Synthesis of Non-nucleoside Analogs of Toyocamycin, Sangivamycin, and Thiosangivamycin:  Influence of Various 7-Substituents on Antiviral Activity

• Published in: Journal of medicinal chemistry 1996-02, Vol.39 (4), p.873-880
• Main Authors: Renau, Thomas E, Wotring, Linda L, Drach, John C, Townsend, Leroy B
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Cell Survival - drug effects; Cells, Cultured; Cytomegalovirus - drug effects; Fibroblasts; herpes simplex virus 1; Herpesvirus 1, Human - drug effects; Humans; Indicators and Reagents; Magnetic Resonance Spectroscopy; Male; Microbial Sensitivity Tests; Molecular Structure; Pyrimidine Nucleosides - chemical synthesis; Pyrimidine Nucleosides - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Skin; Structure-Activity Relationship; Thionucleosides - chemical synthesis; Thionucleosides - pharmacology; Toyocamycin - analogs & derivatives; Toyocamycin - chemical synthesis; Toyocamycin - pharmacology; Viral Plaque Assay
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm950444j

A number of 7-substituted 4-aminopyrrolo[2,3-d]pyrimidine-5-carbonitrile, -5-carboxamide, and -5-thiocarboxamide derivatives related to the nucleoside antibiotics toyocamycin and sangivamycin were prepared and tested for their activity against human cytomegalovirus (HCMV) and herpes simplex virus type-1 (HSV-1). Treatment of 2-amino-5-bromo-3,4-dicyanopyrrole (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 achieved with methanolic ammonia affording the 7-substituted 4-amino-6-bromopyrrolo[2,3-d]pyrimidine-5-carbonitrile derivatives 3a−k. Debromination of 3a−k, via catalytic hydrogenation, gave the corresponding 7-substituted 4-aminopyrrolo[2,3-d]pyrimidine-5-carbonitrile analogs 4a−j,l. A selective reduction of 4-amino-6-bromo-7-allylpyrrolo[2,3-d]pyrimidine-5-carbonitrile (3k) in zinc and acetic acid furnished 4-amino-7-allylpyrrolo[2,3-d]pyrimidine-5-carbonitrile (4k). Conventional functional group transformations involving the 5-cyano group of 4 furnished the 5-carboxamide derivatives 5a−l and the 5-thioamide analogs 6a−l. A similar transformation of the aglycone of toyocamycin (4m) furnished the corresponding aglycone of thiosangivamycin (6m). Several of the new compounds (4−6a−e,j−l) were evaluated for their ability to inhibit the growth of L1210 murine leukemic cells. Whereas a number of the carboxamide (5) and thioamide (6) derivatives had modest activity, the corresponding nitrile analogs (4) were all inactive. All compounds were tested for activity against HCMV and HSV-1. The non-nucleoside nitrile analogs 4a−m and carboxamide derivatives 5a−l were, with a few exceptions, essentially inactive against HCMV and HSV-1 and relatively nontoxic. In direct contrast, nearly all of the thioamide derivatives 6a−l, including the aglycone of thiosangivamycin (6m), were good inhibitors of HCMV and HSV-1. Most were noncytotoxic in their antiviral concentration range. Cytotoxicity which was observed appeared to be a consequence of DNA synthesis inhibition. Several of these compounds, such as 6b,e, were particularly interesting inhibitors of HCMV with IC50's ranging from 0.1 to 1.3 μM. The antiviral activity of both compounds was well separated from cytotoxicity in KB, HFF, and L1210 cells.