Isodideoxynucleosides: a conceptually new class of nucleoside antiviral agents.

Abstract

Among active site directed inhibitors of HIV reverse transcriptase are the "natural" dideoxynucleosides: 2',3'-dideoxyadenosine (ddA) and its metabolite, 2',3'-dideoxyinosine (ddl), 2',3'-dideoxyguanosine (ddG), and 2',3'-dideoxycytidine (ddC).1-5 However, dideoxynucleosides, particularly those of the purine family, are inherently unstable with respect to cleavage of the glycosidic bond,2 3456•7 ***because of the absence of the -I effect of the OH groups and the involvement in hydrolysis of the proximal ring oxygen. The discovery of therapeutically useful antiviral com-

Antiviral, metabolic, and pharmacokinetic properties of the isomeric dideoxynucleoside 4(S)-(6-amino-9H-purin-9-yl)tetrahydro-2(S)-furanmethanol

“…The syntheses of enantiomerically pure (S,S)-isodideoxyadenosine and (S,S)-isodideoxyinosine from D-xylose have been reported previously by Nair and coworkers (4,30). [ 6 Ci/mmol) was prepared from IsoddA by Moravek Biochemicals (Brea, Calif.).…”

“…1). The synthesis of this compound has been reported by us, and its absolute stereochemistry has been established by X-ray crystallography (4,30). The enantiomer of this compound has been synthesized and discussed elsewhere (18).…”

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

“…a See Table 1 (S,S)-IsoddA was found to be very stable with respect to hydrolysis of the glycosidic bond, with a half-life of greater than 16 days at pH 1 (59). Likewise, (R,R)-IsoddA was found to be stable at pH 3.0 (37ЊC) for more than 2 weeks (37).…”

Synthesis of novel bicarbocyclic nucleosides

“…Chemical shifts are referenced to an internal TMS standard for 1H-NMR spectra and to solvent (CDCl 3 , DMSO-d 6 , Acetone-d 6 or CD 3 OD) for 13 C NMR spectra. Column chromatographic separations were carried out using 230-400 mesh silica gel.…”

“…Fractions were monitored by a Pharmacia UV-2 ultraviolet monitor and were collected on a Gilson FC-100 fraction collector. Purities of intermediates and final products were determined by a combination of 1 H and 13 C NMR spectra, quantitative UV data and HPLC analysis. ol (5a).…”