Synthesis of Non-nucleoside Analogs of Toyocamycin, Sangivamycin, and Thiosangivamycin:  The Effect of Certain 4- and 4,6-Substituents on the Antiviral Activity of Pyrrolo[2,3-d]pyrimidines

A number of 4-substituted 7-(ethoxymethyl)- and 7-[(2-methoxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine-5-carbonitrile and -5-thiocarboxamide derivatives and several 7-substituted 4,6-diaminopyrrolo[2,3-d]pyrimidine-5-carbonitrile, -5-carboxamide, and -5-thiocarboxamide analogs related to the nucleoside...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1996-08, Vol.39 (18), p.3470-3476
Main Authors: Renau, Thomas E, Kennedy, Christopher, Ptak, Roger G, Breitenbach, Julie M, Drach, John C, Townsend, Leroy B
Format: Article
Language:English
Subjects:
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Antiviral Agents - chemical synthesis
Antiviral Agents - pharmacology
Biological and medical sciences
Cytomegalovirus - drug effects
Herpesvirus 1, Human - drug effects
Humans
Medical sciences
Pharmacology. Drug treatments
Pyrimidine Nucleosides - chemical synthesis
Pyrimidines - chemical synthesis
Pyrimidines - pharmacology
Structure-Activity Relationship
Thionucleosides - chemical synthesis
Toyocamycin - chemical synthesis
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Summary:A number of 4-substituted 7-(ethoxymethyl)- and 7-[(2-methoxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine-5-carbonitrile and -5-thiocarboxamide derivatives and several 7-substituted 4,6-diaminopyrrolo[2,3-d]pyrimidine-5-carbonitrile, -5-carboxamide, and -5-thiocarboxamide analogs related to the nucleoside antibiotics toyocamycin and sangivamycin were prepared and tested for activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1). Biologically, modifications at the 4-position were not well tolerated in cell culture, and in almost all cases no activity against HCMV or HSV-1 was observed. Furthermore, none of the compounds inhibited the growth of L1210 murine leukemic cells in vitro. In sharp contrast to the 4-substituted compounds, all of the 4,6-diamino 5-nitrile and the 5-thioamide analogs were active against HCMV, whereas the 5-carboxamides were inactive. The corresponding 4-amino 6-methylamino and 6-dimethylamino 5-nitrile analogs were inactive against HCMV, establishing that an amino group at both C-4 and C-6 is a likely requirement for antiviral activity. Overall, our results demonstrate that an amino group at C-4 and a thioamide moiety at C-5 of a 7-substituted pyrrolo[2,3-d]pyrimidine are essential for activity against HCMV, whereas a 4,6-diamino analog does not necessarily require a thioamide group at C-5 for activity against HCMV.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm950835y