamide, DMSO
= dimethyl sulfoxide. The compounds were isolated as crystaline products. The structure of 1
and 2 were determined by X-ray crystallography. Elemental Analysis, IR and Mass
spectroscopies are in accordance with the determined crystallographic structure.
Figure 1. Reaction scheme of Cu-complexes synthesis.
The compound was characterized by electrochemical and spectroelectrochemical methods.
The oxidation of veratryl alcohol occurs in DMF in presence of hydrogen peroxyde with a
convertion of 5%. The catalytic activity of 4 on DNA (pUC19) plasmid occurs with a
quantitative cleavage into nicked-circular and linear plasmid.
Acknowledgements
This work is dedicated to the memory of Prof. Constantin Turta. Campus France is thanked for
financial support UR/EIFFEL-DOCTORAT 2015 / 840918H.
Design & Synthesis of Quinolone Analogues to Block Antibiotic
Efflux in Gram-negative Bacteria
Jessica Hernandez, Joannah N'Gompaza Diarra, Estelle Dumont, Gérard Boyer,
Jean-Michel Bolla, Jean-Marie Pages, Sandrine Alibert
Aix-Marseille University / IRBA, UMR-MD1, Membrane Transporters-ChemoresistanceDrug Design, Faculties of Medicine and Pharmacy, 27 boulevard Jean Moulin, 13385
Marseille cedex 05, France
The emergence of multidrug-resistant (MDR) pathogens is a worldwide health problem. In
Gram-negative bacteria, transporters belonging to the resistance-nodulation-cell division
(RND) superfamily play an essential role in MDR phenotype. Indeed, efflux pumps (EP)
extrude out of the bacterial cell a wide range of substrates, especially different families of
antibiotics that contribute more and more to the treatment failure of infectious diseases.[1,2]
In this context, a new strategy to overcome antimicrobial resistance is to find the way to block
the active drug efflux using “escort molecules” of usual antibiotics, to restore or improve their
efficacy. [3]
Screening of various chemical libraries on Enterobacteriaceae allowed selecting BG1190 as hit
compound (figure 1) to design and synthesize quinolone antibiotic chemosensitizers based on
the quinazolinone scaffold able to target AcrAB-TolC EP (figure 2) on Enterobacter aerogenes
strains. The challenge is to identify pharmacophores that bind AcrB moiety of this transporter
and to determine their role in the pump activity. Molecular modeling and QSAR studies guide
the pharmacomodulations and the rational synthesis of new blockers of antibiotic efflux.
Project funding was supported by grant ANR-11-BS07-019-01 “IBEF” in collaboration with
Isabelle Broutin (LCRB, UMR-8015, Paris V), Catherine Etchebest and Kaouther Benouirane
(DSIMB, UMR-S 665, Paris VII) for the cristallogenesis and molecular modeling of the target.
Figure 1: BG1190 Hit molecule
Figure 2: AcrB model of E.aerogenes
References:
[1] Davin-Regli A, Bolla JM, James CE, Lavigne JP, Chevalier J, Garnotel E, Molitor A & Pagès JM. Current
Drug Targets, 2008, 9, 750–759.
[2] Piddock LJ. Nature Reviews Microbiology, 2006, 4, 629–636
[3] Bolla JM, Alibert-Franco S, Handzlik J, Chevalier J, Mahamoud A, Boyer G, Kiec-Kononowicz K, Pagès JM.
FEBS letters, 2011, 585, 1682-1690
Simulation and decomposition kinetics of “cold” free radical
polymerization (FRP) with a peroxide/amine initiation system
A. Zoller*a, Y. Guillaneufa, D. Gigmesa
a
ICR, UMR 7273, Aix-Marseille Université
Web site: http://icr-amu.cnrs.fr/spip.php?rubrique10&lang=fr
Over the last years, an increasing interest in the initiation system between benzoyl
peroxide (BPO) and dimethylaniline derivatives arose for several applications. It is widely
used for free radical polymerizations at room temperatures, e.g. for glues, in dentistry or in
construction.[1]
In line with this topic, we will present two major issues: a computational model of the
bulk polymerization of methyl methacrylate (MMA) in the presence of the BPO/amine
initiation system with the simulation package PREDICI®. In order to simulate this
polymerization there is a need of kinetic data of the decomposition reaction between BPO and
several dimethylaniline derivatives such as dimethylaminobenzyl alcohol and others.[2] The
mechanism had been already studied, but it is a very complex reaction sequence.[3] There is
also literature data about the half-life times of BPO with several amines. The data was
obtained by iodometric titration at different time points.[4] Our approach is an in-situ
measurement of the decomposition by using an IR-probe. The advantage is the possibility of
taking constantly a large number of time points, what might lead to more precise results as the
error of each measurement is minimized. Further the rates had been measured at different
temperatures in order to calculate the Arrhenius parameters. These kinetic results had been
applied to different models for the simulation of the MMA polymerization.
[1]
D. S. Zhao, N. Moritz, P. Laurila, R. Mattila, L. V. J. Lassila, N. Strandberg, T. Mäntylä, P. K. Vallittu,
H. T. Aro, Med. Eng. Phys. 2009, 31, 461–469.
[2]
B. Vazquez, B. Levenfeld, J. San Roman, Polym. Int. 1998, 46, 241–250.
[3]
X.-D. Feng, Makromol. Chemie. Macromol. Symp. 1992, 63, 1–18.
[4]
L. Horner, K. Scherf, Justus Liebigs Ann. Chem. 1951, 573, 35–55.
Triple iron/copper/iminium activation for the efficient redox neutral
catalytic enantioselective functionalization of allylic alcohols
Mylène Roudiera, Thierry Constantieuxa, Adrien Quintarda, Jean Rodrigueza
a
iSm2, STeRéO, UMR 7313, Aix-Marseille Université
Web site: http://ism2.univ-amu.fr/etudiants/ROUDIER.php
Based on recent enantioselective functionalization of allylic alcohols, 1 we developed
an unprecedented cascade reaction combining an iron catalyst and a pyrolidine-based catalyst
for the preparation of -chiral alcohols in a formal redox-, atom- and step-economical
approach. The efficiency of this method involving a dual catalysis (borrowing
hydrogen/iminium catalysis) and a retro-Claisen fragmentation was further demonstrated in
the short synthesis of several key fragments of biologically active natural products or odorant
molecules.2 This methodology was incremented by a complete mechanistic study allowing an
improvement of the system thanks to a triple catalysis.3
1
A. Quintard, T. Constantieux, J. Rodriguez, Angew. Chem. Int. Ed., 2013, 52, 12883-12887.
(a) M. Roudier, T. Constantieux, A. Quintard, J. Rodriguez, Org. Lett., 2014, 16, 2802-2805, (b) M. Roudier,
T. Constantieux, A. Quintard, J. Rodriguez, Chimia, 2016, 70, 97-101.
3
M. Roudier, T. Constantieux, A. Quintard, J. Rodriguez, submitted.
2
Synthesis and study of naphthalimide chromophores as
photoinitiators
Nicolas ZIVICa, Frédéric DUMURa, Jacques LALEVÉEb, Didier GIGMESa
a
Institut de Chimie Radicalaire, CROPS, UMR 7273, Aix-Marseille Université
b
Institut de Sciences des Matériaux de Mulhouse, UMR 7361, ENSCMu-UHA
Photoinitiated polymerization plays a more and more important role in industry as
reflected by the continuously growing number of applications of this technique in
conventional areas such as coatings, inks, and adhesives but also in high-tech domains, like
optoelectronics, laser imaging, stereolithography and nanotechnology.
Indeed, Photopolymerization presents several advantages such as very short reaction
time even at room temperature and the absence of solvents avoiding the formation of volatile
organic compounds. Moreover, the possibility to irradiate with high precision specific zones
allows the spatial-control of the polymerization1. Since 2011, photoinitiating systems able to
initiate polymerization under soft light irradiation sources have been the subject of intense
efforts to minimize the risks and the costs related to the conventional UV irradiation.
However, even if some results are promising, the reported systems still present low to
moderate reactivity and can hardly compete with actual UV systems.
Scheme: Stages of photopolymerization process from naphthalimide derivatives
In this context, we recently synthesize a large library of photosensitive molecules
based on naphthalimide derivatives able to initiate the polymerization under soft irradiation
sources. The ad hoc functionalization of the chromophore and the consequent tuning of the
photochemical properties have been used to develop highly efficient photoinitiating systems
able to absorb light into the near UV and visible spectra emitted by LED. In this
communication, we will present the synthesis of the compounds as well as their
photochemical properties investigated by luminescence, cyclic voltammetry, laser flash
photolysis and ESR experiments2,3.
1
Fouassier, J. P.; Lalevée, J. "Photoinitiators for Polymer Synthesis: Scope, Reactivity and Efficiency", WileyVCH., Weinheim, 2012.
2
Zhang, J.; Zivic, N.; Dumur, F.; Xiao, P.; Graff, B.; Fouassier, J.P.; Gigmes, D.; Lalevée, J. Polymer, 2014, 55,
6641-6648.
3
Zhang, J.; Zivic, N.; Dumur, F.; Xiao, P.; Graff, B.; Gigmes, D.; Fouassier, J.P.; Lalevée, J. J. Polym. Sci. A
Polym. Chem., 2015, 53, 665-674.
