Synthèse d'une nouvelle famille de nucléosides par cycloaddition dipolaire-1,3 et des réactions tandem (application en cancérologie)

NICE-BU Sciences (060882101) / SudocSudocFranceMoroccoFRM

Microwave-assisted synthesis of bioactive six-membered heterocycles and their fused analogues

International audienceThis review describes the formation of six-membered heterocyclic compounds and their fused analogues under microwave activation using modern organic transformations including cyclocondensation, cycloaddition, multicomponents and other modular reactions. The review is divided according to the main heterocycle types in order of increasing complexity, starting with heterocyclic systems containing one, two and three heteroatoms and their fused analogues. Recent microwave applications are reviewed, with special focus on the chemistry of bioactive compounds. Selected examples from the 2006 to 2015 literature are discussed

Synthesis of novel series of 7,7 '-(substituted methylene) bis-imidazo 1,2-b pyrazoles via an acid catalyzed one-pot three-component reaction

Supplementary filesInternational audienceAn efficient and rapid synthesis of new series of N-alkyl-2-aryl-5H-imidazo[1,2-b]pyrazoles has been achieved in high yields through a three-component reaction of 3-amino-4-substituted pyrazoles, aromatic aldehydes and isocyanides mediated by acid catalysts. In addition, a novel and straightforward approach to a sequential one-pot multicomponent reaction has been developed for the synthesis of hitherto undescribed 7,7'-(substituted methylene) bis-imidazo[1,2-b] pyrazoles, starting from 3-amino-5-substituted (or unsubstituted) pyrazoles, various aldehydes and isocyanides. The reaction was performed under mild conditions in the presence of inexpensive zirconium(IV) chloride as a catalyst. A library of 22 products was obtained in moderate to good yields

Microwave-Assisted Syntheses of Bioactive Seven-Membered, Macro-Sized Heterocycles and Their Fused Derivatives

International audienceThis review describes the recent advances in the microwave-assisted synthesis of 7-membered and larger heterocyclic compounds. Several types of reaction for the cyclization step are discussed: Ring Closing Metathesis (RCM), Heck and Sonogashira reactions, Suzuki-Miyaura cross-coupling, dipolar cycloadditions, multi-component reactions (Ugi, Passerini), etc. Green syntheses and solvent-free procedures have been introduced whenever possible. The syntheses discussed herein have been selected to illustrate the huge potential of microwave in the synthesis of highly functionalized molecules with potential therapeutic applications, in high yields, enhanced reaction rates and increased chemoselectivity, compared to conventional methods. More than 100 references from the recent literature are listed in this review

Solvent-free regioselective synthesis of novel isoxazoline and pyrazoline N-substituted saccharin derivatives under microwabe irradiation.

International audienceNovel isoxazoline and pyrazoline derivatives of N-substituted saccharin were synthesized in good yields by 1,3-dipolar cycloaddition of N-crotonoyl- or N-cinnamoylsaccharin as dipolarophile to arylnitrile oxides or nitrile imines using p-HAP300 as catalyst under solventfree microwave conditions. In this process, the yields were significantly improved compared to classical conditions without alteration of the selectivity. The regioselectivity as well as the nonthermal specific microwave effect are discussed

Solvent-free regioselective synthesis of novel isoxazoline and pyrazoline N-substituted saccharin derivatives under microwave irradiation

Novel isoxazoline and pyrazoline derivatives of N-substituted saccharin were synthesized in good yields by 1,3-dipolar cycloaddition of N-crotonoyl- or N-cinnamoylsaccharin as dipolarophile to arylnitrile oxides or nitrile imines using p-HAP300 as catalyst under solvent-free microwave conditions. In this process, the yields were significantly improved compared to classical conditions without alteration of the selectivity. The regioselectivity as well as the nonthermal specific microwave effect are discussed.This work was funded by grants from the CNRSTMorocco “Centre National de la Recherche Scientifique et Technique” and the University Mohammed V of Rabat. It was also supported by Egide PHC Toubkal (30330ZF, MA/14/304), CNRS-France “Centre National de la Recherche Scientifique” and UNSA “University Nice-Sophia Antipolis”. The authors would like to thank UATRS “Unités d’Appui Technique à la Recherche Scientifique” – CNRST for spectral analysis

