Synthesis and biological evaluation of acyclic 3-[(2-hydroxyethoxy)methyl] analogues of antiviral furo- and pyrrolo[2,3-d]pyrimidine nucleosides.
The remarkably potent and specific activity against varicella-zoster virus (VZV) shown by 2'-deoxynucleosides of furo[2,3-d]pyrimidin-2(3H)-one and related ring systems is dependent on key structural features including the length and nature of the side-chain at C6 and the structure and stereochemistry of the sugar moiety at N3. Removal of the 3'-hydroxyl group from potent anti-VZV 2'-deoxynucleosides results in loss of the VZV activity, but such 2',3'-dideoxynucleoside analogues have shown anti-HCMV activity. We now report acyclic analogues with comparable side-chains at C6, but with the sugar moiety at N3 replaced with the (2-hydroxyethoxy)methyl group (present in the antiherpes drug acyclovir). Examples of both furo[2,3-d]- and pyrrolo[2,3-d]pyrimidin-2(3H)-one acyclic analogues were prepared and evaluated in a number of virus-infected cells and in tumor cell cultures. Certain of the long-chain analogues showed activity against VZV and HCMV. No significant activity against other DNA and RNA virus replication or against tumor cell proliferation was observed.
Janeba
Zlatko
Z
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700, USA.
Balzarini
Jan
J
Andrei
Graciela
G
Snoeck
Robert
R
De Clercq
Erik
E
Robins
Morris J
MJ
D000212:Acyclovir / Q000737:chemistry; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides; D011758:Pyrroles; D000212:Acyclovir