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.
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700, USA.
Zlatko
Z
Janeba
Jan
J
Balzarini
Graciela
G
Andrei
Robert
R
Snoeck
Erik
E
De Clercq
Morris J
MJ
Robins
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