LaVoie, E.J.

Li, T.K

Lia, D.

Liu, A.

Liu, L.F.

Sim, S.P

Zhao, B.

Unimas Institutional Repository

 Bioorganic & Medicinal Chemistry Volume 11, Issue 4, 20 February 2003, Pages 521–528  2,3-Dimethoxybenzo[i]phenanthridines: topoisomerase I-targeting anticancer agents  Dajie Lia,   Baoping Zhaoa,   Sai-Peng Simb,   Tsai-Kun Lib,   Angela Liub,   Leroy F Liub, c,   Edmond J LaVoiea, c, , ,   a Department of Pharmaceutical Chemistry, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA  b Department of Pharmacology, The University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA  c The Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA  Abstract Appropriately substituted benzo[i]phenanthridines structurally related to nitidine, a benzo[c]phenanthridine alkaloid with antitumor activity, are active as topoisomerase I-targeting agents. Studies on benzo[i]phenanthridines have indicated analogues that possess a 2,3-methylenedioxy moiety and at least one and preferably two methoxyl groups at the 8- and 9-positions, such as 8,9-dimethoxy-2,3-methylenedioxybenzo[i]phenanthridine, 2, are active as topoisomerase I-targeting agents. Tetramethoxylated benzo[i]phenanthridines, wherein the 2,3-methylenedioxy moiety is replaced with methoxyl groups at the 2- and 3-position, are inactive as a topoisomerase I-targeting agent. These results initially suggested that the 2,3-methylenedioxy moiety was critical to the retention of potent activity. Further studies revealed that 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine, 7a, is more potent than 2as a topoisomerase I-targeting agent. The observation that 2,3-dimethoxylated benzo[i]phenanthridines can actually exhibit enhanced activity prompted the present study in which several 8-substituted 2,3-dimethoxybenzo[i]phenanthridines were prepared and their pharmacological activities evaluated. The influence of NH2, CN, CH2OH, OBn, OCH3, OH, and NHCOCH3 substituents at the 8-position on the relative activity of these 2,3-dimethoxybenzo[i]phenanthridines was examined. Relative to these derivatives, 7a was the most potent topoisomerase I-targeting agent, possessing similar cytotoxicity to that of nitidine in the human lymphoblast tumor cell line, RPMI8402.  

2,3-Dimethoxybenzo[i]phenanthridines_ topoisomerase I-targeting anticancer agents

http://ir.unimas.my/id/eprint/2197/1/2%2C3-Dimethoxybenzo%5Bi%5Dphenanthridines%20topoisomerase%20I-targeting%20anticancer%20agents.pdf

2,3-Dimethoxybenzo[i]phenanthridines_ topoisomerase I-targeting anticancer agents

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