Enantioselective synthesis of 4-arylpyridine atropisomers
by central-to-axial chirality conversion
Ophélie QUINONERO, Marion JEAN, Nicolas VANTHUYNE, Christian
ROUSSEL, Damien BONNE, Thierry CONSTANTIEUX, Cyril BRESSY*,
Xavier BUGAUT*, Jean RODRIGUEZ*
iSm2, UMR 7313, Aix-Marseille Université
Web site: http://ism2.univ-amu.fr
In the past decade, organocatalysis has emerged as a powerful tool for the control of
central chirality of heteroaromatic compounds.1 Nevertheless, the control of axial chirality has
been much less investigated,2 especially using central to axial chirality conversion.3
Based on our knowledge in organocatalysis, we have recently developed an enantioselective
synthesis of dihydropyridines which would lead, after an original conformer-specific oxidative
process, to the corresponding enantioenriched and stable 4-arylpyridines (Figure 1).4
Figure 1: Development of a new organocatalytic methodology for the enantioselective 4-arylpyridine synthesis.
This strategy is currently investigated in the total synthesis of a natural product (antibiotic,
antitumoral) containing this kind of hetero-biaryl atropisomer: (+)-streptonigrin (Figure 2).5 The
progress towards its synthesis will be presented.
Figure 2: (+)-Streptonigrin.
1
H. Thu Pham, I. Chataigner, J.-L. Renaud, Curr. Org. Chem. 2012, 16, 1754-1775.
O. Quinonero, C. Bressy, X. Bugaut, Angew. Chem. Int. Ed. 2014, 53, 10861-10863.
3
a) J. A. Berson, E. Brown, J. Am. Chem. Soc. 1955, 77, 450. b) D. G. Wettlaufer, A.I. Meyers, J. Am. Chem. Soc.
1984, 106, 1136-1137. c) A. Goehrt, A. Straub, Angew. Chem. Int. Ed. Engl. 1996, 35, 2662-2664.
4
O. Quinonero, M. Jean, N. Vanthuyne, C. Roussel, D. Bonne, T. Constantieux, C. Bressy, X. Bugaut, J. Rodriguez,
Angew. Chem. Int. Ed. 2016, 55, 1401-1405.
5
T. J. Donohoe, C. R. Jones, A. F . Kornahrens, L. C. A. Barbosa, L. J. Walport, M. R. Tatton, M. O’Hagan, A. H.
Rathi, D. B. Baker , J. Org. Chem. 2013, 78, 12338-12350, and references included therein.
2
A la recherche de l'origine de la matière organique des comètes
Aurélien FRESNEAUa, Grégoire DANGERa, Thierry CHIAVASSAa
a
Aix-Marseille Université, PIIM UMR-CNRS 7345, 13397 Marseille, France
Collaborations : IPAG (R. Thissen), IAS (L. d’Hendecourt)
Website: http://piim.univ-amu.fr/
La compréhension des processus chimiques qui ont lieu à la surface des grains
cométaires ou interstellaires passe par l’étude d’analogues formés en laboratoire. Les glaces
présentes sur ces grains subissent différents processus énergétiques (thermiques ou radiatifs)
qui sont reproduit en laboratoire et mènent à la formation de résidus organiques présentant
une importante complexité moléculaire. Ces résidus sont analysés dans un premier temps par
spectroscopie infrarouge pour identifier les principaux produits formés1, puis par
spectrométrie de masse à très haute résolution (VHRMS par LTQ-Orbitrap) qui révèle la
présence de plusieurs milliers de molécules organiques différentes2. L’analyse des données
issues de la VHRMS constitue donc un défi. Des outils informatiques sont mis en place pour
organiser et représenter ces données de manière à en extraire le maximum d’information.
L’enjeu sous-jacent est de déterminer quelles molécules auraient pu être disponibles à la
surface de la terre pour permettre l’émergence d’une chimie prébiotique suite à un apport
exogène de matière organique par des comètes ou des astéroïdes3, et de confronter ces
résultats avec les observations astronomiques.
Figure 1 : Représentation « défaut de masse vs masse exacte » des données ORBITRAP obtenues pour un résidu formé à
partir d’une glace CH3OH:NH3:H2O
1
Fresneau A. – Trapping in water – an important prerequisite for complex reactivity in astrophysical ices: the
case of acetone and ammonia – MNRAS 2014, 443, 2991–3000.
2
Danger G. – Characterization of laboratory analogs of interstellar/cometary organic residues using very high
resolution mass spectrometry – Geochim. Cosmochim. Acta 2013, 118, 184−201.
3
Le Sergeant d’Hendecourt L. (2011) – Molecular complexity in astrophysical environments: from
astrochemistry to “astrobiology”? In AstrOHP 2010, 06001.
Mass Spectrometry of Poly(4-vinylpyridine) synthesized by
Nitroxide-Mediated Polymerization : a case of reactive MALDI
Christophe Chendo,a Trang N.T. Phan,b Sylvain Marque,c Didier Gigmesb and
Laurence Charlesa
a
Institut de Chimie Radicalaire, équipe SACS, UMR 7273, Aix-Marseille Université
b
Institut de Chimie Radicalaire, équipe CROPS, UMR 7273, Aix-Marseille Université
c
Institut de Chimie Radicalaire, équipe CRAB, UMR 7273, Aix-Marseille Université
Web site: http://icr-amu.cnrs.fr/
Mass spectrometry of synthetic polymers is most usually performed using MALDI to generate
gas phase ions, in order to avoid spectral complexity due to multiple charging readily faced
with electrospray ionization of increasing size chains. However, MALDI is sometimes
regarded as a quite “hard” ionization technique, leading to spontaneous dissociation of fragile
end-groups carried by macromolecules synthesized using controlled radical polymerization
(CRP) processes.1 For example, in the case of polystyrene (PS) prepared by nitroxide
mediated polymerization (NMP), the labile nitroxide terminal group is cleaved from the
polymeric skeleton upon the mild activation experienced by macromolecules during
ionization. Then, rearrangements of the PS chains in the gas phase lead to new terminations,
typically an endo- or an exo-double bond. In this context, the original end-groups can no
longer be characterized but mass data can still be used to determine molecular weight
parameters. A different scenario was observed during MALDI of poly(4-vinylpyridine)
(P4VP) prepared by NMP. P4VPs exhibit the same structure as PS but contain a nitrogen
atom in each aromatic ring. Elimination of the nitroxide end-group conducted to P4VP
macromolecules carrying a terminal H atom or an exo-double bond, as well as new endgroups involving a matrix moiety, as determined by accurate mass measurements and MS/MS
analyses. The latter species revealed that a chemical reaction has occurred between P4VP
chains and the matrix used to assist their ionization. Experiments conducted with a series of
matrices (2,3-, 2,5- and 2,6-DHB, DCTB, sinapinic acid and dithranol) showed that this
reaction was highly matrix-dependent, favored by strong interactions between acidic matrices
and highly accessible nitrogen atoms in P4VP,2 and would involve radicals generated upon i)
photolysis of the matrix and ii) cleavage of the original nitroxide termination. Electron
paramagnetic resonance experiments and molecular modeling are currently performed to
support the radical mechanism proposed to account for this reactive MALDI process.
1
Charles L. ‘MALDI of Synthetic Polymers with Labile End-Groups’, Mass Spectrometry Reviews, 33 (2014),
523–543.
2
Narayan R. and Asha S. K. ‘Solvent -Induced Self-Assembly of Hydrogen Bonded P4VP-Perylenebisimide
Comb Polymer’, Journal of Materials Chemistry C, 1 (2013), 5925–5934.
Electrochemical hydroxylation of nonreactive C-H bonds of
aminoindane substrates mediated by copper complexes
Maria-Chrysanthi P. Kafentzia, Raffaello Papadakisa, Nicolas Le Poulb, Bruno
Faurea, Yves Le Mestb, Thierry Trona, Marius Régliera, A. Jalila Simaana
a
Aix-Marseille Université, Institut de Sciences Moléculaires de Marseille/ BiosCiences, UMR
CNRS 7313, Marseille, France
b
Université de Bretagne Occidentale, CEMCA, UMR CNRS 6521, Brest, France
Web site: http://ism2.univ-amu.fr/equipes/Biosciences_1.htm
Water splitting reaction by means of robust and biocompatible molecular systems has
attracted much interest because it is the key challenge in the conversion of sunlight into
chemical fuels1. One of these key reactions is the water oxidation to dioxygen. This reaction is
performed in Nature by the Oxygen Evolving Centre of Photosystem II composed of 4
manganese ions and 1 calcium ion2. However, there are examples in the literature which
report that this reaction can be catalyzed by other metals such as copper ions3. Although, we
still need to understand and control several key reactions and trap their intermediates.
Moreover, in view of the significance of catalyzed oxidations for industrial applications, a key
goal in current research is the photochemical oxygen atom transfer to different substrates
through water activation. To achieve this goal we need to understand mechanisms of
oxidation catalysis by studying copper-oxygen intermediates.
In a previous work of our lab using CuI precursors, Réglier et al. have described the
stereoselective hydroxylation of a substrate after exposure in O2.3 The substrate is bound
covalently to the tertiary amino group of the ligand so that an intramolecular oxygen atom
transfer from copper to the ligand is favored, obtaining the cis-hydroxylated product.
Following that work, we investigate the oxygen atom transfer on 2-aminoindane group via
H2O activation and CuII complexes using electrochemical methods. Also, we analyze the
products formed after the bulk electrolysis of our copper complex (cis-hydroxylated product
and O2) and we try to characterize the copper-oxygen species involved (Figure 1).
Figure 1: Schema of the followed strategy for water activation
1. McEvoy, J.P., Brudvig, G.W. Chem. Rev. 2006, 106, 4455-4483.
2. Mayer, J.M. et al., Nature Chem. 2012, 4, 498; Mayer, T. J. Am. Chem. Soc., 2013, 135 (6), 2048–2051;
Angew. Int.Ed., 2014, 53, 12226-12230; Angew. Int.Ed., 2013, 52(2), 700-703.
