Enantiomeric synthesis of (+)-BCH-189 [(+)-(2S,5R)-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine] from D-mannose and its anti-HIV activity

Abstract

Enantiomerically pure (+)-BCH-189 has been synthesized from D-mannose via 1,6-thioanhydro-~-mannose and its anti-HIV activity has been determined in peripheral blood mononuclear cells.

Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine

“…In fact, these compounds are good substrates for mammalian cytidine kinase and are rapidly phosphorylated in cells that express this enzyme (15,37). A review of the current status of L-enantiomers of antiviral nucleosides was recently provided by several groups (2,5,6,35,41). Prior to those reports, the activities of most nucleosides were associated only with the D-isomers.…”

Antiviral activities of isometric dideoxynucleosides of D- and L-related stereochemistry

“…To date, no drug has cured HIV infection, but some that are the most successful in inhibiting the cytopathic effect of HIV and that are in clinical use are the dideoxynucleosides (ddNs): 2Ј,3Ј-dideoxyinosine (ddI), 2Ј,3Ј-dideoxycytidine (ddC), 2Ј,3Ј-didehydro-3Ј-deoxythymidine, and 3Ј-substituted dideoxynucleosides such as 3Ј-azido-3Ј-deoxythymidine (AZT) (3, 4, 13, 22, 48-50, 69, 81). Others such as the oxathiolane ddNs which show promise as potent anti-HIV compounds are also being developed (6,12,14,74,82). As prodrugs, these ddNs must be sequentially phosphorylated intracellularly to yield ddN 5Ј-triphosphates, thus becoming nucleotide analogs of the 2Ј-ddN 5Ј-triphosphates before they can act, at the reverse transcriptase level, as competitive inhibitors and/or alternate substrates (chain terminators) with respect to the natural deoxynucleotide substrates (1,15,16,19).…”

Bicyclic nucleoside analogues from d-glucose: synthesis of chiral as well as racemic 1,4-dioxepane ring-fused derivatives

“…Calcd for C 15 4.9. (3aR,3bR,8S,8aS,9aR) 2,2-Dimethylhexahydro-1,3,4,7,9-pentaoxacyclopenta[a]azulen-8-ol (12) The conversion of 11 (100 mg, 0.3 mmol) to 12 (33 mg, 48%) was performed through reduction of the ester…”

“…10 Later on, dideoxy nucleoside prototypes such as dioxolane-T 11 and BCH-189 12 having two heteroatoms within the carbohydrate framework, and dioxepanyl nucleoside analogues 13 have also been added to the list. The fact that the presence of one more heteroatom in the ribose ring of a nucleoside 11,12 imparts anti-HIV/anti-neoplastic activities to it prompted us to take up a programme on the synthesis of bicyclic nucleosides having dioxygenated heterocycles of varied ring sizes fused to the ribose ring, on which no work appears to have been reported so far. In this communication we wish to report a simple convergent approach for the synthesis of bicyclic nucleosides with a fused dioxepane ring.…”