Synthesis and anti-cancer activities of new sulfonamides 4-substituted-triazolyl nucleosides

International audienceNucleoside analogues are among the most known drugs commonly used in antiviral and anticancer chemotherapies. Among them, those featuring a five-membered ring nucleobase are of utmost interest such as the anti-cancer agent AICAR or the anti-viral drug ribavirin. Despite its low activity in vitro in different cell lines, AICAR is under clinical development for several pathologies, thanks to its original mode of action. Indeed, AICAR induced autophagy cell death and is able, following this mechanism, to circumvent resistance to apoptotic drugs including kinase inhibitors currently on the market. To improve the activity of AICAR, we report herein an efficient synthesis of new series of sulfonamide-4-substituted-1,2,3-triazolyl nucleosides using a Cu-catalyzed 1,3-dipolar cycloaddition. All these molecules have been fully characterized and evaluated against two aggressive tumor cell lines, RCC4 and MDA-MB-231. Among them, nucleoside analogue 5i belonging to the ribose series was found to be 19 to 66-fold more active than AICAR. Western blot analyses on RCC4 cells showed that 5i displayed an interesting mode of action by inducing both apoptosis and autophagy cell death, making therefore this class of molecules highly promising for further hit-to-lead optimization

In Vitro and in Vivo Evaluation of Fully Substituted (5-(3-Ethoxy-3-oxopropynyl)-4-(ethoxycarbonyl)-1,2,3-triazolyl-glycosides as Original Nucleoside Analogues to Circumvent Resistance in Myeloid Malignancies

International audienceA series of nucleoside analogues bearing a 1,4,5-trisubstituted-1,2,3-triazole aglycone was synthesized using a straightforward click/electrophilic addition or click/oxidative coupling tandem procedures. SAR analysis, using cell culture assays, led to the discovery of a series of compounds belonging to the 5-alkynyl-1,2,3-triazole family that exhibits potent antileukemic effects on several hematologic malignancies including chronic myeloid leukemia (CML) and myelodysplastic syndromes (MDS) either sensitive or resistant to their respective therapy. Compound 4a also proved efficient in vivo on mice xenografted with SKM1-R MDS cell line. Additionally, some insights in its mode of action revealed that this compound induced cell death by caspase and autophagy induction

Dual Covalent Inhibition of PKM and IMPDH Targets Metabolism in Cutaneous Metastatic Melanoma

International audienceAbstract Overcoming acquired drug resistance is a primary challenge in cancer treatment. Notably, more than 50% of patients with BRAFV600E cutaneous metastatic melanoma (CMM) eventually develop resistance to BRAF inhibitors. Resistant cells undergo metabolic reprogramming that profoundly influences therapeutic response and promotes tumor progression. Uncovering metabolic vulnerabilities could help suppress CMM tumor growth and overcome drug resistance. Here we identified a drug, HA344, that concomitantly targets two distinct metabolic hubs in cancer cells. HA344 inhibited the final and rate-limiting step of glycolysis through its covalent binding to the pyruvate kinase M2 (PKM2) enzyme, and it concurrently blocked the activity of inosine monophosphate dehydrogenase, the rate-limiting enzyme of de novo guanylate synthesis. As a consequence, HA344 efficiently targeted vemurafenib-sensitive and vemurafenib-resistant CMM cells and impaired CMM xenograft tumor growth in mice. In addition, HA344 acted synergistically with BRAF inhibitors on CMM cell lines in vitro. Thus, the mechanism of action of HA344 provides potential therapeutic avenues for patients with CMM and a broad range of different cancers. Significance: Glycolytic and purine synthesis pathways are often deregulated in therapy-resistant tumors and can be targeted by the covalent inhibitor described in this study, suggesting its broad application for overcoming resistance in cancer