3. Réglier et al., Eur.J.Inorg.Chem., 1998, 1297-1304.
Two-dimensional Covalent Organic Frameworks on surface
Kawtar Mouhata*, Yangchun Xieb, Natalia Kalashnykb, Matthieu Abelb,
Sylvain Clairb, Frédéric Dumura, Didier Gigmesa
a
b
Aix-Marseille Université, CNRS, ICR UMR 7273, 13397 Marseille Cedex 20
Aix Marseille Université, CNRS, Université de Toulon, IM2NP UMR 7334, 13397
Marseille
http://icr-amu.cnrs.fr
[email protected]
The engineering of highly organized systems from molecular buildings-blocks opens up new
perspectives for the control of matter and the exploration of nanodevice concepts.1 Precise
control of the spatial arrangement of nanometer-sized elementary buildings-blocks during the
“bottom-up” construction of two-dimensional monolayers is the key step to get well-defined
functional surfaces. Supramolecular chemistry has been successfully applied in the last
decade to create well-organized structures on surfaces.2 The possibility of extending this
concept to formation of covalent bonds between organic molecules has attracted recent focus3
to create more robust networks, in particular under thermal conditions. Moreover, a
fundamental progress has been made with the demonstration that covalent linkages can be
created directly on a metal surface.4 However, these preliminary researches reveal the
difficulties encountered during the delicate growth mode: the strong covalent bonds lack
flexibility and reversibility during the formation process in the low-dimensional environment
of a surface and there strongly limit the possibility of defect self-healing. The successful
realization of 2D polymers can be achieved in ambient conditions5, up to now mainly limited
to growth in ultrahigh vacuum conditions6, by controlling the growth mode (through
generation of thermodynamic equilibrium).7 In this context, we are mainly interested in
synthesizing and studying boronic acids buildings-blocks as precursors to construct twodimensional polymers via dehydration reactions at the solid-liquid interface.
HO
B
Ar
OH
Ar = Aromatic
R
HO
Ar
B
R = Alkyl, ...
OH
Figure 1 : boronic acid buildings-blocks
Figure 2 : 2D-Covalent Organic Framework
[1] Barth J.V. et al., Nature, 2005, 437, 671-679.
[2] Elemans J., Lei. S.B., De Feyter S., Angew. Chem. Int. Ed., 2009, 48, 7298-7332.
[3] Colson J.W., Ditchel W.R., Nature Chemistry, 2013, Review Article.
[4] Zwaneveld N. et al., J. Am. Chem. Soc., 2008, 130, 6678-79.
[5] Lackinger M. et al., ACS Nano, 2013, 7, 3014-21.
[6] Franc G., Gourdon A, Phys. Chem. Chem. Phys., 2011, 13, 14283-92.
[7] Masashi K. et al., ACS Nano, 2011, 5, 3923-29.
Constitutive expression of recombinant human gastric lipase and
some clones in Pichia pastoris
Laura Sams1, 2, Almahdi Chakroun1, Sébastien Coudre1, Sawsan Amara1,
Julie Paume2, Jacqueline Giallo2 and Frédéric Carrière1
1
CNRS, Aix Marseille Université, UMR7282 Enzymologie Interfaciale et Physiologie de la
Lipolyse, Marseille, France
2
GERME S.A., Marseille, France
Web sites: http://eipl.cnrs-mrs.fr/ ; http://germesa.com/ / Email: [email protected]
Human gastric lipase (HGL) cDNA was subcloned into the pGAPZαA vector and further
integrated into the genome of Pichia pastoris X-33, under the control of the glyceraldehyde 3phosphate dehydrogenase (GAP) constitutive promoter. rHGL with lipase activity was found
to be produced and secreted in the culture medium but activity levels and stability appeared to
be dependent on the pH. A culture medium buffered at pH 5 was required to observe an
increase in lipase activity with time until a plateau was reached. Above pH 5, lipase activity
was only transiently observed and was lost after various period of time depending on pH,
probably due to proteolytic degradation. rHGL secreted from Pichia pastoris was found to be
partly bound to the yeast cell but could be released from the cell wall by using an acid
stripping solution containing hydrochloric acid and glycine. This process could be used as a
first purification step and pure rHGL was further obtained after a size exclusion
chromatography on Superose 12 column. N-terminal sequence analysis revealed that rHGL
was produced under its mature form. A global mass of 50,906 ± 3 Da was measured by
MALDI-ToF mass spectrometry, indicating an additional mass of 7713 Da versus the
theoretical mass of HGL polypeptide (43,193 Da), corresponding to rHGL N-glycosylation.
The lipase activity of rHGL was measured using various triacylglycerol substrates and its
optimum activity on Intralipid (soybean oil emulisified with lecithin) was found to be 650 ±
40 U/mg at pH 4, thus confirming the functional production of a secreted and active gastric
lipase by Pichia pastoris. Moreover, some amino-acids involved in the adsorption step of the
enzyme to its substrate were mutated. Five clones were obtained and they are currently
characterized.
Influence of steric effects on rotational barrier of
N-Aryl-Thiazoline-2-(thi)one
Vincent BELOT, a Nicolas VANTHUYNE,a Marion JEAN,a
Christian ROUSSEL a and Daniel FARRANa
a
Aix-Marseille Université, Centrale Marseille, CNRS, iSm2 UMR7313, 13397 Marseille,
France
Web site: http://ism2.univ-amu.fr/equipes/Chirosciences_1.htm
Effective size of common substituent used in organic chemistry1,2 has many interests in drug
design, mechanism studies or catalyst optimization. The establishment of such hindrance scale
can be performed by the determination and comparison of rotational barriers on a scaffold in
which structural modifications are directly involved in the restricted rotation. We focused our
efforts on N-aryl-thiazoline-2-(thi)one (see scheme below), framework exhibiting a broad
scope of applications in organic synthesis, medicinal chemistry and chiral studies. A huge
molecular diversity can be introduced in R- position and atropisomers of these compounds are
easily separable using chiral HPLC. Preliminary results (synthesis and rotational barriers) will
be present and discuss on my poster.
S
N
S
R
1
2
G. Bott, L. Field, S.Sternhell J. Am. Chem. Soc. 1980, 17, 5619.
R. Ruzziconi, S. Spizzichino, L. Lunazzi, A. Mazzanti, M. Schlosser Chem. Eur. J. 2009, 15, 2645.
Design and synthesis of stable free radicals as polarizing agents
for Dynamic Nuclear Polarization Magic-Angle Spinning (MAS)
solid-state NMR at high frequency
Florian BERNADAa, Gilles CASANOa, Hakim KAROUIa, Mélanie ROSAYb,
Paul TORDOa, Olivier OUARIa
a
b
SREP, ICR UMR 7273, Aix-Marseille Université, Marseille (France)
Bruker BioSpin Corporation 15 Fortune Drive, Billerica, MA 01821 (USA)
Web site: http://www.icr-amu.cnrs.fr/
Dynamic Nuclear Polarization coupled to solid-state NMR (DNP / ss-NMR) is a powerful
technique to overcome the intrinsic low sensitivity of NMR spectroscopy. The DNP method
exploits the microwave-driven transfer of polarization from the electron spins of a
paramagnetic center to surrounding nuclei, and its coupling with NMR allows to investigate
previously inaccessible systems such as membrane proteins1and hybrids materials.2 Among
the different factors, the success of a DNP experiment depends strongly on the efficiency of
the paramagnetic polarizing agent. Recently, very large enhancement factors have been
obtained with AMUPol (Figure 1) and TEKPol at 9.4 T (400 MHz, 260 GHz at 100 K), with
values of 250 and 200, respectively.3,4 However, at higher fields, 18.4 T, the DNP efficiency
of AMUPol and TEKPol is reduced dramatically, with DNP factors of around 30. Because
higher fields are required to improve spectral resolution, the development of new polarizing
agents for high field DNP is needed. We will present our work on the design, synthesis and
characterization of a series of new nitroxide biradicals for high field DNP.
O
O
O
O
N
O
N
H
N
N
R
O
O
R = (-CH2CH2O)4Me, AMUPol
13
13
15
Figure 1 : AMUPol C CPMAS spectra of 0.25 M U- C- N proline with 10 mM AMUPol in glycerol-d8/D2O/H2O
(60/30/10 volume ratio) with (top trace) and without (bottom trace) microwave irradiation at 14 kHz MAS, 97 K
sample temperature
1
Q. Z. Ni, E. Daviso, T. V. Can, E. Markhasin, S. K. Jawla, T. M. Swager, R. J. Temkin, J. Herzfeld, R. G.
Griffin, Acc. Chem. Res., 2013, 46, 1933-1941.
2
A. J. Rossini, A. Zagdoun, M. Lelli, A. Lesage, C. Copéret, L. Emsley, Acc. Chem. Res., 2013, 46, 1942-1951.
3
C. Sauvée, M. Rosay, G. Casano, F. Aussenac, R. T. Weber, O. Ouari, P. Tordo, Angew. Chem. Int. Edit.,
2013, 52, 10858-10861.
4
A. Zagdoun, G. Casano, O. Ouari, M. Schwarzwälder, A. J. Rossini, F. Aussenac, M. Yulikov, G. Jeschke, C.
Copéret, A. Lesage, P. Tordo, L. Emsley, J. Am. Chem. Soc., 2013, 135, 12790–12797.
