Arabinofuranosylpyrrolo[2,3-d]pyrimidines as potential agents for human cytomegalovirus infections.
Protection of the 3'- and 5'-hydroxyl groups of the nucleoside antibiotic toyocamycin (1) with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane was followed by (trifluoromethyl)sulfonylation of the 2'-hydroxyl group. A displacement of the resulting triflate ester moiety with lithium chloride, lithium bromide, sodium iodide, and lithium azide in hexamethylphosphoramide was followed by a removal of the disilyl moiety with tetra-n-butylammonium fluoride to afford the appropriate (2'-deoxy-2'-substituted-arabinofuranosyl)toyocamycin analogues 6a-d. Hydrolysis of the carbonitrile moieties of 6a-d with hydrogen peroxide gave the corresponding sangivamycin analogues (7a-d). A reduction of the azido moiety of 6a and 7a with 1,3-propanedithiol furnished the corresponding amino derivatives (6e and 7e). The antiproliferative activity of 6a-e and 7a-e was evaluated in L1210 cell cultures. None of these compounds caused significant inhibition of cell growth. Evaluation of these compounds for antiviral activity showed that all the toyocamycin analogues were active against human CMV, but of the sangivamycin analogues, only (2'-deoxy-2'-azidoarabinosyl)sangivamycin (7a) was active against this virus. None of the compounds were active against HSV-1 or HSV-2. (2'-Deoxy-2'-aminoarabinofuranosyl)toyocamycin (6e) was studied more extensively and showed some separation between antiviral activity and cytotoxicity as measured by effects on DNA synthesis, cell growth, and cell-plating efficiency. Although 6e also was active against murine CMV in vitro, it was not active against this virus in infected mice. We conclude that arabinosylpyrrolopyrimidines have potential as antivirals, but no members of the current series are potent enough to show significant activity in vivo.
Krawczyk
S H
SH
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109-1065.
Bernier-Rodriguez
M
M
Nassiri
M R
MR
Kern
E R
ER
Wotring
L L
LL
Drach
J C
JC
Townsend
L B
LB
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D001087:Arabinonucleosides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D003587:Cytomegalovirus / Q000187:drug effects*; D003586:Cytomegalovirus Infections / Q000188:drug therapy*; D006801:Humans; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice; D015394:Molecular Structure; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D018139:Simplexvirus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014127:Toyocamycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D001087:Arabinonucleosides; D011741:Pyrimidine Nucleosides; C005699:sangivamycin; D014127:Toyocamycin