SYNTHESIS OF NONNUCLEOSIDE ANALOGS OF TOYOCAMYCIN, SANGIVAMYCIN, AND THIOSANGIVAMYCIN - INFLUENCE OF VARIOUS 7-SUBSTITUENTS ON ANTIVIRAL ACTIVITY

A number of 7-substituted 4-aminopyrrolo[2,3-d]pyrimidine-5-carbonitri le, -5-carboxamide, and -5-thiocarboxamide derivatives related to the nucleoside antibiotics toyocamycin and sangi-vamycin were prepared and tested for their activity against human cytomegalovirus (HCMV) and he rpes simplex virus type-1 (HSV-1). Treatment of 2-amino-5-bromo-3,4-di cyanopyrrole (1) with triethyl orthoformate followed by alkylation via the sodium salt method with a variety of alkylating agents furnished the corresponding 1-substituted pyrroles 2a-k. Ring annulation was ach ieved with methanolic ammonia affording the 7-substituted ino-6-bromop yrrolo[2,3-d]pyrimidine-5-carbonitrile derivatives 3a-k. Debromination of 3a-k, via catalytic hydrogenation, gave the corresponding 7-substi tuted 4-aminopyrrolo[2,3-d]pyrimidine-5-carbonitrile analogs 4a-j,l. A selective reduction of mo-7-allylpyrrolo[2,3-d]-pyrimidine-5-carbonit rile (3k) in zinc and acetic acid furnished o-7-allylpyrrolo-[2,3-d]-p yrimidine-5-carbonitrile (4k). Conventional functional group transform ations involving the 5-cyano group of 4 furnished the 5-carboxamide de rivatives 5a-l and the 5-thioammide analogs 6a-l. A similar transforma tion of the aglycone of toyocamycin (4m) furnished the corresponding a glycone of thiosangivamycin (6m). Several of the new compounds (4-6a-e j-l) were evaluated for their ability to inhibit the growth of L1210 m urine leukemic cells. Whereas a number of the carboxamide (5) and thio amide (6) derivatives had modest activity, the corresponding nitrile a nalogs (4) were all inactive. All compounds were tested for activity a gainst HCMV and HSV-1. The non-nucleoside nitrile analogs 4a-m and car boxamide derivatives 5a-l were, with a few exceptions, essentially ina ctive against HCMV and HSV-1 and relatively nontoxic. In direct contra st, nearly all of the thioamide derivatives 6a-l, including the aglyco ne of thiosangivamycin (6m), were good inhibitors of HCMV and HSV-1. M ost were noncytotoxic in their antiviral concentration range. Cytotoxi city which was observed appeared to be a consequence of DNA synthesis inhibition. Several of these compounds, such as 6b,e, were particularl y interesting inhibitors of HCMV with IC50's ranging from 0.1 to 1.3 m u M. The antiviral activity of both compounds was well separated from cytotoxicity in KB, HFF, and L1210 cells.