Formation of complex organic molecules in the interstellar medium by
radical chemistry
Butscher T.1, Duvernay F.1, Theulé P.1, Danger G.1, Chiavassa T.1, Carissan Y.2,
Haugebaum-Reignier D.2
1
Université d’Aix-Marseille, Laboratoire PIIM - Centre de St-Jérôme, Avenue Escadrille
Normandie-Niemen, 13397 Marseille, France.
2
Université d’Aix-Marseille, ISM2 - Centre de St-Jérôme, Avenue Escadrille NormandieNiemen, 13397 Marseille, France.
Email : [email protected]
In the interstellar medium (ISM), multiple organic molecules were observed and
characterized by different spectroscopic techniques. Some of these molecules carries a large
number of atoms and are called Complex Organic Molecules (COMs). COMs are of primal
interest since they are part of small bodies of the ISM and are supposed to have played a role
in the emergence of life on the Early Earth.
COMs are observed in multiple kind of environment such as hot cores and cometary
environments. Each environment presents their own processes. These processes – VUV
irradiation, hydrogen bombardments, thermal changes – are closely linked to the formation
mechanisms of COMs but we still do not clearly understand such mechanisms. Our work
focuses on the role of radical species in the formation of COMs under astrophysical
conditions. ISM conditions are reproduced in laboratory to produce cometary ice analogues.
These analogues are submitted to energetic and non-energetic processes. The changes in the
chemical composition of the ice analogues are observed by spectroscopic techniques –
infrared and mass spectrometries.
Radical chemistry is particular since reactive intermediates are so unstable that, in
most of cases, we are not able to identify them before they react. The properties of cryogenic
matrix technique, combined with quantum calculations, enable the characterization of
unstable species (HCO, CH2OH…) at low temperature. We are also able to study their
reactivity using the very same technique.
These intermediates lead to the formation of some of the most massive detected COMs
(glycolaldehyde, ethylene glycol) or to COMs potentially detectable in a particular
astrophysical environment. These results could be of use for the understanding of ROSETTA
mission results or to the discovery of new COMs in the ISM.
[1] Butscher, T. ; Duvernay, F. ; Theulé, P. ; Danger, G. ; Carissan, Y. ; Haugebaum-Reignier, D. ; Chiavassa, T.
; MNRAS, 453, 1587-1596 (2015).
[2] Woods, P. M.; Slater, B.; Raza, Z.; Viti, S.; Brown, W. A.; Burke, D. J.; ApJ, 777, 90 (2013).
[3] Feedoseev, G.; Cuppen, H.; Ioppolo, S.; Lamberts, T.; Linnartz, H.; MNRAS, 448, 1288 (2015).
[4] Hudson, R. L.; Moore, M. H.; Cook, A. M.; Adv. Space Res., 36, 184 (2005).
[5] Bennett, C. J.; Kaiser, R. I.; ApJ, 661, 899 (2007).
Synthesis, structure-based lead optimization, and biological
evaluation of 4,5-dimethoxybenzene derivatives as novel inhibitors
of rhinovirus 14
L. Da Costa,a M. Roche,a E. Scheers,b A. Coluccia,c J. Neyts,b T. Terme,a
P. Leyssen,b R. Silvestri,c and P. Vanelle.a
(a) Aix-Marseille Université, Institut de Chimie Radicalaire, UMR 7273 CNRS, 27 Boulevard
Jean Moulin, Marseille, France.
(b) KU Leuven-University of Leuven, Department of Microbiology and Immunology, Rega
Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven,
Belgium.
(c) Institut Pasteur Italy, Department of Drug Chemistry and Technologies, Sapienza
University, I-00185 Rome, Italy.
Web site: icr-amu.cnrs.fr
Human rhinoviruses (HRV) are the predominant cause of common colds, but are also
responsible for virus-induced exacerbations of asthma and chronic obstructive pulmonary
disease. Currently, treatment is limited to symptomatic therapy. So, several small-molecule
inhibitors have been developed over the last couple of decades, but none of these candidates
reached the market. In this way, our research team has recently identified a class of new
small-molecules inhibitors with the same action mechanism as the capsid-binder pleconaril
(EC50 = 0.2 ± 0.1 µM; CC50 = 50.2 ± 5 µM)1,2. 4,5-Dimethoxybenzene skeleton of these VP1
inhibitors results from a synthesis method using Tetrakis(DimethylAmino)Ethylene (TDAE).
In order to increase interactions between VP1 hydrophobic pocket and our inhibitors,
an extension about the open end of the pocket was first considered. For the further
optimization of this compound class, it was decided to make use of the available crystal
structure data and to use docking experiments (in silico design) to focus the chemistry effort.
So, a first compound LPCRL_2043 drew our attention as a potent HRV14 inhibitor with
micromolar activity (EC50 = 3.4 ± 1.0 µM) and a toxicity for HeLa cells that was significantly
lower than that of our previous hit (LPCRW_0005, CC50 = 104 ± 22.2 µM; LPCRL_2043,
CC50 > 263 µM)3.
LPCRL_2043
EC50 = 3.4 ± 1.0 µM
CC50 > 263 µM
1
M. Roche, C. Lacroix, O. Khoumeri, D. Franco, J. Neyts, T. Terme, P. Leyssen, P. Vanelle, Eur. J. Med.
Chem., 2014, 76, 445-459.
2
C. Lacroix, J. Querol-Audí, M. Roche, D. Franco, M. Froeyen, P. Guerra, T. Terme, P. Vanelle, N. Verdaguer,
J. Neyts, P. Leyssen, J. Antimicrob. Chem., 2014, 69, 2723-2732.
3
L. Da Costa, M. Roche, E. Scheers, A. Coluccia, J. Neyts, T. Terme, P. Leyssen, R. Sylvestri, P. Vanelle, Eur.
J. Med. Chem., 2016, accepted.
Synthesis of challenging eight-membered rings thanks to dual
catalysis
Chouraqui G.* Parrain J.-L. * Dousset M.
Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille cedex
20, France.
Web site: http://ism2.univ-amu.fr/equipes/Stereo_1.htm
Email:
[email protected] / [email protected] / [email protected]
A preeminent goal of synthesis is the generation of structural complexity and functional
value with step economy. Cycloaddition reactions are especially powerful in this regard. They
proceed in one step with the convergent assembly of simple components into a new ring
system with multiple stereocenters. On one hand, studies on metal-mediated cycloadditions
for the synthesis of medium-sized rings represent a particularly important area of research,
given the number of structurally novel and biologically potent targets that incorporate such
rings. And, on the other hand, new reactions play a uniquely important role in the evolution of
synthesis as they enable new ways to think about bond construction, often leading to practical,
step economical and green options for high value target preparation.
In this context, this research proposal aims to study a cooperative catalytic strategy for the
synthesis of eight-membered ring compounds because, not only this medium-sized ring is an
important structural motif that occur in a wide range of biologically active natural products
(the most famous one being the Taxol and its derivatives) 1 but also, there is a limited number
of approaches available for its elaboration.2 Accordingly, owing to ring strain and
transannular interactions, the formation of medium-sized rings has proven difficult.
Our strategy relies on the utilization of two different partners. A Donor-Acceptor
cyclopropane (DAC) and a vinyl cyclopropane (VCP) would serve as 3C and 5C partners
respectively in a dual catalyzed-[5+3] cyloaddition. Such an approach should allow a one-pot
multiple bond-forming transformation in a very powerful synergistic manner.
1
(a) T. Oishi, Y. Ohtsuks In Studies in Natural Products Synthesis; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, The
Netherlands, 1989; Vol. 3, p73; (b) J. H. Rigby In Studies in Natural Products Synthesis; Atta-ur-Rahman, Ed.; Elsevier:
Amsterdam, The Netherlands, 1993; Vol. 12, p233.
2
For reviews on the construction of cyclooctanoid systems, see: (a) A. Michaut, J. Rodriguez, Angew. Chem. Int. Ed. 2006,
45, 5740; (b) G. Mehta, V. Singh, Chem. Rev. 1999, 881; (c) S. Sieburth, N. Cunard, Tetrahedron, 1996, 52, 6251; (d) N.
Petasis, M. A. Petane, Tetrahedron 1992, 48, 5757.
How to Split Water: UV Photochemistry of Pyridine-Water
Complex
N. Esteves-Lopeza, C. Dedondera, C. Jouveta, S. Coussana
a
Laboratoire Physique des Interactions Ioniques et Moléculaires, UMR-7345, Aix-Marseille
Université
Web site: http://www.piim.univ-amu.fr
A major challenge to generate green energy from sunlight would be to split water into
H and OH• radicals via photo-sensitisation using a simple organic catalyst. Although the
ultimate goal is to use visible radiation, we will start with simple prototype systems and UV
light. Recently ab-initio calculations1 predict that pyridine (Py) can act as a photo-catalyst to
split water by absorption of a UV photon (Figure 1), following the reaction:
•
Py-H2O + hν → Py*-H2O → PyH• + OH•
To test this prediction, we study the Py-H2O system in isolated cold molecular cluster
of a well-defined stoichiometry using a supersonic expansion2. The setup is composed of a
pulsed supersonic expansion combined with a time of flight mass spectrometer.
We performed two different types of experiments. In one, we characterized the
electronic spectroscopy of the PyH• radical in the gas phase, produced by a pulsed high
voltage discharge placed after the supersonic expansion. In the second one, we evidenced the
reaction through UV excitation of Py-(H2O)n clusters monitoring the PyH• reaction product.
For this, we performed a two lasers (pump-probe) experiment, where the pump laser excites
Py and the PyH• is probed by ionization.
We have demonstrated that the UV excitation of Py-(H2O)n clusters leads to the
formation of the pyridinyl radical (PyH•), thus we have evidenced the water splitting reaction.
To fully characterize this reaction, we are studying the cluster sizes that lead to the reaction.
