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1. Alkyl-Resorcinol Derivatives as Inhibitors of GDP-Mannose Pyrophosphorylase with Antileishmanial Activities

Author

Hélène Levaique, Olivier Pamlard, Cécile Apel, Jérôme Bignon, Margaux Arriola, Robin Kuhner, Khalijah Awang, Philippe M. Loiseau, Marc Litaudon, and Sébastien Pomel

Subjects
Leishmania, therapeutic target, GDP-Mannose pyrophosphorylase, natural products, alkyl-resorcinol, Organic chemistry, QD241-441
Abstract

Leishmaniasis is a vector-borne disease caused by the protozoan parasite Leishmania found in tropical and sub-tropical areas, affecting 12 million people around the world. Only few treatments are available against this disease and all of them present issues of toxicity and/or resistance. In this context, the development of new antileishmanial drugs specifically directed against a therapeutic target appears to be a promising strategy. The GDP-Mannose Pyrophosphorylase (GDP-MP) has been previously shown to be an attractive therapeutic target in Leishmania. In this study, a chemical library of 5000 compounds was screened on both L. infantum (LiGDP-MP) and human (hGDP-MP) GDP-MPs. From this screening, oncostemonol D was found to be active on both GDP-MPs at the micromolar level. Ten alkyl-resorcinol derivatives, of which oncostemonols E and J (2 and 3) were described for the first time from nature, were then evaluated on both enzymes as well as on L. infantum axenic and intramacrophage amastigotes. From this evaluation, compounds 1 and 3 inhibited both GDP-MPs at the micromolar level, and compound 9 displayed a three-times lower IC50 on LiGDP-MP, at 11 µM, than on hGDP-MP. As they displayed mild activities on the parasite, these compounds need to be further pharmacomodulated in order to improve their affinity and specificity to the target as well as their antileishmanial activity.

Published
2021
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2. Alkyl-Resorcinol Derivatives as Inhibitors of GDP-Mannose Pyrophosphorylase with Antileishmanial Activities

Author

Robin Kuhner, Khalijah Awang, Jérôme Bignon, Philippe M. Loiseau, Cécile Apel, Hélène Levaique, Olivier Pamlard, Marc Litaudon, Margaux Arriola, Sébastien Pomel, CNRS, Centrale Lille, ENSCL, Univ. Artois, Université de Lille, Institut de Chimie des Substances Naturelles [ICSN], Unité de Catalyse et Chimie du Solide (UCCS) - UMR 8181, Biomolécules : Conception, Isolement, Synthèse [BioCIS], University of Malaya = Universiti Malaya [Kuala Lumpur, Malaisie] [UM], Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Centre National de la Recherche Scientifique (CNRS), and Université Paris-Saclay

Subjects
natural products, Antiprotozoal Agents, Pharmaceutical Science, GDP-Mannose pyrophosphorylase, Context (language use), Analytical Chemistry, Chemical library, Leishmania, Small Molecule Libraries, lcsh:QD241-441, Mice, 03 medical and health sciences, chemistry.chemical_compound, lcsh:Organic chemistry, Drug Discovery, medicine, Animals, Humans, [CHIM]Chemical Sciences, Physical and Theoretical Chemistry, Axenic, Amastigote, Leishmaniasis, IC50, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, biology, 030306 microbiology, Chemistry, Communication, Organic Chemistry, therapeutic target, Resorcinols, alkyl-resorcinol, biology.organism_classification, medicine.disease, Nucleotidyltransferases, 3. Good health, RAW 264.7 Cells, Enzyme, Pharmaceutical Preparations, Biochemistry, Chemistry (miscellaneous), Molecular Medicine
Abstract

Leishmaniasis is a vector-borne disease caused by the protozoan parasite Leishmania found in tropical and sub-tropical areas, affecting 12 million people around the world. Only few treatments are available against this disease and all of them present issues of toxicity and/or resistance. In this context, the development of new antileishmanial drugs specifically directed against a therapeutic target appears to be a promising strategy. The GDP-Mannose Pyrophosphorylase (GDP-MP) has been previously shown to be an attractive therapeutic target in Leishmania. In this study, a chemical library of 5000 compounds was screened on both L. infantum (LiGDP-MP) and human (hGDP-MP) GDP-MPs. From this screening, oncostemonol D was found to be active on both GDP-MPs at the micromolar level. Ten alkyl-resorcinol derivatives, of which oncostemonols E and J (2 and 3) were described for the first time from nature, were then evaluated on both enzymes as well as on L. infantum axenic and intramacrophage amastigotes. From this evaluation, compounds 1 and 3 inhibited both GDP-MPs at the micromolar level, and compound 9 displayed a three-times lower IC50 on LiGDP-MP, at 11 µM, than on hGDP-MP. As they displayed mild activities on the parasite, these compounds need to be further pharmacomodulated in order to improve their affinity and specificity to the target as well as their antileishmanial activity.

