Synthesis and biological evaluation of 6-(alkyn-1-yl)furo[2,3-d]pyrimidin-2(3H)-one base and nucleoside derivatives.
Derivatives of the 2'-deoxynucleoside of furo[2,3-d]pyrimidin-2(3H)-one with long-chain alkyl (or 4-alkylphenyl) substituents at C6 exhibit remarkable anti-VZV (varicella-zoster virus) potency and selectivity, and analogous 2',3'-dideoxynucleoside derivatives show anti-HCMV (human cytomegalovirus) activity. We now report a synthetic approach that enables the preparation of long-chain 6-(alkyn-1-yl)furo[2,3-d]pyrimidin-2(3H)-ones in which the rodlike acetylene spacer replaces the 4-substituted-phenyl ring at C6. Analogues with methyl, beta-d-ribofuranosyl, beta-d-arabinofuranosyl, and 2-deoxy-beta-d-erythro-pentofuranosyl substituents at N3 have been prepared. Long-chain derivatives at C6 in the 2'-deoxynucleoside series showed virus-encoded nucleoside kinase-sensitive anti-VZV activity. Surprisingly, 3-methyl-6-(octyn-1-yl)furo[2,3-d]pyrimidin-2(3H)-one (prepared as a negative anti-VZV test control) exhibited anti-HCMV activity, which supports the possibility of development of non-nucleoside anti-HCMV agents originating from uncomplicated derivatives of such bicyclic ring systems.
Robins
Morris J
MJ
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700, USA. morris_robins@byu.edu
Miranda
Karl
K
Rajwanshi
Vivek K
VK
Peterson
Matt A
MA
Andrei
Graciela
G
Snoeck
Robert
R
De Clercq
Erik
E
Balzarini
Jan
J
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003587:Cytomegalovirus / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides