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).
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.
Satyanarayana
Mavurapu
M
Department of Pharmaceutical Chemistry, Rutgers, Ernest Mario School of Pharmacy, The State University of New Jersey, Piscataway, NJ 08854-8020, USA.
Feng
Wei
W
Cheng
Liang
L
Liu
Angela A
AA
Tsai
Yuan-Chin
YC
Liu
Leroy F
LF
LaVoie
Edmond J
EJ
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D059004:Topoisomerase I Inhibitors