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 purine 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'-thioarabinofuranosyl 5-substituted uracils had selective antiviral activities, but were not superior to 4'-oxo nucleosides, except for the activity 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 exhibited reduced activity against varicella-zoster virus compared with the parent compounds. The 4'-thioarabinosyluracils, except for 5-methyluracil derivatives, were inactive against human cytomegalovirus (HCMV). 4'-Thioarabinofuranosyl guanine and diaminopurine had the most potent anti-HCMV and anti-proliferative activities, whereas arabinosyl guanine and diaminopurine had only marginal antiviral activity. 2'-Fluoro-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 activity equipotent to that of arabinosyl guanine and diaminopurine. 4'-Thio- and 2'-fluoro-4'-thioarabinofuranosyladenines exhibited biological activities similar to that of arabinosyladenine. Both 4'-thio-FaraG and 4'-thio-FaraDAP had a 6-fold lower ED50 than ganciclovir against clinical isolates of HCMV. A ganciclovir-resistant isolate, obtained from a patient who had received long-term ganciclovir-treatment, was susceptible to 4'-thio-FaraG and 4'-thio-FaraDAP.
Machida
H
H
Biochemicals Division, Yamasa Corporation, Choshi, Japan.
Ashida
N
N
Miura
S
S
Endo
M
M
Yamada
K
K
Kitano
K
K
Yoshimura
Y
Y
Sakata
S
S
Ijichi
O
O
Eizuru
Y
Y
D000998:Antiviral Agents / Q000494:pharmacology; D001087:Arabinonucleosides / Q000494:pharmacology*; D002455:Cell Division; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D011684:Purine Nucleosides / Q000494:pharmacology*; D014529:Uridine / Q000494:pharmacology*
C116334:2'-fluoro-(4'-thioarabinofuranosyl)guanine; C116335:2'-fluoro-4'-(thioarabinofuranosyl)-2,6-diaminopurine; D000998:Antiviral Agents; D001087:Arabinonucleosides; D011684:Purine Nucleosides; D014529:Uridine