ANTI-HERPESVIRUS ACTIVITY PROFILE OF 4'-THIOARABINOFURANOSYL PURINE AND URACIL NUCLEOSIDES AND ACTIVITY OF 1-BETA-D-2'-FLUORO-4'-THIOARABINOFURANOSYL GUANINE AND 2,6-DIAMINOPURINE AGAINST CLINICAL ISOLATES OF HUMAN CYTOMEGALOVIRUS

Newly synthesized 4 '-thio- and 2 '-fluoro-4 '-thioarabinofuranosyl pu rine and pyrimidine nucleosides were compared with the corresponding 4 '-oxo type arabinosyl nucleosides for anti-herpesvirus and anti-cell proliferative potencies. 4 '-thioarabinosyl- and 2 '-fluoro-4 '-thioar abinofuranosyl 5-substituted uracils had selective antiviral activitie s, but were not superior to 4 '-oxo nucleosides, except for the activi ty of 5-ethyl-uracil 4 '-thio nucleosides against herpes simplex virus . Furthermore, 4 '-thio substituted derivatives of sorivudine (BV-araU ) and related compounds, and 2 '-fluoro-5-methyl-arabinosyluracil exhi bited reduced activity against varicella-zoster virus compared with th e parent compounds. The 4 '-thioarabinosyluracils, except for 5-methyl uracil derivatives, were inactive against human cytomegalovirus (HCMV) . 4 '-Thioarabinofuranosyl guanine and diaminopurine had the most pote nt anti-HCMV and anti-proliferative activities, whereas arabinosyl gua nine and diaminopurine had only marginal antiviral activity. 2 '-Fluor o-4 '-thioarabinofuranosyl derivatives of guanine (4 '-thio-FaraG) and 2,6-diaminopurine (4 '-thio-FaraDAP), however, had particularly high activity against all herpesviruses tested with anti-proliferative acti vity equipotent to that of arabinosyl guanine and diaminopurine. 4 '-T hio- and 2 '-fluoro-4 '-thioarabinofuranosyladenines exhibited biologi cal activities similar to that of arabinosyladenine. Both 4 '-thio-Far aG and 4 '-thio-FaraDAP had a 6-fold lower ED,, than ganciclovir again st clinical isolates of HCMV. A ganciclovir-resistant isolate, obtaine d from a patient who had received long-term ganciclovir-treatment, was susceptible to 4 '-thio-FaraG and 4 '-thio-FaraDAP. (C) 1998 Elsevier Science B.V. All rights reserved.