The last step of the process, that is the regeneration of the catalyst by absorption of a second
UV photon (PyH• + hν → Py + H•) remains to be studied. Moreover, other aromatic
molecules witch are expected to lead the photochemical dissociation of water, will be tested in
the near future.
hn
Photon induced Water splitting in pyridine-H2O clusters
observed through the spectroscopy
pyridinile radical
Figure 1: Schema of the photo-induced
waterof the
splitting
of Py-H2O clusters
1
2
Liu, X; Sobolewski, A; Borrelli, R; Domcke, W. PCCP, 2013, 15, 5957-5966.
N. Esteves-Lopez, S. Coussan, C. Dedonder-Lardeux, C. Jouvet, 2016, in preparation.
An extensive study of hydrogen behaviour in beryllium
Laura FERRYa, François VIROTa, Marc BARRACHINa, Yves FERROb
a
Institut de Radioprotection et Sûreté Nucléaire (IRSN), Cadarache,
Saint Paul-lez-Durance, 13115, France
b
Aix-Marseille Université, CNRS, PIIM UMR 7345, 13397, Marseille, France
Beryllium will be used as a plasma-facing material for the experimental fusion facility
ITER. Significant amounts of hydrogen isotopes can be retained in the beryllium walls in
normal conditions. Although much experimental data have been acquired in the past on
hydrogen retention and its transport in beryllium, the details of the elementary processes that
influence the hydrogen behaviour in beryllium are still not completely clear. Hydrogen can be
trapped in interstitial positions in the beryllium hexagonal compact structure as well as in
point defects (vacancies). Vacancies are known to be dominant defects in beryllium1 and
efficient traps for hydrogen2. The hydrogen stability in different interstitial positions, the
migration barrier, and the trapping in vacancies and de-trapping energies have been
investigated in the present work, with a quantum mechanical modeling based on density
functional theory (DFT).
First, the different interstitial sites of hexagonal compact structure have been studied.
The most energetically favorable sites for hydrogen are the basal tetrahedral and the
octahedral ones. The most probable diffusion pathway for hydrogen in beryllium involves
jumps between basal tetrahedral and octahedral positions, with the effective migration energy
of 0.39 eV. The diffusion is shown to be an isotropic process. This is in agreement with
previous work of Ganchenkova2. Then, the formation of a monovacancy and its ability to trap
hydrogen have been investigated. For a hydrogen atom in a vacancy, an off-center nearly
basal tetrahedral position is shown to be definitely preferred. The addition of more hydrogen
atoms in a vacancy has been studied from an energetic point of view. The energy landscape
around a single vacancy has been calculated. This puts in evidence the most preferential
migration pathways of several hydrogen atoms towards the vacancy and the corresponding
activation energies for trapping and de-trapping. Our data could be used for the interpretation
of hydrogen retention experiments in beryllium3.
Figure 1: Interstitial hydrogen positions in the hexagonal closed-packed (HCP) structure of beryllium
1
Middleburgh, S.C.; Grimmes, R.W. Acta Materialia 2011, 59(18), 7095.
Ganchenkova, M.G.; Borodin, V.A.; Nieminen, R.M. Phys. Rev. B 2009, 79(13), 134101.
3
Piechoczek, R.; Reinelt, M.; Oberkofler, M.; Allouche, A.; Linsmeier, Ch. J. Nucl. Mater. 2013, 438, S1072.
2
Functionalization of a 3-nitroimidazo[1,2-a]pyridine
antileishmanial scaffold via various palladium-catalyzed crosscoupling reactions
Cyril Fersinga, Caroline Castera-Ducrosa, Nicolas Primasa, Anita Cohenb,
Sébastien Hutterb, Michèle Lagetb, Pierre Verhaeghec, Nadine Azasb,
Pascal Rathelota, Patrice Vanellea.
a
Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de Pharmaco-Chimie
Radicalaire. bAix-Marseille Université, UMR MD 3, Infections Parasitaires, Transmission et
Thérapeutique. cLaboratoire de Chimie de Coordination, CNRS UPR 8241, Université Paul
Sabatier, Toulouse.
Visceral leishmaniasis remains a public health problem: caused by a protozoan of the
Leishmania genus, this neglected tropical disease causes 20 000 deaths each year1. Because of
the lack of effective, safe and affordable antileishmanial agents, the search for new active
molecules against this parasite is fully justified. Within the framework of our research
program, we optimized a former antileishmanial hit-compound2 in order to obtain a 3nitroimidazo[1,2-a]pyridine lead molecule bearing a p-chlorophenylsulfane substituent at
position 8 and a chlorine atom at position 6. This lead molecule displayed a very good in vitro
activity against both the promastigote and the amastigote stage of Leishmania donovani.
To expand the structural diversity of this antileishmanial scaffold, a
pharmacomodulation work at position 8 of the imidazo[1,2-a]pyridine ring has been
undertaken, involving palladium-catalyzed cross-coupling reactions. Thereby, novel 8-anilino
molecules have especially been synthesized in Buchwald-Hartwig reaction conditions, in
order to increase the hydrosolubility of these compounds. Suzuki-Miyaura and Sonogashira
cross-coupling products were also obtained in good yields. Biological evaluation of these new
derivatives will be conducted shortly.
1
WHO; Investing to overcome the global impact of neglected tropical diseases, Third WHO report on neglected
tropical diseases (2015) [online] http://www.who.int/neglected_diseases/9789241564861/en/ (2016/03/18).
2
Castera-Ducros, C.; Paloque, L.; Verhaeghe, P.; et al. Bioorg. Med. Chem. 2013, 21, 7155–7164.
Azacalixarènes, Relation Structure/Activité : une approche
théorique
Benjamin GRENIERa, Philippe MARSALa,
a
CINAM-CNRS, UMR 7325, Aix-Marseille Université
Web site: http://www.cinam.univ-mrs.fr/cinam/index.php
Les azacalixarènes sont des oligomères cycliques d’unités phenol reliées entre elle par
des ponts azotés. Ces molécules comme on peut le voir sur la Figure 1 ci-dessous ont une forme
de calice d’où leur nom de azacalixarènes. Par cette cavité ces molécules peuvent capter
différents types de composés et sont utilisées dans le domaine de la chimie hôte-invité1.
Une grande variété de substituants peut être fixés sur ces azacalixarènes1,2 (Figure1).
Expérimentalement on peut suivre facilement les effets des variations de structures au niveau
des propriétés physico-chimique par la RMN (Résonnance Magnétique Nucléaire).
Afin de calculer les effets de différentes substitutions, Figure 1, mais également de
quantifier l’effet de changements d’isomérisations sur les propriétés physico-chimique (densité
électronique et encombrement stérique) un de nos buts est de simuler les spectres de RMN de
différentes molécules modèles à l’aide de méthodes de DFT (Density Functional Theory en
Anglais). Nous avons pour projet d’utiliser la dynamique moléculaire, pour générer des
structures qui seront utilisées comme point de départ pour des calculs de DFT. On pourra ainsi
simuler le spectre RMN à l’aide de la méthode GIAO3 (Gauge-Independent Atomic Orbital en
Anglais). Dans un premier temps il nous faut valider la partie méthodologie DFT afin de voir
comment les choix de fonctionnelles et de bases peuvent influencer les spectres obtenus. Nous
pourrons ainsi prédire comment, en fonction de changements de structures, il est possible de
faire évoluer les propriétés physico-chimiques et ainsi contrôler la capacité des azacalixarènes
à jouer leur rôle chélateur.
=H ou CH3
=O2 ou H2
Tsue, H., Ishibashi, K., Tamura, R., 2007. Azacalixarene: A New Class in the Calixarene Family, in:
Matsumoto, K. (Ed.), Heterocyclic Supramolecules I, Topics in Heterocyclic Chemistry. Springer
Berlin Heidelberg, pp. 73–96.
2
Tsue, H., Oketani, R., 2015. Azacalixarene: An Ever-Growing Class in the Calixarene Family, in: Tamura,
R., Miyata, M. (Eds.), Advances in Organic Crystal Chemistry. Springer Japan, pp. 241–261.
3
Wolinski, K., Hinton, J.F., Pulay, P., 1990. Efficient implementation of the gauge-independent atomic
orbital method for NMR chemical shift calculations. J. Am. Chem. Soc. 112, 8251–8260.
doi:10.1021/ja00179a005
1
Solid-phase Synthesis of Libraries of Triazine Dendrimers and
Orthogonal Staining Methods for Tracking Reactions on Resin
Adela Ya-Ting HUANGa,b
a
b
CNRS CINaM UMR 7325, Aix-Marseille Université
Department of Applied and Medicinal Chemistry, Kaohsiung Medical University, Taiwan
Reaction tracking is important in solid-phase synthesis, especially for the preparation
of dendrimers. Herein, a pair of orthogonal staining methods involving ninhydrin and Alizarin
R was used to monitor the presence of alkyl amines or aryl chlorides, respectively, for
tracking a reaction’s progress. This staining method was applied to the solid-phase dendrimer
synthesis of a small library of triazine dendrimers that varied in generation from 1 to 3 and
with specific ratios of surface groups. Commencing with a Rink amide resin, iterative
reactions of cyanuric chloride and a linking diamine, aminomethylpiperidine, provided the
desired materials. Peripheral dichlorotriazines could be reacted selectively with two different
amine nucleophiles to yield a multifunctional surface in an 81% to 87% total yield. The whole
preparation process could be accomplished within one week, which dramatically improved
the preparation efficiency.