Published
2021
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3. Identification of a new series of flavopiridol-like structures as kinase inhibitors with high cytotoxic potency

Author

Mouad Alami, Jean-Daniel Brion, Pascal Bonnet, Abdallah Hamze, Nada Ibrahim, Pierre Colas, Jean-François Peyrat, Thomas Robert, Samir Messaoudi, Jérôme Bignon, Stéphane Bach, Béatrice Josselin, Hélène Levaique, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Fédération de recherche de Roscoff (FR2424), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Messaoudi, Samir

Subjects
Stereochemistry, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Antineoplastic Agents, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Favopiridol, 01 natural sciences, Thiosugars, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, Thioether, Piperidines, Drug Discovery, Tumor Cells, Cultured, Structure–activity relationship, Cytotoxic T cell, Humans, Cytotoxicity, Kinase inhibition, Protein Kinase Inhibitors, 030304 developmental biology, Cell Proliferation, Pharmacology, chemistry.chemical_classification, Flavonoids, 0303 health sciences, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Kinase, Organic Chemistry, [CHIM.CATA] Chemical Sciences/Catalysis, General Medicine, [CHIM.CATA]Chemical Sciences/Catalysis, In vitro, structure-activity relationship. Highlights, 0104 chemical sciences, 3. Good health, Amino acid, Molecular Docking Simulation, chemistry, cytotoxicity, Drug Screening Assays, Antitumor, Protein Kinases
Abstract

International audience; In this work, unique structure of flavopiridol analogs bearing thiosugars, amino acids and heterocyclic moieties tethered to the flavopiridol via thioether and amine bonds mainly on its C ring have been prepared. The analogs bearing thioether-benzimidazoles as substituents have demonstrated high cytotoxic activity in vitro against up to seven cancer cell lines. Their cytotoxic effects are comparable to those of flavopiridol. The most active compound (13c) found after the structure-activity relationship (SAR) showed the best antiproliferative activity and was more efficient than the reference compound. In addition, compound 13c showed significant nanomolar inhibition against CDK9 and GSK3β protein kinases.

Published
2020
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4. Synthesis and Anticancer Properties of Oxazepines Related to Azaisoerianin and IsoCoQuines

Author

Shannon Pecnard, Joëlle Dubois, Jérôme Bignon, Guillaume Bernadat, Hélène Levaique, Mouad Alami, Olivier Provot, Ilhem Khelifi, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Institut de Chimie des Substances Naturelles (ICSN), and Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Cell Survival, Antineoplastic Agents, 01 natural sciences, Biochemistry, chemistry.chemical_compound, Structure-Activity Relationship, Tubulin, Biological property, Drug Discovery, Tumor Cells, Cultured, Humans, [CHIM]Chemical Sciences, General Pharmacology, Toxicology and Pharmaceutics, Cytotoxicity, IC50, neoplasms, Cell Proliferation, Pharmacology, Aza Compounds, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, Quinoline, Cell Cycle, Tubulin Modulators, 3. Good health, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Oxazepines, chemistry, Cell culture, Biophysics, Molecular Medicine, Oxazepine, Drug Screening Assays, Antitumor, Lead compound, K562 cells
Abstract

International audience; In this article, we report the synthesis and biological properties of a series of novel oxazepines related to isoCA-4 having significant antitumor properties. Among them, three oxazepin-9-ol derivatives display a nanomolar or a (sub)nanomolar cytotoxicity level against five human cancer cell lines (HCT116, U87, A549, MCF7 and K562). It was demonstrated that the lead compound in this series inhibits tubulin assembly with an IC50 value of 1 M and totally arrested the cellular cycle in the G2/M phase at a low concentration of 5 nM in HCT116 and K562 cells. Molecular modelling studies perfectly corroborates these promising results.

