SYNTHESIS AND EVALUATION OF CERTAIN THIOSANGIVAMYCIN ANALOGS AS POTENTIAL INHIBITORS OF CELL-PROLIFERATION AND HUMAN CYTOMEGALOVIRUS

A series of 7-substituted 4-aminopyrrolo[2,3-d]pyrimidines related to the nucleosides toyocamycin and thiosangivamycin were prepared and tes ted for their activity against human cytomegalovirus (HCMV). The nucle osides 2'-deoxytoyocamycin (1), xylo-toyocamycin (2), 3'-deoxytoyocamy cin (3), 2',3'-dideoxy-2',3'-didehydrotoyocamycin (4), 2',3'-dideoxyto yocamycin (5), ara-toyocamycin (6), 2'-deoxy-2'-amino-ara-toyocamycin (7), and 5'-deoxytoyocamycin (8) were treated with sodium hydrogen sul fide generated in situ to afford the corresponding thiosangivamycin an alogs (9-16). The cyano derivatives 1-8 were synthesized by modificati ons of Literature procedures. All of the thioamide derivatives (9-16) were active against HCMV with IC50's ranging from 0.5 to 6 mu M. Most also were active against herpes simplex virus type 1 (HSV-1) but at hi gher concentrations. The antiviral activity was not completely separat ed from cytotoxicity in two human cell lines. The antiproliferative ac tivity was strongly influenced by the position of the modification on the carbohydrate moiety. The xylosyl and 3'-deoxy derivatives were sig nificantly more potent than those with modifications at the 2', 5', or 2',3' position(s). Interestingly, 5'-deoxythiosangivamycin (16) posse ssed both antiviral and antiproliferative activity suggesting that pho sphorylation of the 5'-hydroxyl may not be required for these compound s to have biological activity.