Synthesis, Cytotoxicity, and Antiviral Activity of Certain 7-pyrrolopyrimidine Nucleosides Related to Toyocamycin and Sangivamycin

Article abstract of DOI:10.1021/jm00127a003

A number of 7-<(2-hydroxyethoxy)methyl>pyrrolo<2,3-d>pyrimidine derivatives related to the nucleoside antibiotics toyocamycin and sangivamycin were prepared and tested for their biological activity.Treatment of the sodium salt of 4-amino-6-bromo-5-cyanopyrrolo<2,3-d>pyrimidine (1) with (2-acetoxyethoxy)methyl bromide (2) afforded a mixture of 4-amino-6-bromo-5-cyano-7-<(2-acetoxyethoxy)methyl>pyrrolo<2,3-d>pyrimidine (3) and the corresponding N₁ isomer.Debromination of this mixture gave the corresponding 4-amino-5-cyano-7-<(2-acetoxyethoxy)-methyl>pyrrolo<2,3-d>pyrimidine (4) and 4-amino-5-cyano-1-<(2-acetoxyethoxy)methyl>pyrrolo<2,3-d>pyrimidine (5).Deacetylation of 4 and 5 furnished 4-amino-5-cyano-7-<(2-hydroxyethoxy)methyl>pyrrolo<2,3-d>pyrimidine (6) and the corresponding N₁ isomer (7), respectively.The sites of attachment for the acyclic moiety for 6 and 7 were assigned on the basis of UV spectral studies as well as (13)C NMR spectroscopy.Conventional functional group transformation of 6 provided a number of novel 5-substituted derivatives (8-10), including the sangivamycin derivative 8.The methyl formimidate derivative 10 was converted to the thioamid derivative 11 and the carbohydrazide derivative 12.Compounds 6 and 8-12 were tested for cytotoxicity to L1210 murine leukemic cells in vitro.None of these compounds caused significant inhibition of cell growth.Evaluation of compounds 4 and 6-12 for activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) revealed that only the thioamide (11) was active.It inhibited HCMV but not HSV-1 at concentrations producing only slight cytotoxicity in the human foreskin fibroblasts (HFF cells) and KB cells.