Published
2020
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5. Cyclic bridged analogs of isoCA-4: Design, synthesis and biological evaluation

Author

Sophie Michallet, Laurence Lafanechère, Mouad Alami, Shannon Pecnard, Olivier Provot, Marie-Catherine Laisne, Jérôme Bignon, Abdallah Hamze, François Saller, Laurie Askenatzis, Delphine Borgel, Hélène Levaique, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), and Lafanechère, Laurence

Subjects
pyridine, Stereochemistry, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, [SDV.CAN] Life Sciences [q-bio]/Cancer, Tubulin, Cell Line, Tumor, Neoplasms, Drug Discovery, Stilbenes, Structure–activity relationship, Humans, cancer, combretastatin A-4, tubulin inhibitor, 030304 developmental biology, Cell Proliferation, Pharmacology, Combretastatin A-4, Indole test, Combretastatin, 0303 health sciences, biology, 010405 organic chemistry, quinaldine, Organic Chemistry, Quinaldine, General Medicine, Cell Cycle Checkpoints, Tubulin Modulators, 0104 chemical sciences, 3. Good health, Molecular Docking Simulation, chemistry, Cell culture, Cyclization, Drug Design, Cancer cell, biology.protein
Abstract

International audience; In this work, a series of cyclic bridged analogs of isocombretastatin A-4 (isoCA-4) with phenyl or pyridine linkers were designed and synthesized. The synthesis of the desired analogs was performed by the formation of nitro-vinyl intermediates, followed by a Cadogan cyclization. Structure activity relationship (SAR) study demonstrates the critical role of the combination of quinaldine as ring A, pyridine as the linker, and indole as ring B in the same molecule, for the cytotoxic activity. Among all tested compounds, compound 42 showed the highest antiproliferative activity against a panel of cancer cell lines with average IC50 values of 5.6 nM. Also, compound 42 showed high antiproliferative activity against the MDR1-overexpressing K562R cell line; thus, it was 1.5-and 12-fold more active than the reference compounds, isoCA-4 and CA-4, respectively. Moreover, 42 displayed a strong antiproliferative activity against the colon-carcinoma cells (HT-29), which are resistant to combretastatin A-4 and isoCA-4, and it was found to be 8000-fold more active than natural CA-4. Compound 42 also effectively inhibited tubulin polymerization both in vitro and in cells, and induced cell cycle arrest in G2/M phase. Next, we demonstrated that compound 42 dose-dependently caused caspase-induced apoptosis of K562 cells through mitochondrial dysfunction. Finally, we evaluated the effect of compound 42 in human no cancer cells compared to the reference compound. We demonstrated that 42 was 73 times less cytotoxic than isoCA-4 in quiescent peripheral blood lymphocytes (PBLs). In summary, these results suggest that compound 42 represents a promising tubulin inhibitor worthy of further investigation.

Published
2020
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6. Pyrrolo-imidazo[1,2- a ]pyridine Scaffolds through a Sequential Coupling of N -Tosylhydrazones with Imidazopyridines and Reductive Cadogan Annulation, Synthetic Scope, and Application

Author

Abderrahman El Bouakher, Mouad Alami, Pascal Retailleau, Jérôme Bignon, Kena Zhang, Abdallah Hamze, Hélène Levaique, Laboratoire de Chimie Physique & de Chimie Bioorganique, URAC 22 (LCPCB), Faculte des sciences et Techniques Mohammedia [Casablanca] (FSTM), Université Hassan II [Casablanca] (UH2MC)-Université Hassan II [Casablanca] (UH2MC), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), and Université Paris-Seine-Université Paris-Seine

Subjects
Annulation, 010405 organic chemistry, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, Context (language use), Biological activity, 010402 general chemistry, 01 natural sciences, Small molecule, Combinatorial chemistry, 0104 chemical sciences, chemistry.chemical_compound, Sequential coupling, Pyridine, Rapid access, Nitro, [CHIM]Chemical Sciences, ComputingMilieux_MISCELLANEOUS
Abstract

A new strategy for the construction of 3-phenyl-1H-pyrrolo-imidazo[1,2-a]pyridine backbone is described. The reaction starts from the coupling between N-tosylhydrazones and 2-chloro-3-nitroimidazo[1,2-a]pyridines leading to the formation of 3-nitro-2-(arylvinyl)imidazo[1,2-a]pyridine derivatives. Optimization of Cadogan-reductive conditions allowed the conversion of the obtained nitro derivative to a new scaffold of the type 3-aryl-1H-pyrrolo-imidazo[1,2-a]pyridine. This method provides rapid access to new libraries in the context of diversity-oriented synthesis, which intends to generate small molecules with a large structure diversity in an efficient manner. Screening of the biological activity of the newly generated compounds leads to the identification of a new promising compound 5cc, which exhibits good antiproliferative activity in the submicromolar range against a human colon cancer cell line.

