Indenoindolone derivatives as topoisomerase II–inhibiting anticancer agents Maneesh Kashyap a , Somnath Kandekar a , Ashish T. Baviskar b , Dipon Das c , Ranjan Preet c , Purusottam Mohapatra c , Shakti Ranjan Satapathy c , Sumit Siddharth c , Sankar K. Guchhait a,⇑ , Chanakya N. Kundu c,⇑ , Uttam C. Banerjee b a Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab 160062, India b Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab 160062, India c School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Odisha 751024, India article info Article history: Received 14 September 2012 Revised 5 December 2012 Accepted 20 December 2012 Available online 3 January 2013 Keywords: Indenoindolone (Thio)semicarbazone Oxime Topoisomerase II Anticancer agent abstract Based on known heterocyclic topoisomerase II inhibitors and anticancer agents, various indenoindolone derivatives were predicted as potential topoisomerase II–inhibiting anticancer agents. They are hydra- zones, (thio)semicarbazones, and oximes of indenoindolones, and indenoindolols. These derivatives with suitable substitutions exhibited potent specific inhibition of human DNA TopoIIa while not showing inhi- bition 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 enhance- ment of anticancer activities. Ó 2012 Elsevier Ltd. All rights reserved. Topoisomerase II plays key role in transcription, replication, and chromosome segregation. This enzyme maintains topological changes of DNA by creating double-stranded DNA breaks and pas- sage of a second double-stranded DNA through the transiently bro- ken duplex. 1 Its b isozyme expresses almost constant and at relatively low level throughout the cell cycle. However, the expres- sion of a isozyme increases throughout S phase and peaks with 2- to 3-fold at G2/M phase of mitosis. The concentration of a isozyme is even higher in rapidly proliferating tissues than in quiescent cell populations. 2 Some of antitumoral drugs that target topoisomerase II are doxorubicin and daunorubicin (anthracycline class), etopo- side and teniposide (epipodophyllotoxin class), mitoxantrone, amonafide, and amsacrine. 3 Topoisomerase II has been recognized as an important target in anticancer drug discovery 4 and the devel- opment of its novel inhibitors is recently emerging. 5 Recently, we developed N-fused imidazole as topoisomerase II-targeting novel anticancer agents. 6 Towards development of novel anticancer agents, the structural modification/hybridization of known natural/synthetic target-spe- cific anticancer agents is a valuable approach. 7 Certain moieties such as functional side chains or monocyclic rings when attached to the key scaffold are known to enhance potency in inhibition of topoiso- merase II. They act as minor groove binders to DNA and prevent it to be available in suitable geometry for binding with topoisomerase II. These moieties can also directly bind to topoisomerase II. The pres- ence of such moieties have led to the development of novel thera- peutic agents in the form of derivatives of original scaffolds. 8 These derivatizations improve pharmacodyanamic as well as phar- macokinetic properties. 8c-e Mitoxantrone, which acts as a topoiso- merase II poison, on derivatization with incorporation of extended alkylamine shows its enhanced DNA-binding affinity. 8f The thio- semicarbazone derivatives of a-hererocyclic carboxaldehyde inhibit catalytic activity of topoisomerase IIa. 2-Benzoxazolylhydrazones have been found to be potent anticancer agents. 8g,h Compared to b-lapachone, its 7-hydroxy derivative have been found to possess higher antiproliferating activity in human solid tumor cell lines. 8i As a part of our research on anticancer drug discovery, we have recently explored that indenoindolones possess anticancer activi- ties. 9 Based on the relevance of side chains/moieties towards enhancement of the topoisomerase II-inhibitory and anticancer activities; we considered various indenoindolone derivatives as potential topoisomerase II–inhibiting anticancer agents (Fig. 1). In this Letter, we present relevant indenoindolone derivatives (hydrazones, (thio)semicarbazones, and oximes of indenoindol- ones, and indenoindolols) as potent topoisomerase II–inhibiting 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2012.12.063 ⇑ Corresponding authors. Tel.: +91 (0)172 2214683; fax: +91 (0)172 2214692 (S.K.G.); tel.: +91 (0)674 272 5466; fax: +91 (0)674 272 5732 (C.N.K.). E-mail addresses: skguchhait@niper.ac.in (S.K. Guchhait), cnkundu@gmail.com (C.N. Kundu). Bioorganic & Medicinal Chemistry Letters 23 (2013) 934–938 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl