Antitumor agents 294. Novel E-ring-modified camptothecin–4β-anilino-4′-O-demethylepipodophyllotoxin conjugates as DNA topoisomerase I inhibitors and cytotoxic agents

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 14; pp. 4489 - 4494
• Main Authors: Ye, Deyong, Shi, Qian, Leung, Chung-Hang, Kim, Seung-Whan, Park, Shin-Young, Gullen, Elizabeth A., Jiang, Zao Li, Zhu, Hao, Morris-Natschke, Susan L., Cheng, Yung-Chi, Lee, Kuo-Hsiung
• Format: Journal Article
• Language: English
• Published: 19.05.2012
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.05.030

Two conjugates ( 1 and 2 ) of camptothecin (CPT) and 4β-anilino-4′- O -demethylepipodophyllotoxin were previously shown to exert antitumor activity through inhibition of topoisomerase I (topo I). In this current study, two novel conjugates ( 1E and 2E ) with an open E-ring in the CPT moiety were first synthesized and evaluated for biological activity in comparison with their intact E-ring congeners. This novel class of CPT derivatives exhibits its antitumor effect against CPT-sensitive and -resistant cells, in part, by inhibiting topo I-linked DNA (TLD) religation. An intact E-ring was not essential for the inhibition of TLD religation, although conjugates with an open E-ring were less potent than the closed ring analogs. This lower religation potency resulted in decreased formation of protein-linked DNA breaks (PLDBs), and hence, less cell growth inhibition. In addition to their impact on topo I, conjugates 1E , 2 , and 2E exhibited a minor inhibitory effect on topo II-induced DNA cleavage. The novel structures of 1E and 2E may present scaffolds for further development of dual function topo I and II inhibitors with improved pharmacological profiles and physicochemical properties.