Synthesis and biological evaluation of novel thioapio dideoxynucleosides

Abstract

On the basis of the bioisosteric rationale to apio dideoxynucleosides, novel thioapio dideoxynucleosides have been synthesized, starting from 1,3-dihydroxyacetone via thioapio sugar acetate 6 as a key intermediate. The intermediate 6 was condensed with silylated pyrimidine bases such as N 4-benzoylcytosine, uracil or thymine in the presence of TMSOTf to give the β-anomers (8a, 11a, and 12a) and α-anomers (8b, 11b, and 12b), respectively. The intermediate 6 was also condensed with silylated 6-chloropurine to give the 6-chloropurine derivatives 14a and 14b which were converted to adenine derivatives 15a and 15b, N 6-methyladenine derivatives 16a and 16b, and hypoxanthine derivatives 17a and 17b, respectively. The guanine analogues 20a and 20b were also synthesized from the condensation of sugar acetate 6 with 2-acetamido-6-chloropurine. All synthesized final compounds were tested against HIV-1. Most of the synthesized compounds exhibited toxicity-dependent anti-HIV-1 activity, among which 6-chloropurine derivative 14b was found to be the most cytotoxic and showed good cytotoxicity against colon cancer cell lines. Although we could not find good anti-HIV agents in this study, findings of some anticancer activity in this series will allow this class of nucleosides to be the new template for the development of new anticancer agents (Fig. 1). © 2002 Elsevier Science Ltd. All rights reserved.