Julien Braire

A novel series of fourteen fluorinated naphtho[2,3- b ]furan-4,9-dione derivatives (5a–n) was designed, synthesized, and structurally mapped as conformational equivalents of the microtubule-disrupting agent combretastatin A-4 (CA-4).

A convenient microwave-assisted three-component synthetic approach was developed for the synthesis of new benzo[ a ]pyrano[2,3- c ]phenazine derivatives starting from benzo[ a ]phenazin-5-ol, benzaldehyde derivatives, and enaminone derivatives.

L’objectif de la thèse est de développer une méthodologie efficace d’allylboration énantiosélective d’alpha-céto-amides permettant de former des alcools homoallyliques tertiaires énantio-enrichis. Le premier chapitre est une étude bibliographique recensant les réactions d’addition énantiosélective et catalysées par des dérivés du BINOL sur les cétones ainsi que les organocatalyseurs utilisés dans la réaction d’allylboration asymétrique des cétones, ce qui étaye le choix des alpha-cétoamides comme substrat et de dérivés de BINOL comme catalyseur. Le deuxième chapitre décrit la préparation des catalyseurs dérivant du BINOL et des allylboronates diversement substitués nécessaires à l’étude, ainsi que des résultats préliminaires. Le troisième chapitre est consacré à la mise au point des conditions d’allylboration stéréosélective des isatines catalysée par des dérivés du BINOL. De nombreux 3-allyl-3-hydroxyindoles ont été préparés avec d’excellents rendements et excès énantiomériques, ce qui a permis de synthétiser un produit naturel, la (R)-chimonamidine. Des éléments de mécanisme sont proposés à partir de calculs théoriques. Le quatrième chapitre rapporte l’optimisation du système catalytique développé pour former à partir de céto-béta-lactames des alpha-hydroxy-alpha-allyl-béta-lactames originaux hautement énantio- enrichis. Les réactivités de la fonction alcool et de la liaison carbone-carbone insaturée de ces molécules a été exploitée pour synthétiser des dérivés spiraniques originaux.

Cpd 8n induced G0/G1 arrest without apoptosis and showed favorable binding to the CDK4/cyclin D1 active site.

A series of new fluorinated γ‐butyrolactone fused aza‐anthraquinone derivatives were synthesized through a two‐step procedure involving a three‐component reaction followed by dehydro‐aromatization. The final compounds were fully characterized by infrared, nuclear magnetic resonance, and high resolution mass spectroscopy. The cytotoxic activity of these compounds was assessed by screening against KB, HepG2, A549, MCF7 cell lines using MTT assay. The result revealed that 10 out of the 13 synthesized derivatives exhibited moderate to high cytotoxicity against all tested cancer cell lines. Among these compounds, compounds 6d (Ar = 2,5‐difluoro‐4‐methoxyphenyl), 6e (Ar = 4‐methoxy‐2‐(trifluoromethyl)phenyl), and 6i (Ar = 4‐(trifluoromethyl)phenyl) have exhibited pronounced cytotoxicity for A549 cancer cell line. The interaction of new synthesized compounds with the colchicine‐binding site of tubulin was investigated in silico to examine the tubulin inhibition activity of ten cytotoxic compounds. Molecular docking revealed that compounds 6d , 6e , and 6i had relatively strong binding affinity with the colchicine‐binding site of tubulin and formed stable chelation with Zn ²⁺ . Besides that, physicochemical and absorption, distribution, metabolism, excretion, and toxicity (ADMET)‐related properties were predicted to evaluate the drug‐likeness of the most active compounds.

Allylboration reactions of ketones catalyzed by BINOL derivatives can exhibit highly variable stereochemical courses depending on the nature and reactivity of the ketone substrate. In this Article, we put into perspective the relationship between the nature of the starting material and the active species involved in the asymmetric allyboration catalyzed by BINOL derivatives. This work, aimed at comparing different plausible mechanisms by density functional theory (DFT) at the M06-2X/6-311+G(d,p) level involving different types of allylboronates in the presence of the organocatalyst, leads to the confirmation of the hitherto accepted hypothesis of a reaction promoted by the transient cyclic allyl-1,3,2-dioxaborolane derived from BINOLs in the case of unactivated or weakly activated ketones such as indanone. A hypothetical scenario involving dimeric boronate species as chiral catalysts was also investigated.

Synthesis, molecular docking analysis and in vitro evaluation of new heterocyclic hybrids of 4-aza-podophyllotoxin as potent cytotoxic agents.

An improvement in the catalytic enantioselective allylboration of isatins with 2-allyl-1,3,2-dioxaborolane in the presence of chiral BINOL derivatives is reported, offering an efficient one-step access to enantioenriched N-unprotected 3-allyl-3-hydroxy-2-oxindoles. This catalytic process is also effective for the crotylboration reaction with enantiomeric ratios (er) up to 97:3, as well as for the asymmetric synthesis of homopropargylic alcohols via an allenyl addition to indoline-2,3-diones. Origins of the high enantioselectivity in chiral BINOL-catalyzed allylboration of isatins were examined by DFT calculations. A hypothetical scenario suggested a crucial internal hydrogen bonding between the amide group (C═O···H-O) and the ethylene hydroxyl of the transient chiral mixed boronate ester, generating a rigid and stabilized system that favors the addition of the allylboron species to the Re face of the ketone function. The key role of the alcohol additive (t-BuOH or t-AmOH) in the enantioselective allylboration reaction of isatins has also been shown on the basis of a kinetics study and computational calculations by favoring the transesterification of the 2-allyl-1,3,2-dioxaborolane with BINOL via proton transfer processes.