Transesterification mechanism in alkyl
hydrogenophenylphosphinates
Guilhem JAVIERRE a, Rémy FORTRIE a, Delphine MORALEDA a,
Jean-Valère NAUBRON b, Frédéric FOTIADU a
a
iSm2 - Chirosciences, UMR 1713, Aix-Marseille Université
b
Spectropole, Aix-Marseille Université
Web site: http://ism2.univ-amu.fr/equipes/Chirosciences_1.html
During the enantioselective synthesis of tert-butylphenylphosphine oxyde from chiral
alkyl phenylphosphinates (APP), it has been showed that the enantioselectivity of the
synthesis depends on the alkyl group of the APP reactant (menthyl1: ee = 86 %, adamantyl2:
ee = 99 %). It has been assumed that the alcoholic molecules freed during the synthesis are
responsible for this loss of enantioselectivity. The underlying reaction mechanism would then
consist in a transesterification of the APP with inversion of configuration.
Experimental studies on the reaction between APP and alcohols showed that an
increasing hindrance of the alkyl groups decreases the rate of the nucleophilic substitution of
the alcohol on the phosphinate. This has been interpreted as a slow down in the
transesterification mechanism. On the basis of these observations, we quantitatively studied
this hypothetic transesterification mechanism using theoretical chemistry.
From a theoretical point of view (SMD//M06-2X/6-31++G**), we first focused on the
heart of the mechanism by eliminating the influence of alkyl chains. In other words, we used
the methylphenylphosphinate and the methanol as model reactants. The dominant mechanism
has been shown to proceed through a pentavalent phosphorus intermediate in which both
methoxy groups occupy apical positions. It results from a nucleophilic attack opposite to the
leaving methoxy group, followed by a hydrogen transfer via the oxy function of the
phosphinate (rGo≠(50°C) = 123 kJ.mol-1). We also calculated that the replacement of either
or both methyls by tert-butyls significantly decreases the kinetic of the reaction, which is in
agreement with previous experimental observations.
This mechanism is reasonable, both chemically and numerically, which makes it a
good candidate to explain the loss of enantioselectivity observed during the synthesis of tertbutylphenylphosphine oxyde from APP. No need then of bimolecular exchange mechanism
involving two phosphinates, as sometimes assumed.
1
2
Leyris, A.; Bigeault, J.; Nuel, D.; Giordano, L.; Buono, G. Tetrahedron Lett. 2007, 48 (30), 5247.
Gatineau, D.; Nguyen, D. H.; Hérault, D.; Vanthuyne, N.; Leclaire, J.; Giordano, L.; Buono, G. J. Org. Chem.
2015, 80 (8), 4132.
Theoretical Investigation of the Reaction of
Dialkylzincs with α-Alkoxycarbonyl
Radicals. Evaluation of α-Bromoacrylates as
Radical Acceptors in Radical-Polar Crossover Processes
Hugo Lingua*, François Vibert, Julien Maury, Eric Besson, Didier Siri,
Michèle P. Bertrand* and LaurenceFeray*
Aix-Marseille Université, CNRS, Institut de Chimie Radicalaire, UMR 7273, Equipes CMO
and CT, Campus Saint-Jérôme, Avenue Normandie-Niemen, 13397 Marseille Cedex 20,
France
Web site: http://icr-amu.cnrs.fr
Under non-degassed medium ethyl -bromoacrylate reacts with diethylzinc to give a
bromocyclopropane. The reaction involves successively radical addition, SH2 at zinc,
conjugate addition of the resulting enolate to the electrophilic substrate and ring closure. [1] In
the presence of t-butyl iodide the bromocyclopropane resulting from the addition of t-butyl
radical is formed.
Theoretical calculations were performed to get a better insight into the detailed mechanism.
They highlight the impact of zinc(II) chelation on the formal SH2 step.
[1] Vibert, F; Maury, J; Lingua, H; Besson, E; Siri, D; Bertrand, M.P.; Feray, L. Tetrahedron 2015, 71, 8991–
9002
Ruthenium-Catalyzed [2+2+2] cycloaddition of 1,6-Enynes with
Alkynes
Rui LIUa, Laurent GIORDANO*, Alphonse TENAGLIA*
a
Ism 2, UMR 7313, Ecole Centrale de Marseille
Web site: http://ism2.univ-amu.fr/pages-bleues/index2.htm
Transition metal catalyzed [2+2+2] cycloaddition have become a powerful tool for the
construction of carbon/heteroatom cyclic structures in organic synthesis [1]. Over the past three
decades, great deals of related [2+2+2] cycloaddition reaction have been reported. However,
there are several drawbacks for this transformation[2], such as 1) controlling of regioselectivity
and chemoselectivity; 2) self-coupling of the partners; 3) employing expensive transition
metal catalysts.
Here, we describe a one-step and atom-economical protocols to construct 1,3cyclohexadiene in the presence of ruthenium catalyst. We first studied the behaviors of 1,6enynes in the presence of excess symmetrical alkynes, as shown in scheme 1-2, to give the
corresponding adducts in fairly good yields. Next, the reaction was also studied with
unsymmetrical alkynes, such as trimethylsilyl ethyne, affording the expected [2+2+2] adducts
with excellent regioselectivity (97/3). Interestingly, this transformation was also tolerant to a
wide range of functional groups.
[1] a) Dominguez, G.; Perez-Castells, J. Chem. Soc. Rev. 2011, 40, 3430-3444; b) Chopade, P. R.; Louie, J. Adv.
Synth. Catal. 2006, 348, 2307-2327.
[2] a) Shibata, T.; Arai, Y.; Tahara, Y.-k. Org. Lett. 2005, 7, 4955-4957; b) Evans, P. A.; Lai, K. W.; Sawyer, J. R.
J. Am. Chem. Soc. 2005, 127, 12466-12467; c) Yoshizaki, S.; Nakamura, Y.; Masutomi, K.; Yoshida, T.;
Noguchi, K. Org. Lett. 2016, 18, 388-391.
One-pot regioselective bis-Suzuki-Miyaura or Suzuki-Miyaura/
Sonogashira reaction: Efficient access to 2,4-disubstituted
5-nitroimidazoles
F. Mathiasa, Y. Kabria, K. Neildea, M. D. Crozeta, P. Vanellea*
a
Aix-Marseille Univ, CNRS, Institut de Chimie Radicalaire ICR, UMR 7273, Laboratoire de
Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Bd J. Moulin -CS 30064- 13385
Marseille cedex 05, France.
Web site: icr-amu.cnrs.fr
The 5-nitroimidazoles are compounds widely used for their anti-infectious properties.1
There are currently 4 marketed like metronidazole, which is on the WHO Model Lists of
Essential Medicines.
Two new challenges have emerged in the last decade: on the one hand, resistant strains to
metronidazole lead to increase dosages and therefore adverse effects,2 on the other hand a
potential mutagenicity of these compounds in the long term.3
In this context it is interesting to consider the synthesis of new 5-nitroimidazoles to improve
the activity on resistant strains while controlling mutagenicity. Structure-activity Relationship
(SAR) studies made to present have shown that simultaneous functionalization of 2 and 4
positions of this scaffold allowed to approach the both objectives.4
We decided to exploit the difference of reactivity at the C2 and C4 positions 5 to synthesize 2,4
substituted 5-nitroimidazoles using selective Suzuki-Miyaura cross-coupling, followed in a
sequential one-pot process by another Suzuki-Miyaura or Sonogashira cross-coupling, starting
from 2,4-dibromo-1-methyl-5-nitro-1H-imidazole.
R1
N
R2 B(OH)2 (1.3 équiv.)
O2N
Br
O2N
N
R1
R1 B(OH)2 (1.3 équiv.)
N
Br
Pd(OAc)2 (0.04 équiv.)
Na2CO3 (3 équiv.)
DME/EtOH/H2O (3/2/1)
MW, 60°C, 2h
N
O2N
N
N
PPh3 (0.1 équiv.)
Na2CO3 (3 équiv.)
MW, 100°C, 1h
R2
Br
R1
R3
N
(1.3 équiv.)
PPh3 (0.1 équiv.)
Et3N (2 équiv.)
CuI (0.1 équiv.)
MW, 70°C, 1h
O2N
N
R3
The structure of synthesized 5-nitroimidazoles and the methodologies employed will be
reported and discussed. Determinations of antibacterial and anti-parasitic properties of this
scope are in progress and will allow us to establish new SAR.
1
Crozet, M. D.; Terme, T.; Vanelle, P. Lett. Drug. Des. Discov. 2014, 11, 531.
Schwebke, J. R.; Burgess, D. Clin. Microbiol. Rev. 2004, 17, 794.
3
Friedman, G. D.; Jiang, S. F.; Udaltsova, N.; Quesenberry, C. P.; Chan, J.; Habel, L. A. Int. J. Cancer. 2009,
125, 2173.
4
Crozet, M. D.; Botta, C.; Gasquet, M.; Curti, C.; Rémusat, V.; Hutter, S.; Chapelle, O.; Azas, N.; De Méo, M.;
Vanelle, P. Eur. J. Med. Chem. 2009, 44, 653.
5
Scott, T. H.; Yanan, Z. Chem. Commun. 2006, 3, 299–301.
2
Multi-steps enzymatic cascad involving Baeyer-Villiger
MonoOxygenases and a rare Alcohol Dehydrogenase
Sidiky Ménila, Thomas Reigniera, Katia Duquesnea, Aline Mariageb, Jean-Louis
Petitb, Valérie Deyrisa, Véronique de Berardinisb, Véronique Alphanda
a
ISM2, Biosciences2, UMR 7313, Aix-Marseille Université
b
CEA, Genoscope, Université Evry Val d’Essonne
Web site: http://ism2.univ-amu.fr/pages-bleues/index2.htm
Baeyer-Villiger MonoOxygenases (BVMOs) are well known flavoenzymes able to transform
efficiently ketone into ester or lactone with high regio-and stereoselectivities [1].
