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Synthesis and anti-HIV activity of conformationally restricted bicyclic hexahydroisobenzofuran nucleoside analogs.

ABSTRACT: A chiral synthesis of a series of hexahydroisobenzofuran (HIBF) nucleosides has been accomplished via glycosylation of a stereo-defined (syn-isomer) sugar motif 16 with the appropriate silylated bases. All nucleoside analogs were obtained in 52-71% yield as a mixture of alpha- and beta-anomeric products increasing the breadth of the novel nucleosides available for screening. The structure of the novel bicyclic HIBF nucleosides was established by a single crystal X-ray structure of the beta-HIBF thymine analog 22b. Furthermore, the sugar conformation for these nucleosides was established as N-type. Among the novel HIBF nucleosides synthesized, twenty-five compounds were tested as inhibitor of HIV-1 in human peripheral blood mononuclear (PBM) cells and seven were found to be active (EC(50) = 12.3-36.2 microM). Six of these compounds were purine analogs with beta-HIBF inosine analog 22o being the most potent (EC(50) = 12.3 microM) among all compounds tested. The striking resemblance between didanosine (ddI) and 22o may explain the potent anti-HIV activity.

SUBMITTER: Diaz-Rodriguez A

PROVIDER: S-EPMC7733237 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Synthesis and anti-HIV activity of conformationally restricted bicyclic hexahydroisobenzofuran nucleoside analogs.

Díaz-Rodríguez Alba A Sanghvi Yogesh S YS Fernández Susana S Schinazi Raymond F RF Theodorakis Emmanuel A EA Ferrero Miguel M Gotor Vicente V

Organic & biomolecular chemistry 20090211 7

A chiral synthesis of a series of hexahydroisobenzofuran (HIBF) nucleosides has been accomplished via glycosylation of a stereo-defined (syn-isomer) sugar motif 16 with the appropriate silylated bases. All nucleoside analogs were obtained in 52-71% yield as a mixture of alpha- and beta-anomeric products increasing the breadth of the novel nucleosides available for screening. The structure of the novel bicyclic HIBF nucleosides was established by a single crystal X-ray structure of the beta-HIBF ...[more]

PMID: 19300828

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Project description:The tropomyosin receptor kinase A (TrkA) family of receptor tyrosine kinases (RTKs) emerge as a potential target for glioblastoma (GBM) treatment. Benzenesulfonamide analogs were identified as kinase inhibitors possessing promising anticancer properties. In the present work, four known and two novel benzenesulfonamide derivatives were synthesized, and their inhibitory activities in TrkA overexpressing cells, U87 and MEF cells were investigated. The cytotoxic effect of benzenesulfonamide derivatives and cisplatin was determined using trypan blue exclusion assays. The mode of interaction of benzenesulfonamides with TrkA was predicted by docking and structural analysis. ADMET profiling was also performed for all compounds to calculate the drug likeness property. Appropriate QSAR models were developed for studying structure-activity relationships. Compound 4-[2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfon-amide (AL106) and 4-[2-(1,3-dioxo-1,3-dihydro-2H-inden-2-ylidene)hydrazinyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide (AL107) showed acceptable binding energies with the active sites for human nerve growth factor receptor, TrkA. Here, AL106 was identified as a potential anti-GBM compound, with an IC50 value of 58.6 µM with a less toxic effect in non-cancerous cells than the known chemotherapeutic agent, cisplatin. In silico analysis indicated that AL106 formed prominent stabilizing hydrophobic interactions with Tyr359, Ser371, Ile374 and charged interactions with Gln369 of TrkA. Furthermore, in silico analysis of all benzenesulfonamide derivatives revealed that AL106 has good pharmacokinetics properties, drug likeness and toxicity profiles, suggesting the compound may be suitable for clinical trial. Thus, benzenesulfonamide analog, AL106 could potentially induce GBM cell death through its interaction with TrkA and might be an attractive strategy for developing a drug targeted therapy to treat glioblastoma.

Dataset Information

Synthesis and anti-HIV activity of conformationally restricted bicyclic hexahydroisobenzofuran nucleoside analogs.

Publications

Synthesis and anti-HIV activity of conformationally restricted bicyclic hexahydroisobenzofuran nucleoside analogs.

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