Synthesis and antiherpetic activity of (+/-)-9-[[(Z)-2-(hydroxymethyl)cyclopropyl]methyl]guanine and related compounds.
A series of analogues of acyclovir and ganciclovir were prepared in which conformational constraints were imposed by incorporation of a cyclopropane ring or unsaturation into the side chain. In addition, several related base-modified compounds were synthesized. These acyclonucleosides were evaluated for enzymatic phosphorylation and DNA polymerase inhibition in a staggered assay and for inhibitory activity against herpes simplex virus types 1 and 2 in vitro. Certain of the guanine or 8-azaguanine derivatives were good substrates for the viral thymidine kinase and were further converted to triphosphate, but none was a potent inhibitor of the viral DNA polymerase. Nevertheless, one member of this group, (+/-)-9-[[(Z)-2-(hydroxymethyl)cyclopropyl]methyl]guanine (3a), displayed significant antiherpetic activity in vitro, superior to that of the corresponding cis olefin 4a. Another group, typified by (+/-)-9-[[(E)-2-(hydroxymethyl)cyclopropyl]methyl]adenine (17b), possessed modest antiviral activity despite an apparent inability to be enzymatically phosphorylated. The relationship of side-chain conformation and flexibility to biological activity in this series is discussed.
Ashton
W T
WT
Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
Meurer
L C
LC
Cantone
C L
CL
Field
A K
AK
Hannah
J
J
Karkas
J D
JD
Liou
R
R
Patel
G F
GF
Perry
H C
HC
Wagner
A F
AF
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D015774:Ganciclovir; D019384:Nucleic Acid Synthesis Inhibitors; D010766:Phosphorylation; D018139:Simplexvirus / Q000187:drug effects* / Q000201:enzymology; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D019384:Nucleic Acid Synthesis Inhibitors; D015774:Ganciclovir; D000212:Acyclovir