Indenoindolone derivatives as topoisomerase II–inhibiting anticancer agents

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 4; pp. 934 - 938
• Main Authors: Kashyap, Maneesh, Kandekar, Somnath, Baviskar, Ashish T., Das, Dipon, Preet, Ranjan, Mohapatra, Purusottam, Satapathy, Shakti Ranjan, Siddharth, Sumit, Guchhait, Sankar K., Kundu, Chanakya N., Banerjee, Uttam C.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.02.2013; Elsevier
• Subjects: (Thio)semicarbazone; Anticancer agent; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Chemistry; Chemistry, Medicinal; Chemistry, Organic; DNA Topoisomerases, Type II - chemistry; DNA Topoisomerases, Type II - metabolism; Humans; Indenoindolone; Indoles - chemistry; Indoles - pharmacology; Indoles - therapeutic use; Life Sciences & Biomedicine; Models, Molecular; Neoplasms - drug therapy; Neoplasms - enzymology; Oxime; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Topoisomerase II; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; Topoisomerase II Inhibitors - therapeutic use; Indenoindolone; Oxime; Anticancer agent; (Thio)semicarbazone; Topoisomerase II; CELLS; DESIGN; POTENT; ANTITUMOR
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.12.063

Indenoindolones are known poor/moderate inhibitors of topoisomerase II, however, their derivatives as hydrazones, (thio)semicarbazones, and oximes, and indenoindolols with suitable substitutions were found to possess potent specific inhibition of hTopoIIα while not showing inhibition of topoisomerase I and DNA intercalation. These derivatives exhibited enhanced anticancer activities compared to parent indenoindolones, potent activities relative to anticancer drugs etoposide and 5-fluorouracil, and relatively low toxicity to normal cells. Based on known heterocyclic topoisomerase II inhibitors and anticancer agents, various indenoindolone derivatives were predicted as potential topoisomerase II–inhibiting anticancer agents. They are hydrazones, (thio)semicarbazones, and oximes of indenoindolones, and indenoindolols. These derivatives with suitable substitutions exhibited potent specific inhibition of human DNA TopoIIα while not showing inhibition of topoisomerase I and DNA intercalation, despite the fact that parent indenoindolones are known poor/moderate inhibitors of topoisomerase II. The potent topoisomerase II inhibitor indenoindolone derivatives exhibited good anticancer activities compared to etoposide and 5-fluorouracil, and relatively low toxicity to normal cells. These derivatizations of indenoindolones were found to result in enhancement of anticancer activities.