Synthesis and biological evaluation of novel thioapio dideoxynucleosides.
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 as a key intermediate. The intermediate was condensed with silylated pyrimidine bases such as N(4)-benzoylcytosine, uracil or thymine in the presence of TMSOTf to give the beta-anomers and alpha-anomers, respectively. The intermediate was also condensed with silylated 6-chloropurine to give the 6-chloropurine derivatives and which were converted to adenine derivatives and, N(6)-methyladenine derivatives and, and hypoxanthine derivatives and, respectively. The guanine analogues and were also synthesized from the condensation of sugar acetate 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 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).
Moon
Hyung Ryong
HR
College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.
Kim
Hea Ok
HO
Lee
Sang Kook
SK
Choi
Won Jun
WJ
Chun
Moon Woo
MW
Jeong
Lak Shin
LS
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000473:pathology; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D013329:Structure-Activity Relationship; D013872:Thionucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry; D014407:Tumor Cells, Cultured / Q000187:drug effects
D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D015224:Dideoxynucleosides; D013872:Thionucleosides; D013876:Thiophenes