Diaza- and triazachrysenes: potent topoisomerase-targeting agents with exceptional antitumor activity against the human tumor xenograft, MDA-MB-435.
Several 5,12-diazachrysen-6-ones and 5,6,11-triazachrysen-12-ones were synthesized with varied substituents at the 5- or 11-position, respectively. Each compound was evaluated for its potential to stabilize the cleavable complex formed with TOP1 and DNA. Two analogues with very potent TOP1-targeting activity, 3a and 4a, exhibited cytotoxic activity with IC(50) values at or below 2nM against RPMI8402. Compound 3a was active in vivo by either ip or po administration in the human tumor xenograft athymic nude mice model.
Ruchelman
Alexander L
AL
Department of Pharmaceutical Chemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8020, USA.
Singh
Sudhir K
SK
Wu
Xiaohua
X
Ray
Abhijit
A
Yang
Jin-Ming
JM
Li
Tsai-Kun
TK
Liu
Angela
A
Liu
Leroy F
LF
LaVoie
Edmond J
EJ
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D001372:Aza Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002911:Chrysenes / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D059004:Topoisomerase I Inhibitors; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001372:Aza Compounds; D002911:Chrysenes; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D004247:DNA