Publications by authors named "Coura Diene"

PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel "MTA-cooperative" compounds identified through a high-throughput biochemical screening approach. Optimization of hits was achieved through structure-based design with a focus on improvement of oral drug-like properties.

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  • Achieving oral bioavailability in Proteolysis Targeting Chimeras (PROTACs) is difficult, and this study examines the pharmacokinetic properties of four oral PROTACs in mice, rats, and dogs.
  • Using NMR, the researchers analyzed the 3D structures of these compounds and introduced two new experimental descriptors, solvent-exposed hydrogen bond donors (eHBD) and acceptors (eHBA).
  • The findings highlight that oral PROTACs with eHBD values greater than 2 have significantly lower bioavailability, leading to the development of an experimental guideline, or "Rule-of-oral-PROTACs," to help medicinal chemists improve oral bioavailability.
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  • Androgen receptor (AR) signaling is crucial in the development of prostate cancer, prompting research into effective treatments.
  • The study focused on creating and refining AR PROTAC degraders, which work by recruiting the Cereblon (CRBN) E3 ligase to induce AR degradation.
  • The lead compound, AZ'3137, exhibited strong degradation of AR and its L702H mutant, good oral bioavailability, and effectively inhibited AR signaling and tumor growth in mouse models.
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  • Targeting the estrogen receptor alpha (ERα) pathway is a proven strategy for treating estrogen receptor-positive (ER+) breast cancers, leading to the development of a new type of drug called a PROTAC designed to degrade ERα.
  • In laboratory tests, this PROTAC showed strong effectiveness in degrading ERα and blocking its activity in breast cancer cells, but results did not match when tested in live models.
  • The discrepancy is attributed to the PROTAC’s linker being metabolically unstable, which leads to the creation of competing metabolites that interfere with the drug's ability to degrade ERα; this emphasizes the importance of designing more stable PROTACs for better treatment outcomes.
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In vitro metabolism studies of the spleen tyrosine kinase inhibitors AZ-A and AZ-B identified four unusual metabolites. M1 (mass-to-charge ratio 411) was formed by both molecules and was common to several analogs (AZ-C to AZ-H) sharing the same core structure, appearing to derive from the complete loss of a pendent 3,4-diaminotetrahydropyran ring and pyrazole ring cleavage resulting in a nonobvious metabolite. M2-M4 were formed by AZ-A and a subset of the other compounds only and apparently resulted from a sequential loss of H from parent.

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The preparation of bridged benzo[1,5]oxazocines and benzo[1,4]diazepines is demonstrated from simple aniline and aldehyde starting materials. A one-pot condensation/6π electrocyclization is followed by an intramolecular trapping of the 2,3-dihydroquinoline intermediate by nitrogen or oxygen nucleophiles to give bridged seven- and eight-membered products. Using 3-hydroxypyridinecarboxaldehydes results in a stable zwitterionic structure that can undergo a diastereoselective reduction under hydrogenative conditions.

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In this article, we report the discovery of a series of pyrimidopyridones as inhibitors of IRAK4 kinase. From a previously disclosed 5-azaquinazoline series, we found that switching the pyridine ring for an N-substituted pyridone gave a novel hinge binding scaffold which retained potency against IRAK4. Importantly, introduction of the carbonyl established an internal hydrogen bond with the 4-NH, establishing a conformational lock and allowing truncation of the large basic substituent to a 1-methylcyclopyl group.

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  • - This article discusses the enhancement of human drug clearance for a group of compounds known as 5-azaquinazolines through targeted chemical modifications.
  • - Researchers conducted extensive studies on drug metabolism and pharmacokinetics (DMPK) to address issues related to high metabolism by Aldehyde Oxidase and inconsistencies in drug clearance rates observed in liver models.
  • - The efforts led to the identification of a specific compound, 5-azaquinazoline 35, which not only demonstrated strong selectivity for the target IRAK4 but also showed promising combined effects against a particular type of lymphoma when used alongside the drug acalabrutinib.
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  • Researchers optimized a palladium-catalyzed Buchwald-Hartwig amination reaction for lenalidomide-derived aryl bromides using high throughput experimentation (HTE).
  • They evaluated the optimized conditions with various alkyl- and aryl- amines and functionalized aryl bromides to broaden the substrate scope.
  • This method enables the creation of new cereblon-based bifunctional proteolysis targeting chimeras, simplifying the process and increasing yields.
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Herein we report the preparation of 2'-deoxy-2'-spirocyclopropylcytidine via an alternative cyclopropanation reaction starting from γ-silyl tertiary alcohols. Activation of the hydroxyl function with thionyl chloride in the presence of 4-DMAP allows the ring-closing step under mild conditions. Participation of the uracil moiety in the cyclization step is proposed.

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Pim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.

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Highly functionalized aldol-type products bearing a β-quaternary center and a stereoselectively controlled γ-hydroxy function are readily prepared by the diastereoselective addition of an allylic zinc reagent embedded in an isoxazole ring to various aromatic and heteroaromatic aldehydes, in the presence of Lewis acids, such as MgCl2 or LaCl3⋅2 LiCl. After reductive cleavage of the N-O bond by using Fe, NH4Cl, aldol-type products bearing a stereocontrolled β-quaternary center and a γ-hydroxy group were observed. The benzylic reactivity of the isoxazolylmethylzinc reagent towards other electrophiles, such as acid chlorides, aryl and allylic halides, as well as aldehydes in the presence of BF3⋅OEt2 are also described.

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A general, transition-metal-free, highly stereoselective cross-coupling reaction between glycosyl bromides and various arylzinc reagents leading to β-arylated glycosides is reported. The stereoselectivity of the reaction is explained by invoking anchimeric assistance via a bicyclic intermediate. Stereochemical probes confirm the participation of the 2-pivaloyloxy group.

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A new Fe- or Co-catalyzed Cl/Zn-exchange reaction allows the direct transformation of aryl, heteroaryl, and also alkyl chlorides into the corresponding zinc reagents. The method tolerates functional groups such as a nitrile or an ester. Remarkably, secondary and tertiary alkyl chlorides are suitable substrates for the Cl/Zn exchange.

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