Syntheses and biological activities of rebeccamycin analogues with uncommon sugars.
Rebeccamycin analogues containing uncommon sugars and substitutions on the imide nitrogen have been synthesized. Their cytotoxicities were tested in colon cancer and leukemia cells. Their ability to target topoisomerase I was examined using the in vivo complex of the topoisomerase bioassay in Hela cells. Compared with aglycon 1, the modified compounds with various sugar moieties showed more potent cytotoxicities and topo I targeting ability. In addition, the rebeccamycin analogues with various uncommon sugars showed distinct cytotoxicities and topo I targeting activities. The activity of compounds with 2-deoxyglucose (8 and 9) > compounds with 2,6-deoxyglucose (5 and 6) > compounds with 2,3,6-deoxyglucose (10). Furthermore, the anticancer activity of compounds correlated with their ability to target endogenous topo I. These results suggest that the sugar moiety, especially the 2-OH and 6-OH group of the sugar, rather than the modifications in imide structure on the indolocarbazole ring, is a key element for its activity.
Zhang
Guisheng
G
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, USA.
Shen
Jie
J
Cheng
Hao
H
Zhu
Lizhi
L
Fang
Lanyan
L
Luo
Sanzhong
S
Muller
Mark T
MT
Lee
Gun Eui
GE
Wei
Lijun
L
Du
Yuguo
Y
Sun
Duxin
D
Wang
Peng George
PG
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D002227:Carbazoles; D007211:Indoles; D059004:Topoisomerase I Inhibitors; C053339:rebeccamycin