Nevertheless, BVMOs are strictly NADPH-dependent, and therefore require a stoichiometric
amount of the expensive nicotinamide cofactor. To address this issue, the multi-enzyme
syntheses provide the opportunity to generate efficient auto-sufficient systems.
Only a limited number of multi-enzymatic systems involving BVMOs has been reported to
date [2]. We will present here a new efficient two-enzyme mediated oxidation of secondary
alcohol involving Alcohol Dehydrogenase (ADH) and BVMO. The originality of our
approach comes from the features of ADH: a NADP-dependent and non-enantioselective
enzyme was required to enable on the one hand cofactor recycling and on the other hand a
complete transformation of the racemic alcohol. This rare enzyme was discovered via a
dedicated High Throughput Screening.
Racemic
secondary alcohol
ADH
Intermediate
ketone
Ester or lactone
BVMO
Still exploring the diversity of BVMOs activities, we wish to expand the range of potentially
valued compounds obtained using these systems.
___
[1] a) Alphand V., Wohlgemuth R. Curr. Org. Chem.. 2010, 14, 1928-1965. b) Leisch H., Morley K., Lau, P. C. K.
Chem. Rev. 2011. 111, 4165-4222.
[2] a) Rioz-Martínez A., Bisogno F. R.; Rodríguez C., de Gonzalo G., Lavandera I., Torres Pazmiño D. E., Fraaije M.
W., Gotor V. Org. Biomol. Chem. 2010, 8, 1431. b) Mallin H., Wulf H., Bornscheuer U. T. Enzyme Microb.
Technol. 2013, 53, 283–287. c) Liu J., Li Z. ACS Catal. 2013, 3, 908–911. d) N. Oberleitner, C. Peters, F. Rudroff,
U. T. Bornscheuer, M. D. Mihovilovic, J. Biotechnol. 2014, 192, 393–399.
Bioactive lignans, using an intriguing stereo-selective radical coupling control
Camille Modolo, Pierre Rousselot-Pailley, Thierry Tron*, Viviane Robert*
Biosciences, Ism2, UMR 7313, Aix-Marseille Université
Web site: http://ism2.univ-amu.fr/equipes/Biosciences_2.php
Natural products as lignans in plants, are usually product in optically pure form. However, how this
process is realized is not well understood. In presence of one electron oxidant, the coupling of monolignols
leads to non-specific radical-radical coupling to form many racemic lignans. However, the coupling of two
oxydized form of coniferyl alcohol, monolignols is directed in a stereo-selective manner in different plants. A
protein, called Dirigent Protein (DIR) is responsible of the formation of only the pure product, form of
pinoresinol.1 Nowadays some of DIRs are known and they can form (+) or (-)-pinoresinol.2 Until now the
exact mechanism on how substrate interact with DIRs and how DIRs orient them in a stereo-selective
coupling is poorly understood. Investigation of the DIRs mechanism could allow us to develop new
interesting biocatalysts.
Without DIR
(±)-pinoresinol (±)-dehydrodiconyferil alcohol
(±)-guaïacylglycerol
With DIRs
Coniferyl Alcohol
Monolignol
(+)-pinoresinol
Formation of DIR mediated (stereoselective) versus non specific (racemic) coupling products of coniferyl
alcohol radicals
Our goal is to study and understand the mechanism of DIRs, starting from their biochemistry characterization
to their application in catalysis. The reaction mechanism is not known. How do they capture, bind and orient
their phenoxyl substrate? At which step of the radical substrate formation DIR orient the reaction? What are
the determinants of the specificity in the substrate-binding pocket of DIR?
In this poster we will present our results about the production of the AtDIR6 from Arabidopsis thaliana in
Pichia pastoris as well as the results of oxidation coniferyl alcohol. Then, in the goal to decorticate the steps
of the reaction, substrate analogues are required. These synthesis will also be presented.
1. Norman G.Lewis, Science, 1997, 275, 362-366.
2. Andreas Schaller, Angew. Chem. Int. Ed., 2010, 49,202-204
Therapeutic Peptides: From Venom To Drugs
Chloé MOLLETa,c, Ange PUJOLb, Didier GIGMESa, Harold DE POMYERSc,
Marc MARESCAb & Kamel MABROUKa.
a
Equipe CROPS, UMR 7273, Aix-Marseille Université, campus de Saint-Jérôme, 13397
Marseille Cedex 20.
b
ISM2/Biosciences, UMR 7313, Aix-Marseille Université, campus de Saint-Jérôme, 13397
Marseille Cedex 20.
c
LATOXAN SAS, Z.A. des Auréats, 845avenue Pierre Brossolette, 26800 Portes-les-Valence.
Web site: http://icr-amu.cnrs.fr/spip.php?rubrique10
Large amounts of antibiotics used for human and farm animals therapy, resulted in the
selection of pathogenic bacteria resistant to multiple drugs. Since the last decades, resistance
to conventional antibiotics has limited the therapeutic options, causing increased rate in
morbid-mortality in hospitals1,2. In addition since 1960, only two new classes of antibiotics,
oxazolidinones (Linezolid, Pfizer) and cyclic lipopeptides (Daptomycin, Cubist) have come in
the market. More than two thirds of the antibiotics used to treat humans are microbial natural
products or semi synthetic derivatives of these molecules3. Therefore, novel antimicrobial
compounds with new bacterial targets have been searched and found in multiple different
sources, including animal venoms4. Indeed, venoms represent a rich source of unique and
novel pharmacologically active substances from which several compounds have been used for
their antimicrobial effects5. In our study antibacterial properties of more than 200 venoms
from snakes, scorpions, spiders and amphibians supplied by Latoxan have been investigated
against non-pathogenic and pathogenic bacterial reference strains. To identify new
antimicrobial peptides from venoms found bioactive, we plan to isolate the peptides that they
contain, to evaluate their activity on selected bacteria (one Gram - and one Gram + strains)
and to fully characterize the sequences of the active ones. The activity of these new
antimicrobial peptides (i.e. not yet described sequences) will be further tested against a large
number of bacteria (Gram + and Gram -, pathogenic / non-pathogenic, resistant and multiresistant to one or more conventional antibiotics). Here, we will present our preliminary
results showing the potent activity of more than 50% of the tested venoms against pathogenic
and non-pathogenic bacterial reference strains. The purification and the physicochemical
characterization of the first bioactive fractions will also be discussed.
1.
2.
3.
4.
5.
Heinemann, J. A., Ankenbauer, R. G. & Amabile-Cuevas, C. F. Do antibiotics maintain antibiotic
resistance? Drug Discov. Today 5, 195–204 (2000).
Hernandez-Aponte, C. A. et al. Vejovine, a new antibiotic from the scorpion venom of Vaejovis
mexicanus. Toxicon 57, 84–92 (2011).
Coates, A. R., Halls, G. & Hu, Y. Novel classes of antibiotics or more of the same? Br. J. Pharmacol.
163, 184–194 (2011).
Harrison, P. L., Abdel-Rahman, M. A., Miller, K. & Strong, P. N. Antimicrobial peptides from scorpion
venoms. Toxicon 88, 115–137 (2014).
Hardy, M. C., Cochrane, J. & Allavena, R. E. Venomous and Poisonous Australian Animals of
Veterinary Importance: A Rich Source of Novel Therapeutics. Biomed Res. Int. 2014, (2014).
High temperature chemical modification of polymers in presence
of aminyl-based radicals
Mamy Daniel RAKOTONIRINAa, Yohann GUILLANEUFa, Didier GIGMESa,
Anouk SIRIa, Didier SIRIa, Philippe CHAUMONTb, Emmanyel BEYOUb,
Jean-Jacques ROBINc, Sophie MONGEc, Sebastien QUINEBECHEd,
Jean-Jacques FLATd,
a
b
Aix Marseille Université , CNRS, Institut de Chimie Radiclaire UMR 7273, Marseille, France
Université Claude Bernard Lyon 1, CNRS, Ingénierie des Matériaux Polymères, UMR 5233, Lyon, France
c
Université Montpellier II, CNRS, Institut Charles Gerhardt , UMR 5253, Montpellier, France
d
ARKEMA, Cerdato, France
Nowadays, a specific attention is devoted to chemical modification of polymers
allowing the production of original materials with tailored macroscopic properties. Among the
different chemical polymer modification processes, one of the most used consist in
performing the chemical transformation in the polymer melt. Typically, in such case a free
radical-initiators is used to generate radical species able to abstract hydrogen from the
polymer backbone at high temperature (between 190 to 230°C) creating radical sites that may
initiate graft polymerization of a given monomer [1]. However during this process,
conventional radical-initiators such as peroxides could also induce undesired cross-linking
and homopolymerization. Recently, a new family of radical initiators based on the Nacetoxyphtalimide (NAPI) has shown promising results in the modification of polyolefins at
T>190°C [2]. Indeed upon heating, these compounds afford aminyl radicals allowing efficient
hydrogen abstraction while reducing side reactions, , scheme 1.
NAPI
α,α’-dioneaminyl
Scheme 1 : Homolytic decomposition of NAPI under heating
The main purposes of our research project is first to rationalize the efficiency of such
molecules and secondly, prepare NAPI-based initiators specifically designed for
polycondensate (polyesters, polyamides) chemical modification. To reach these goals, our
strategy consists in performing computational chemistry studies, synthesizing a large series
NAPI-based compounds and investigating deeply their homolytic dissociation by means of
NMR, HPLC and GCMS.
