Syntheses and biological evaluation of topoisomerase I-targeting agents related to 11-[2-(N,N-dimethylamino)ethyl]-2,3-dimethoxy-8,9-methylenedioxy-11H-isoquino[4,3-c]cinnolin-12-one (ARC-31)

Bioorg Med Chem. 2008 Aug 15;16(16):7824-31. doi: 10.1016/j.bmc.2008.06.046.

Mavurapu Satyanarayana ¹, Wei Feng, Liang Cheng, Angela A Liu, Yuan-Chin Tsai, Leroy F Liu, Edmond J LaVoie

Affiliations

Affiliation

1 Department of Pharmaceutical Chemistry, Rutgers, Ernest Mario School of Pharmacy, The State University of New Jersey, Piscataway, NJ 08854-8020, USA.

PMID: 18676151 DOI: 10.1016/j.bmc.2008.06.046

Abstract

Several 11-ethyl-2,3-dimethoxy-8,9-methylenedioxy-11H-isoquino[4,3-c]cinnolin-12-ones with varied functionality on the ethyl substituent have exhibited potent Topoisomerase I (TOP1) targeting activity and antitumor activity. The influence of various polar substituents at the 2-position of the 11-ethyl substituent, including N-methylamine, N-isopropylamine, hydroxyl, and hydroxylamino groups, on TOP1-targeting activity and cytotoxicity was assessed. The N-methylamine and N-isopropylamine derivatives were also evaluated as antitumor agents in athymic nude mice with MDA-MB-435 human tumor xenografts. Both compounds were active as antitumor agents upon either parenteral or oral administration.

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