Published
2019
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7. N,N-bis-heteroaryl methylamines: Potent anti-mitotic and highly cytotoxic agents

Author

Mouad Alami, Timothée Naret, Ilhem Khelifi, Jérôme Bignon, Abdallah Hamze, Maria Concepcion Garcia Alvarez, Olivier Provot, Hélène Levaique, Joëlle Dubois, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Institut de Chimie des Substances Naturelles (ICSN), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
Mitosis, Antineoplastic Agents, Apoptosis, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, Methylamines, Structure-Activity Relationship, quinoline, carbazole, Drug Discovery, Quinazoline, Tumor Cells, Cultured, Humans, isoCA-4, Cytotoxicity, 030304 developmental biology, Cell Proliferation, Cancer, Pharmacology, Indole test, 0303 health sciences, Matrigel, biology, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Carbazole, Cytotoxins, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, Quinoline, General Medicine, Cell Cycle Checkpoints, tubulin 2, HCT116 Cells, 3. Good health, 0104 chemical sciences, Tubulin, chemistry, Biochemistry, indole, biology.protein, cytotoxicity, Drug Screening Assays, Antitumor, quinazoline
Abstract

International audience; The synthesis and evaluation of a series of N,N-bis-heterocyclic-methylamines 1 as isoazaerianin analogues are descriebed. It was demonstrated that the replacement of the 3,4,5-trimethoxyphenyl A-ring present in CA-4, isoCA-4 and isoazaerianin by a quinoline or a quinazoline ring is possible and often beneficiary for a high level of cytotoxicity. We have also showed that a carbazole or an indole nucleus are very effective as Brings in this series, leading to anti-cancer drugs 1 having a sub-nanomolar level of cytotoxicity (1a: IC50 = 70 pM against HCT116 cells). 1a also display a high level of cytotoxicity against four other human cancer cells and inhibited tubulin assembly at a micromolar level. Moreover, at a concentration of 5 nM, 1a arrested the cellular cycle in G2/M phase of the cellular cycle and induced apoptosis of HCT116 cells. It was also showed that after few hours 1a at a concentration of 10 nM totally disrupted endothelial network formation on Matrigel.

Published
2019
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8. Design and Synthesis of Tubulin and Histone Deacetylase Inhibitor Based on iso -Combretastatin A-4

Author

François Saller, Cyril Bauvais, Hsin-Ping Lin, Hazar Al-Mouhammad, Guillaume Bollot, Martin Souce, Diana Lamaa, Olivier Pamlard, Athena Kasselouri, Abdallah Hamze, Joëlle Dubois, Lena Zig, Mehdi Ouaissi, Delphine Borgel, Jean Feuillard, Hélène Levaique, Chantal Jayat-Vignoles, Mouad Alami, Jérôme Bignon, Karim Benihoud, Molécules bioactives, conception, isolement et synthèse (MBCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Physico-Chimique, Centre National de la Recherche Scientifique (CNRS), Synsight, Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Chimie Analytique Pharmaceutique - Faculté de Pharmacie (Lip(Sys)2), Université Paris-Sud - Paris 11 (UP11), Groupe de Chimie Analytique de Paris-Sud, Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Université Paris-Sud - Paris 11 (UP11)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Hematology [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), and Université Paris-Seine-Université Paris-Seine-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, medicine.drug_class, Protein Conformation, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, Chemistry Techniques, Synthetic, 01 natural sciences, Histone Deacetylases, 03 medical and health sciences, chemistry.chemical_compound, Tubulin, Drug Discovery, Stilbenes, medicine, Tubulin polymerization, Humans, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Combretastatin A-4, biology, 010405 organic chemistry, Drug discovery, Histone deacetylase inhibitor, HDAC8, HCT116 Cells, 0104 chemical sciences, 3. Good health, Histone Deacetylase Inhibitors, 030104 developmental biology, chemistry, Biochemistry, Drug Design, biology.protein, Molecular Medicine, K562 Cells, Belinostat, K562 cells
Abstract

Designing multitarget drugs have raised considerable interest due to their advantages in the treatment of complex diseases such as cancer. Their design constitutes a challenge in antitumor drug discovery. The present study reports a dual inhibition of tubulin polymerization and HDAC activity. On the basis of 1,1-diarylethylenes ( isoCA-4) and belinostat, a series of hybrid molecules was successfully designed and synthesized. In particular compounds, 5f and 5h were proven to be potent inhibitors of both tubulin polymerization and HDAC8 leading to excellent antiproliferative activity.

