Synthesis and biological evaluation of 2',3'-didehydro-2',3'-dideoxy-9-deazaguanosine, a monophosphate prodrug and two analogues, 2',3'-dideoxy-9-deazaguanosine and 2',3'-didehydro-2',3'-dideoxy-9-deazainosine.
2',3'-Didehydro-2',3'-dideoxy-9-deazaguanosine (1), its monophosphate prodrug (2), and two analogues, 2',3'-dideoxy-9-deazaguanosine (3) and 2',3'-didehydro-2',3'-dideoxy-9-deazainosine (4), have been synthesized from benzoylated 9-deazaguanosine (5). Basic hydrolysis of 5, selective protection of the 2-amino and 5'-hydroxy functions with isobutyryl and silyl groups, respectively, followed by reaction with thiocarbonyldiimidazole gave the cyclic thiocarbonate, which, upon reaction with triethyl phosphite, followed by deprotection, afforded 1. Treatment of 1 with phenyl methoxyalaninylphosphochloridate and N-methylimidazole gave 2. Catalytic hydrogenation of 1 gave 3. Hydrodediazoniation of 1 with tert-butyl nitrite and tris(trimethylsilyl)silane gave 4. Compounds 1-4 were found to be inactive against the human immunodeficiency virus and exhibited minimal to no cytotoxic activity against the L1210 leukemia, CCRF-CEM lymphoblastic leukemia, and B16F10 melanoma in vitro.
Liu
Mao-Chin
MC
Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA.
Luo
Mei-Zhen
MZ
Mozdziesz
Diane E
DE
Dutschman
Ginger E
GE
Gullen
Elizabeth A
EA
Cheng
Yung-Chi
YC
Sartorelli
Alan C
AC
D045744:Cell Line, Tumor; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D006678:HIV / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000188:drug therapy; D006801:Humans; D007288:Inosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology
D011355:Prodrugs; D007288:Inosine; C048839:9-deazainosine; D003849:Deoxyguanosine