Analogs of the marine alkaloid makaluvamines: Synthesis, topoisomerase II inhibition, and anticancer activity

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 10; pp. 2890 - 2893
• Main Authors: Shinkre, Bidhan A., Raisch, Kevin P., Fan, Liming, Velu, Sadanandan E.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.05.2007; Elsevier
• Subjects: Alkaloids - chemistry; Alkaloids - pharmacology; Amsacrine - chemistry; Amsacrine - pharmacology; Analog; Animals; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Drug Design; Drug Screening Assays, Antitumor; General aspects; HCT-116; Humans; Makaluvamine; Marine Biology; MCF-7; MDA-MB-468; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Pyrroles - chemistry; Pyrroles - pharmacology; Quinolones - chemistry; Quinolones - pharmacology; Structure-Activity Relationship; Topoisomerase II; Topoisomerase II Inhibitors; Tumor Cells, Cultured; HCT-116; MDA-MB-468; Makaluvamine; Analog; MCF-7; Topoisomerase II; Antineoplastic agent; Organic cation; Halophenols; Nitrogen heterocycle; Cytotoxicity; Alkaloid; Isomerases; Structure activity relation; Bicyclic compound; MDA-MB-4- 68; Bromine Organic compounds; Aromatic compound; Colon; Mammary gland; Chemical synthesis; Tumor cell; Human; DNA topoisomerase (ATP-hydrolysing); Sulfonamide; Enzyme; Iminium compounds; Benzene derivatives; Enzyme inhibitor; Tricyclic compound; In vitro; Cell line; Phenols; Indole derivatives
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.02.065

Synthesis, topoisomerase II inhibition, and anticancer activities of makaluvamine analogs are presented. Twelve analogs of makaluvamines have been synthesized. These compounds were evaluated for their ability to inhibit the enzyme topoisomerase II. Five compounds were shown to inhibit topoisomerase catalytic activity comparable to two known topoisomerase II targeting control drugs, etoposide and m-AMSA. Their cytotoxicity against human colon cancer cell line HCT-116 and human breast cancer cell lines MCF-7 and MDA-MB-468 has been evaluated. Four makaluvamine analogs exhibited better IC 50 values against HCT-116 as compared to control drug etoposide. One analog exhibited better IC 50 value against HCT-116 as compared to m-AMSA. All 12 of the makaluvamine analogs exhibited better IC 50 values against MCF-7 and MDA-MB-468 as compared to etoposide as well as m-AMSA.