Published
2018
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9. A fluorine scan of a tubulin polymerization inhibitor isocombretastatin A-4: Design, synthesis, molecular modelling, and biological evaluation

Author

Mohamed Benchekroun, Mouad Alami, Timothée Naret, Delphine Borgel, Frédéric R. Leroux, Jean-Daniel Brion, Alain Pruvost, François Saller, Jérôme Bignon, Boris Manoury, Véronique Leblais, Guillaume Bernadat, Etienne Schmitt, Abdallah Hamze, Sébastien Apcher, Christine Lenoir, Joëlle Dubois, Romain Darrigrand, Hélène Levaique, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Service de Pharmacologie et d'Immunoanalyse (SPI), Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, INSERM, UMR-S1176, INSERM, UMR-S1180, INSERM U1015, Laboratoire d'innovation moléculaire et applications (LIMA), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CNRS, Univ. Paris-Sud, La Ligue Nationale Contre le Cancer through an Equipe Labellisee grant, ANR [ANR-10-LABX-33], LABX LERMIT, Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Models, Molecular, Fluorinated analogs, Cytotoxic, Stereochemistry, chemistry.chemical_element, Antineoplastic Agents, 010402 general chemistry, 01 natural sciences, Polymerization, Structure-Activity Relationship, Microtubule, Tubulin, Cell Line, Tumor, Drug Discovery, Stilbenes, Humans, isoCA-4, Cytotoxicity, Cell Proliferation, Cancer, Pharmacology, biology, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, Aromaticity, Tubulin inhibitors, General Medicine, Fluorine, Cell cycle, 0104 chemical sciences, Drug Design, Cancer cell, biology.protein, Drug Screening Assays, Antitumor, Linker
Abstract

International audience; A novel series of tubulin polymerization inhibitors, based on fluorinated derivatives of isocombretastatin A-4 was synthesized with the goal of evaluating the effect of these compounds on the proliferative activity. The introduction of fluorine atom was performed on the phenyl ring or at the linker between the two aromatic rings. The modification of isoCA-4 by introduction of difluoromethoxy group at the para-position (3i) and substitution of the two protons of the linker by two fluorine atoms (3m), produced the most active compounds in the series, with IC50 values of 0.15 -2.2 nM (3i) and 0.1-2 nM (3m) respectively, against a panel of six cancer cell lines. Compounds 3i and 3m had greater antiproliferative activity in comparison with references CA-4 or isoCA-4, the presence of fluorine group leads to a significant enhancement of the antiproliferative activity. Molecular docking studies indicated that compounds 3i and 3m occupy the colchicine binding site of tubulin. Evaluation of cytotoxicity in Human noncancer cells indicated that the compounds 3i and 3m were practically ineffective in quiescent peripheral blood lymphocytes, and may have a selective antiproliferative activity against cancer cells. Analyses of cell cycle distribution, and morphological microtubules organization showed that compound 3m induced G(2)/M phase arrest and, dramatically disrupted the microtubule network.

Published
2018
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10. One-Pot Synthesis of 2-Styrylindoles from Ortho -Substituted Chloroenynes

Author

Jérôme Bignon, Hélène Levaique, Mouad Alami, Olivier Provot, Guangkuan Zhao, Joëlle Dubois, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Institut de Chimie des Substances Naturelles (ICSN), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
Coupling, Indoles, cyclization, 010405 organic chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, One-pot synthesis, Suzuki, chemistry.chemical_element, Antineoplastic Agents, Chemistry Techniques, Synthetic, HCT116 Cells, 010402 general chemistry, palladium, 01 natural sciences, Combinatorial chemistry, 0104 chemical sciences, Isomerism, chemistry, 2-Styrylindole, Humans, coupling, Styrene, Palladium
Abstract

International audience; A facile one pot synthesis of 2-styrylindoles, through Suzuki-arylation of ortho-substituted chloroenynes followed by N-cyclization and N-demethylation has been developed. A variety of 2-styrylindoles were obtained in good to excellent yields and were evaluated for their anticancer properties.

