Improved synthesis and biological evaluation of an acyclic thiosangivamycin active against human cytomegalovirus.
We previously described the synthesis and in vitro antiviral activity of an acyclic thiosangivamycin analog (Gupta et al., 1989a). In order to extend these initial studies, a new, multi-gram synthesis of 4-amino-7-[(2-hydroxy- ethoxy)methyl]pyrrolo]2,3-d]pyrimidine-5-thiocarboxamide (compound 229) was achieved in 5 steps from the known 5-amino-2-bromo-3,4-dicyanopyrrole in good overall yield. In plaque reduction assays with HCMV, compound 229 had an IC50 of 7 microM; in yield reduction assays the IC90 was 25 microM. The compound was less active against MCMV, HSV-1, HSV-2, and least active against VZV. Concentrations of compound 229 up to 32 microM did not affect the growth of KB cells for incubation periods up to 72 h. At 100 microM, a prolongation in population doubling time from 21 h (untreated) to 35 h was noted. This inhibition, however, was reversible upon removal of the compound suggesting the inhibition was cytostatic rather than cytotoxic. Flow cytometric studies with compound 229 in HFF cells revealed an accumulation of cells in S phase and a concurrent loss of cells in G2/M phase, suggesting an early S phase blockage. We conclude there is adequate separation between antiviral activity and cytotoxicity to merit further work with this class of pyrrolopyrimidines.
Renau
T E
TE
Interdepartmental Program in Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109.
Nassiri
M R
MR
Swayze
E E
EE
Kern
E R
ER
Townsend
L B
LB
Drach
J C
JC
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D007624:KB Cells; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology*; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D011743:Pyrimidines; D011758:Pyrroles; C078190:compound 229