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 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.
Renau
T E
TE
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109-1065, USA.
Kennedy
C
C
Ptak
R G
RG
Breitenbach
J M
JM
Drach
J C
JC
Townsend
L B
LB
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013872:Thionucleosides / Q000138:chemical synthesis*; D014127:Toyocamycin / Q000138:chemical synthesis*
D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides; D011743:Pyrimidines; D013872:Thionucleosides; C005699:sangivamycin; C023564:thiosangivamycin; D014127:Toyocamycin