Synthesis and biological activity of 2-aminopurine methylenecyclopropane analogues of nucleosides.
Synthesis and biological activity of racemic 2-aminopurine methylenecyclopropane analogues of nucleosides 4, 5, 10 and 11 is described. One-pot alkylation-elimination of 2-aminopurine (6) with dibromide 7 gave a mixture of four isomeric methylenecyclopropanes. The (E, Z)-N9 and (E, Z)-N7 isomers 8 and 9 were resolved by chromatography on silica gel. Deacetylation of 8 afforded the respective (Z)-N9 and (E)-N9 isomers 4 and 10 which were separated by chromatography on silica gel. In a similar fashion, (E, Z)-N7 mixture 9 furnished (Z)-N7 and (E)-N7 isomers 5 and 11. The S-(+)-enantiomer 4 was obtained by desulfurization of (S)-(+)-6-thiosynguanol (13) with Raney Ni. Compound 13 was obtained from (S)-(+)-2-amino-6-chloro derivative 12 and NaSH in methanol. Racemic analogues 4, 5, 10 and 11 were inactive against HCMV, HSV-1, HSV-2, EBV and VZV. Enantiomer (S)-(+)-4 inhibited replication of HSV-1 in BSC-1 cells (ELISA) with EC50 35 microM and it was non-cytotoxic in KB cells (CC50 > 100 microM). Compound (S)-(+)-4 was also moderately effective against VZV in HFF culture with EC50/CC50 (microM) 60/>460 and it was a substrate for xanthine oxidase.
Developmental Chemotherapy Program, Department of Chemistry, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201-1379, USA.
Ruifang
R
Wang
Xinchao
X
Chen
John C
JC
Drach
Earl R
ER
Kern
Jiri
J
Zemlicka
D015075:2-Aminopurine / Q000031:analogs & derivatives*; D000478:Alkylation; D000998:Antiviral Agents / Q000138:chemical synthesis; D002850:Chromatography, Gel; D003521:Cyclopropanes / Q000737:chemistry*; D008956:Models, Chemical; D019906:Nuclear Magnetic Resonance, Biomolecular; D009705:Nucleosides / Q000138:chemical synthesis* / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D014969:Xanthine Oxidase / Q000737:chemistry / Q000378:metabolism
D000998:Antiviral Agents; D003521:Cyclopropanes; D009705:Nucleosides; D011355:Prodrugs; D015075:2-Aminopurine; D014969:Xanthine Oxidase