Syntheses and biological evaluations of 3'-deoxy-3'-C-branched-chain-substituted nucleosides.
Various 3'-deoxy-3'-C-(hydroxymethyl)-, 3'-deoxy-3'-C-(fluoromethyl)-, 3'-deoxy-3'-C-(azidomethyl)-, and 3'-deoxy-3'-C-(aminomethyl)-substituted nucleosides (total 12 compounds) have been synthesized and evaluated against L1210, P388, S-180, and CCRF-CEM cells and HSV-1, HSV-2, and HIV-1 in culture. Only 3'-deoxy-3'-C-(hydroxymethyl)thymidine (36) was found to show significant anticancer activity against L1210, P388, S-180, and CCRF-CEM cells with ED50 values of 50, 5, 10, and 1 microM, respectively. None of these compounds demonstrated significant antiviral activity against HSV-1, HSV-2, or HIV-1. These compounds were also evaluated against thymidine kinases derived from HSV-I (strain KOS), HSV-2 (strain 333), and mammalian (K562) cells. The thymidine kinase (HSV-1 strain KOS) was inhibited significantly by both 3'-deoxy-3'-C-(hydroxymethyl)- and 3'-deoxy-3'-C-(fluoromethyl)thymidine.
Lin
T S
TS
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.
Zhu
J L
JL
Dutschman
G E
GE
Cheng
Y C
YC
Prusoff
W H
WH
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003853:Deoxyribonucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D015224:Dideoxynucleosides / Q000138:chemical synthesis / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D051379:Mice; D018139:Simplexvirus / Q000187:drug effects; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured; D015215:Zidovudine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D000998:Antiviral Agents; D003853:Deoxyribonucleosides; D015224:Dideoxynucleosides; D015215:Zidovudine; D013937:Thymidine Kinase; C002854:alovudine