ISOSTERES OF THE DNA-POLYMERASE INHIBITOR APHIDICOLIN AS POTENTIAL ANTIVIRAL AGENTS AGAINST HUMAN HERPES VIRUSES

A variety of isosteres of the DNA polymerase inhibitor aphidicolin wer e synthesized as potential antiherpes agents. Modeling studies indicat ed that the bicyclooctane C, D rings of aphidicolin could be replaced by an aromatic moiety while maintaining the spatial arrangement of the hydroxyl group equivalent to the essential C18 hydroxyl group of aphi dicolin. Of the racemic isosteres synthesized only 13, the compound wi th the greatest structural similarity to aphidicolin, showed any signi ficant antiviral activity in primary assays. An enantioselective synth esis of the compound was carried out and the 4aS isomer 36 was shown t o account for the observed antiviral activity noted against herpes sim plex virus 1 and human cytomegalovirus.