[1]
Carlson, D. ; Dubois, P. ; Nie, Li. ; Narayan, R. Polym. Eng. And Sci. 1998, 38, 311-321.
Belekian, D. ; Cassagnau, P. ; Flat, J.-J. ; Quinebeche, S.; Autissier, L. ; Bertin, D. ; Siri, D. ; Gigmes D. ;
Guillaneuf, Y. ; Chaumont, P. ; Beyou, E. Polym. Chem. 2013, 4, 2676-2679.
[2]
A comparative EPR study of demethylmenasemiquinones and
menasemiquinones bound to the same site of Escherichia coli
nitrate reductase A
Maryam Seif-Eddinea, Julia Rendona, Frédéric Biasoa, Eric Pileta,c, Léa Sylvib, Axel
Magalonb, Bruno Guigliarellia, Stéphane Grimaldia
a
Bioénergétique et Ingénierie des Protéines,UMR 7281 CNRS and Aix-Marseille University, 13009 Marseille, France
[email protected]
b
Laboratoire de Chimie Bactérienne, LCB-UMR 7283 CNRS and Aix-Marseille University, 13009 Marseille, France
c
Université Pierre et Marie Curie4 Place Jussieu, Paris 75005
Quinones are liposoluble components of bioenergetic membranes playing an important role in respiratory electron
transfer chains of most living organisms due to their ability to transfer up to two electrons and two protons. The
interaction of these quinones with protein complexes at specific sites allows transient generation of paramagnetic
semiquinone intermediates, which can be detected by Electron Paramagnetic Resonance spectroscopy. Using
Escherichia coli nitrate reductase A (NarGHI) as a model enzyme (Figure 1), we have recently demonstrated that two
endogenous naphthoquinones, namely menaquinones and demethylmenaquinones (Figure 2), can bind to the same
protein pocket located within the membrane subunit NarI[1].
With the aim of studying the mode of interaction of demethylmenasemiquinone to NarGHI, CW-EPR and HYSCORE
experiments combined with 1H2O/2H2O exchanges have been performed and the results were compared to those
observed for menasemiquinones in a previous work[2]. Marked spectral differences are observed between the two
semiquinone species which can be related to the conformational differences of the isoprenyl side chain relative to the
quinone ring[3], which changes depending on whether the methyl group is present or nott. This interpretation is
supported by preliminary DFT calculations. In addition, an original strategy consisting in selectively deuterating the
menaquinone methyl protons is presented to unambiguously characterize the hyperfine interaction with methyl protons
(Figure 2). The data provide an unprecedented view on the binding of two different endogenous quinones to the same
proteic site.
Figure 1. E. coli Nitrate Reductase A.
1.
2.
3.
Figure 2. Demethylmenaquinone (top), Menaquinone
(middle), Menaquinone with deuterated methyl (bottom).
Rendon, J.; Pilet, E.; Fahs, Z.; Seduk, F.; Sylvi, L.; Hajj Chehade, M.; Pierrel, F.; Guigliarelli, B.; Grimaldi, S. Biochim Biophys Acta., 2015,
1847, 739-47.
Grimaldi, S.; Arias-Cartin, R.; Lanciano, P.; Lyubenova, S.; Szenes, R.; Endeward, B.; Prisner, T.; Guigliarelli, B.; Magalon, A. J. Biol. Chem.,
2012, 287, 4662-70.
Zheng, M.; Dismukes, G.C. Biochemistry, 1996, 35, 8955-8963.
Direct electrochemistry and photochemistry of FeFehydrogenases
Matteo SENSIa, Carole Bafferta, Luca Bertinib, Luca De Gioiab,
Christophe Légera
a
b
BIP 6 CNRS, UMR 7281, Aix-Marseille Université.
BTBS, Università degli Studi di Milano-Bicocca (IT)
Web site http://bip.cnrs-mrs.fr/bip06/
FeFe-hydrogenases are enzymes that catalyse the reversible oxidation of dihydrogen.
The active site, called H-cluster, consists of an iron-sulfur cluster bound to a diiron site. The
Fe atoms of the diiron site are coordinated by three intrinsic CO ligands; the binding of a
fourth CO ligand (Hox-CO state) reversibly inhibits the enzyme by preventing H2 binding.
FeFe-hydrogenase could be used to produce H2 from water and light, but an obstacle is the
fact that the H-cluster is sensitive to light in the UV-Vis range, since the irradiation at room
temperature could induce the photo-dissociation of one intrinsic CO and the degradation of
the active site. The photodissociation of extrinsic CO has been studied using spectroscopic
and computational methods1,2,3,4,5. The effect of white light on the binding of extrinsic CO
was also shown with electrochemistry6. However, there are no kinetic data related to the CO
photo-dissociation process and moreover the photo-damage during catalysis has not been
characterized so far. To investigate further and more quantitatively the effect of light on the
active site of FeFe-hydrogenases, we used protein film voltammetry (PFV) to study the
enzymes from Chlamydomonas reinhardtii and Clostridium acetobutylicum at room
temperature, under turnover conditions, irradiating the enzyme film on the electrode with
laser diodes at different wavelengths. The fit of a mathematical model to the experimental
data allowed the determination of the kinetic constants of the inhibition process, in the dark
and under irradiation. We also carried out TD-DFT calculations, on models of the active site,
to study the photochemistry of the diiron site in the CO-inhibited state, to characterize the
electronic structure of excited states and the electronic transitions induced by irradiation.
We show that the kinetics of CO release from the H-cluster are dependent on the wavelength
of the excitation, and that light affects the turnover rate of hydrogenase. We describe the
excited states and the electronic transitions involved in the photodissociation of CO.
1
Albracht, S. P. J.; Roseboom, W.; Hatchikian, E. C. J. Biol. Inorg. Chem. 2006, 11, 88-101.
Kowal, A. T.; Adams M.W.; Jhonson M.K. J. Biol. Chem. 1989, 264, 4342–4348
3
Chen, Z.; Lemon, B.J.; Huang, S.; Swartz, D.J.; Peters, J.W.; Bagley, K. A. Biochemistry 2002, 41, 2036-2043
4
Roseboom, W.; De Lacey, A. L.; Fernandez, V. M.; Hatchikian, E. C.; Albracht, S. P. J. J. Biol. Inorg. Chem.
2006, 11, 102–118.
5
Bertini, L.; Greco, C.; Fantucci, P.; De Gioia, L. Int. J. Quantum Chem. 2014, 114, 851–861
6
Parkin, A.; Cavazza, C.; Fontecilla-Camps J. C.; Armstrong, F. A. J. Am. Chem. Soc. 2006, 128,16808-16815
2
Study of the intramolecular electron transfer within a
molybdoenzyme, the periplasmic nitrate reductase
Kamal ZEAMARIa, Guillaume GERBAUDa, Sandrine GROSSEb, Pascal ARNOUXb,
Monique SABATYb, David PIGNOLb, Bruno GUIGLIARELLIa, Bénédicte BURLATa
a
Laboratoire de Bioénergétique et Ingénierie des Protéines – UMR 7281 CNRS, Aix-Marseille
Université, 31, chemin Joseph Aiguier, 13009 Marseille, FRANCE
b
Laboratoire de Bioénergétique Cellulaire – SBVME UMR 6191 CNRS CEA, Aix-Marseille
Université, CEA Cadarache, 13108 Saint-Paul-lez-Durance FRANCE
Molydboenzymes are ubiquitous in living organisms and catalyze, for most of them, oxidationreduction reactions of a large range of substrates. These enzymes are involved in the biogeochemical
cycles of essential elements (C, S, N) and their studies may find application in the field of energy,
environment or in health (1).
Periplasmic nitrate reductase (NapAB) from
Rhodobacter sphaeroides catalyzes the 2electron reduction of nitrate in nitrite. Its
active site, named the molybdenum
cofactor, is a Mo bis-(pyranopterin guanine
dinucleotide) found in all molybdoenzymes
from the bacterial DMSO reductase family.
A [4Fe4S] cluster and 2 c-type hemes form
the intramolecular electron transfer chain
(3). Lysine 56 (K56) is a highly conserved
amino acid within enzymes from the DMSO
reductase family. This residue connects
through hydrogen-bond network the [4Fe4S] center to the end of one pyranopterin
ligand of the Mo and is expected to be
involved in the electron transfer.
Figure 1 : Crystallographic structure NapAB from Rhodobacter sphaeroides
at 3.2 Å resolution (2)
In this work, we investigated the role of the K56 amino acid by site-directed mutagenesis, activity
assays measurements, redox titrations and EPR and HYSCORE spectroscopies of two mutants K56M
and K56H. Our data show that mutation of K56 strongly affects enzyme’s activity while integrity and
structural properties of the metal centers of the K56M and K56H mutants are conserved. Surprisingly,
we found that kinetics of electron transfer between the two hemes and the [4Fe-4S] was dramatically
impaired in the mutants. These results are discussed in light of the redox properties changes of the
centers.
1. Grimaldi, S., Schoepp-Cothenet, B., Ceccaldi, P., Guigliarelli, B., and Magalon, A. (2013) Biochim. Biophys. Acta
8-9, 1048-1085
2. Arnoux P, Sabaty M, Alric J, Frangioni B, Guigliarelli B, Adriano JM & Pignol D. (2003) Nat. Struct. Biol. 10, 928
– 934
3. Jacques, J. G., Fourmond, V., Arnoux, P., Sabaty, M., Etienne, E., Grosse, S., Biaso, F., Bertrand, P., Pignol, D.,
Leger, C., Guigliarelli, B., and Burlat, B. (2014) Biochim Biophys Acta 2, 277-286

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