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.

Abstract

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.

• Authors: Mao-Chin Liu, Mei-Zhen Luo, Diane E Mozdziesz, Ginger E Dutschman, Elizabeth A Gullen, Yung-Chi Cheng, Alan C Sartorelli
• Journal: Nucleosides, nucleotides & nucleic acids (Nucleosides Nucleotides Nucleic Acids) Vol. 24 Issue 2 Pg. 135-45 ( 2005) ISSN: 1525-7770 [Print] United States
• PMID: 15822619 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Prodrugs
• Inosine
• 9-deazainosine
• Deoxyguanosine

Topics

• Cell Line, Tumor
• Deoxyguanosine (analogs & derivatives, chemical synthesis, pharmacology)
• HIV (drug effects)
• Hematologic Neoplasms (drug therapy)
• Humans
• Inosine (analogs & derivatives, chemical synthesis, pharmacology)
• Prodrugs (chemical synthesis, pharmacology)