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 tested for their activity against human cytomegalovirus (HCMV). The nucleosides 2'-deoxytoyocamycin (1), xylo-toyocamycin (2), 3'-deoxytoyocamycin (3), 2',3'-dideoxy-2',3'-didehydrotoyocamycin (4), 2',3'-dideoxytoyocamycin (5), ara-toyocamycin (6), 2'-deoxy-2'-amino-ara-toyocamycin (7), and 5'-deoxytoyocamycin (8) were treated with sodium hydrogen sulfide generated in situ to afford the corresponding thiosangivamycin analogs (9-16). The cyano derivatives 1-8 were synthesized by modifications of literature procedures. All of the thioamide derivatives (9-16) were active against HCMV with IC50's ranging from 0.5 to 6 microM. Most also were active against herpes simplex virus type 1 (HSV-1) but at higher concentrations. The antiviral activity was not completely separated from cytotoxicity in two human cell lines. The antiproliferative activity was strongly influenced by the position of the modification on the carbohydrate moiety. The xylosyl and 3'-deoxy derivatives were significantly more potent than those with modifications at the 2', 5', or 2',3' position(s). Interestingly, 5'-deoxythiosangivamycin (16) possessed both antiviral and antiproliferative activity suggesting that phosphorylation of the 5'-hydroxyl may not be required for these compounds to have biological activity.
Krawczyk
S H
SH
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109-1065, USA.
Renau
T E
TE
Nassiri
M R
MR
Westerman
A C
AC
Wotring
L L
LL
Drach
J C
JC
Townsend
L B
LB
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects*; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D013329:Structure-Activity Relationship; D013872:Thionucleosides / Q000138:chemical synthesis* / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D000998:Antiviral Agents; D013872:Thionucleosides; C023564:thiosangivamycin