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

• Type of Material: Article
• Authors: Alba Diaz-Rodriguez, University of California, San Diego; Yogesh S. Sanghvi, Rasayan Inc.; Susana Fernandez, Universidad de Oviedo; Raymond Schinazi, Emory University; Emmanuel A. Theodorakis, University of California, San Diego; Miguel Ferrero, Universidad de Oviedo; Vicente Gotor, Universidad de Oviedo
• Language: English
• Date: 2009-01-01
• Publisher: ROYAL SOC CHEMISTRY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2009
• Final Published Version (URL): http://dx.doi.org/10.1039/b818707j
• Title of Journal or Parent Work: ORGANIC & BIOMOLECULAR CHEMISTRY
• Volume: 7
• Issue: 7
• Start Page: 1415
• End Page: 1423
• Grant/Funding Information: Financial support of this work by the Spanish Ministerio de Educación y Ciencia (MEC) (Project MEC-07-CTQ-61126) is gratefully acknowledged. A. D.-R. thanks MEC for a predoctoral fellowship. We also thank Dr A. G. DiPasquale and Professor A. L. Rheingold (UCSD X-Ray Facility) for the reported crystallographic studies and Dr Y. Su (UCSD Mass Spectrometry Facility) for mass analysis and the NSF (CHE-0116662, CHE-9709183 and CHE-0741968) for NMR and MS instrumentation grants. R. F. S. is supported in part by NIH grants 5P30-AI-50409 (CFAR), 5R37-AI-041980 and by the Department of Veterans Affairs.
• Keywords: ADENOSINE-DEAMINASE; CHIRAL BUTENOLIDES; TYPE-1; CYCLOPROPANO ANALOG; Chemistry; Chemistry, Organic; HUMAN-IMMUNODEFICIENCY-VIRUS; ACID; DIELS-ALDER CYCLOADDITIONS; ANTIVIRAL ACTIVITY; DIASTEREOFACIAL SELECTIVITY; Physical Sciences; DERIVATIVES; Science & Technology
• Research Categories: Health Sciences, Public Health; Chemistry, Organic; Biology, Virology

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 α- and β-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 β-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 (EC50 = 12.3-36.2 μM). Six of these compounds were purine analogs with β-HIBF inosine analog 22o being the most potent (EC50 = 12.3 μM) among all compounds tested. The striking resemblance between didanosine (ddI) and 22o may explain the potent anti-HIV activity. © 2009 The Royal Societ of Chemistry.