Text

ETD_825

http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051088

theses

Topoisomerases are ubiquitous enzymes that participate in processes such as DNA replication, transcription and repair. Two camptothecin derivatives, topotecan (Hycamtin®) and irinotican (CPT-11/ Camptosar®), are currently used in the clinic as topoisomerse I targeting anticancer agents. Camptothecins can stabilize the enzyme-DNA cleavage complex, leading to DNA damage and ultimately cell death. Despite their unique tumor suppression mechanism, topotecan and irinotican can undergo hydrolysis and inactivation in vivo due to an unstable lactone moiety. In addition, both topotecan and irinotican are substrates for efflux transporters, BCRP and MDR1, which are associated with drug resistance. 8,9-Dimethoxy-5-(2-dimethylaminoethyl)-2,3-methylenedioxy- 5H-dibenzo[c,h][1,6]naphthyridine-6- one (ARC-111) has been identified as exceptionally active TOP1-targeting agent with potent antitumor activity both in vitro and in vivo. Unlike camptothecins, ARC-111 is not a substrate for major efflux transporters, and does not bind to human serum albumin. ARC-111 structurally related analogs, 12-carboxamides of benzo[i]phenathridine and the "reversed lactams" have also exhibited excellent cytotoxicity and potent TOP1 targeting activity. In this dissertation, further insights into structure-activity relationship of ARC-111 and related compounds have been carefully examined. Alteration of both D-ring and side chain of ARC-111 have afforded potent TOP1-targeting agents. Inspired by the success of ARC-111, the design, synthesis and biological activities of other B-ring modified benzo[i]phenathridines have been systematically investigated. In review of possible metabolites of ARC-111, together with the known structure-activity relationships associated with the "reversed lactams", 11-carboxamides and 12-carboxamides of benzo[i]phenathridine, have prompted the examination of α,α-dimethyl substitution on the amino side chain on pharmacologic activity. Efficient synthetic methods associated with these novel non-camptothecin anticancer agents have also been developed. Several agents identified in this study have demonstrated excellent cancer cell cytotoxicity, TOP1 targeting specificity, as well as in vivo antitumor efficacy, comparable as the lead compound, ARC-111.

Ph.D.

Includes bibliographical references (p. 198-218)

by Wei Feng

doi:10.7282/T3WD40TK

ETD doctoral

The author owns the copyright to this work.

ETD

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