Published
2018
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11. Pipestelides A-C: cyclodepsipeptides from the Pacific marine sponge Pipestela candelabra

Author

Marie-Thérèse Martin, Odile Thoison, Ali Al-Mourabit, Jonathan Sorres, Suzanne Ramos, Cécile Debitus, Sylvain Petek, Thierry Cresteil, Hélène Levaique, Institut de Chimie des Substances Naturelles (ICSN), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
Double bond, Stereochemistry, Pharmaceutical Science, Marine Biology, Peptide, 010402 general chemistry, 01 natural sciences, Pacific ocean, Analytical Chemistry, Polyketide, chemistry.chemical_compound, Depsipeptides, Drug Discovery, Animals, Humans, Nuclear Magnetic Resonance, Biomolecular, AKA, Pharmacology, chemistry.chemical_classification, Pacific Ocean, biology, 010405 organic chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, Chemical modification, biology.organism_classification, Porifera, 0104 chemical sciences, Sponge, Propanoic acid, Complementary and alternative medicine, chemistry, Molecular Medicine, Melanesia
Abstract

International audience; Pipestelides A-C (2-4) are three new NRPS-PKS hybrid macrolides containing uncommon moieties, isolated from the Pacific marine sponge Pipestela candelabra. Their structures were elucidated on the basis of spectroscopic data. These cyclodepsipeptides appear to be biosynthetically related to jaspamide (aka jasplakinolide) (1) by chemical modification of the building blocks of the polyketide or peptide chains. Pipestelides A-C (2-4) contain a bromotyrosine [3-amino-3-(bromo-4-hydroxyphenyl)propanoic acid] unit, a polypropionate with a Z double bond, and a 2-hydroxyquinolinone, respectively. Revised chemical shift assignments are provided for the co-isolated known jasplakinolide C(a) (5). In addition, compounds 2 and 3 exhibited cytotoxic activities in the micromolar range.

Published
2012
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12. Isolation, structure elucidation and biological activity of metabolites from Sch-642305-producing endophytic fungus Phomopsis sp. CMU-LMA

Author

Claudine Servy, Géraldine Le Goff, Pascal Retailleau, Saisamorn Lumyong, Emilie Adelin, Boonsom Bussaban, Sylvie Cortial, Marie-Thérèse Martin, Hélène Levaique, Jamal Ouazzani, Institut de Chimie des Substances Naturelles (ICSN), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
Stereochemistry, Microbial Sensitivity Tests, Plant Science, Horticulture, Crystallography, X-Ray, 010402 general chemistry, 01 natural sciences, Biochemistry, Polyketide, chemistry.chemical_compound, Ascomycota, Cell Line, Tumor, Escherichia coli, Animals, Nuclear Magnetic Resonance, Biomolecular, Molecular Biology, Cell Proliferation, chemistry.chemical_classification, biology, 010405 organic chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Absolute configuration, Biological activity, General Medicine, biology.organism_classification, Antimicrobial, 0104 chemical sciences, 3. Good health, Phomopsis, chemistry, Polyketides, Macrolides, Lactone, Derivative (chemistry), Valsa ambiens
Abstract

International audience; Eight polyketide compounds were isolated from the cultivation broth of Phomopsis sp. CMU-LMA. We have recently described LMA-P1, a bicyclic 10-membered macrolide, obtained as a bioconversion derivative of Sch-642305, the major compound isolated in this study. Benquinol is the ethyl ester derivative of the 13-dihydroxytetradeca-2,4,8-trienoic acid produced by Valsa ambiens. This compound is concomitantly produced with the 6,13-dihydroxytetradeca-2,4,8-trienoic acid (DHTTA) previously isolated from Mycosphaerellarubella. The absolute configuration of the new compound, (2R,3R,4S,5R)-3-hydroxy-2,4-dimethyl-5-[(S,Z)-3-methylpentenyl]-tetrahydro-pyranone LMA-P2 was confirmed by X-ray crystallography. The δ-lactone 2,3-dihydroxytetradecan-5-olide (DHTO) was previously isolated from Seiridium unicorne. This compound may form through the cyclization of the methyl-2,3,5-trihydroxytridecanoate LMA-P3, a new linear polyketide isolated in this study. Benquoine, a new 14-membered lactone generated from the cyclization of benquinol, is proposed as the key precursor for the biosynthesis of Sch-642305. Antimicrobial activity and cancer cell viability inhibition by the new compounds were investigated. Benquoine exhibits antimicrobial activity against Gram positive bacteria, and cytotoxicity against HCT-116 cancer cell line.

Published
2011
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