Synthesis and biological activity of thiazolylindolequinones, analogues of the natural product BE 10988.
A number of analogues of the naturally occurring thiazolylindolequinone BE 10988, a reported potent inhibitor of topoisomerase II, have been prepared and evaluated. The compounds were synthesized from 4-(benzyloxy)-5-methoxy-1-methylindole by appropriate substitution at the indole 3-position followed by standard thiazole ring-forming reactions. The toxicity of these potentially bioreductively activated indolequinones was measured in Chinese hamster V79 cells under aerobic and hypoxic conditions. In addition, toxicity was measured in a human breast cancer cell line that shows amplification of the topo II alpha gene and hypersensitivity to known topo II inhibitors such as mAMSA and mitoxantrone. Using a DNA decatenation assay, a comparison was also made of the inhibitory effects of BE 10988 and mitoxantrone on topo II activity.
Moody
C J
CJ
Department of Chemistry, Loughborough University of Technology, Leicestershire, U.K.
Swann
E
E
Houlbrook
S
S
Stephens
M A
MA
Stratford
I J
IJ
D000332:Aerobiosis; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy; D016466:CHO Cells; D015687:Cell Hypoxia; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D011809:Quinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D007211:Indoles; D011809:Quinones; D013844:Thiazoles; D059005:Topoisomerase II Inhibitors; C069638:BE 10988