Synthesis and Biological Activity of Thiazolylindolequinones, Analogs of the Natural Product BE 10988

• Published in: Journal of medicinal chemistry Vol. 38; no. 6; pp. 1039 - 1043
• Main Authors: Moody, Christopher J, Swann, Elizabeth, Houlbrook, Susan, Stephens, Miriam A, Stratford, Ian J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-03-1995
• Subjects: Aerobiosis; Animals; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - drug therapy; Cell Hypoxia; CHO Cells; Cricetinae; Cricetulus; Drug Evaluation, Preclinical; General aspects; HeLa Cells; Humans; Indoles - chemical synthesis; Indoles - pharmacology; Medical sciences; Pharmacology. Drug treatments; Quinones - chemical synthesis; Quinones - pharmacology; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - pharmacology; Topoisomerase II Inhibitors; Tumor Cells, Cultured; Antineoplastic agent; Human; DNA topoisomerase (ATP-hydrolysing); Enzyme; Quinone; Thiazole derivatives; Enzyme inhibitor; Cytotoxicity; In vitro; Mammary gland diseases; Isomerases; Structure activity relation; Established cell line; V79-Cell line; Indole derivatives; Chemical synthesis; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00006a024

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.