Design and rational synthesis of cytotoxic small molecules for antitumor therapy

Ces travaux de thèse portent sur l'exploration de nouveaux analogues de la combrétastatine A-4, une molécule anticancéreuse utilisée sous le nom de fosbrétabuline en tant que médicament orphelin. Seront exposés dans ce manuscrit le design, la synthèse et les évaluations biologiques de molécules cytotoxiques d’intérêt thérapeutique. L’exploration de nouveaux espaces chimiques permettant la découverte de nouveaux pharmacophores de type pyridoindole et oxazinoindole sera également exposée. La lumière sera faite sur la découverte de deux composés majeurs dans ce manuscrit : les composés CBA-CA4 et azaQnZ-In. Le composé CBA-CA4 présente une sélectivité vis-à-vis des cellules cancéreuses, et le composé azaQnZ-In présente une activité cytotoxique subnanomolaire sur de multiples lignées cancéreuses humaines. Par ailleurs, l’exploration de nouveaux analogues de la combrétastatine A-4 a permis le développement d’une méthodologie de synthèse basée sur la réactivité des N-vinylazoles sous catalyse au molybdène. Cette stratégie de synthèse permettant l’accès aux noyaux 5,10-dihydroindolo[3,2-b]indole et 5,6-dihydroindolo[1,2-c]quinazoline sera également discutée dans ce manuscrit.This manuscript is dedicated to exploring new Combrestatin A-4 analogs, a highly interesting anti-tumor molecule used as “Fosbretabulin” as an orphan drug. In this work, the synthesis of these cytotoxic analogs along with their biological evaluations was addressed and discussed. Also, the discovery of new pharmacophores such as pyridoindole and oxazinoindole derivatives was detailed, and especially, the unique activity of two promising compounds: CBA-CA4 and azaQnz-In molecules. While CBA-CA4 presented a high tumour-selectivity, the azaQnz-In showed a subnormal cytotoxicity to multiple cancer cell lines. On the light of the results obtained with Combretastatin A-4 analogs, we developed a new methodology based on the reactivity of N-vinylazols using molybdenum catalyst to access brand new dihydroindolo[3,2-b]indole and 5,6-dihydroindolo[1,2-c]quinazoline scaffolds. The optimization of the catalytic system and the synthesis of these compounds will also be reviewed in the pages of this manuscript

A Self-Assembling NHC-Pd-Loaded Calixarene as a Potent Catalyst for the Suzuki-Miyaura Cross-Coupling Reaction in Water

International audienceNanoformulated calix[8]arenes functionalized with N-heterocyclic carbene (NHC)-palladium complexes were found to be efficient nano-reactors for Suzuki-Miyaura cross-coupling reactions of water soluble iodo- and bromoaryl compounds with cyclic triol arylborates at low temperature in water without any organic co-solvent. Combined with an improved one-step synthesis of triol arylborates from boronic acid, this remarkably efficient new tool provided a variety of 4′-arylated phenylalanines and tyrosines in good yields at low catalyst loading with a wide functional group tolerance

Anticancer Properties of Indole Derivatives as IsoCombretastatin A-4 analogues

International audienceIn this study, a variety of original ligands related to Combretastatin A-4 and isoCombretastatin A-4, able to inhibit the tubulin polymerization into microtubules, was designed, synthesized, and evaluated. Our lead compound 15d having a quinazoline as A-ring and a 2-substituted indole as Bring separated by a N-methyl linker displayed a remarkable subnanomolar level of cytotoxicity (IC 50 < 1 nM) against 9 human cancer cell lines

Cyclic bridged analogs of isoCA-4: Design, synthesis and biological evaluation

International audienceIn 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

Selective modification of a native protein in a patient tissue homogenate using palladium nanoparticles

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