title: Diaza- and triazachrysenes: potent topoisomerase-targeting agents with exceptional antitumor activity against the human tumor xenograft, MDA-MB-435.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8020, USA.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Ruchelman
authors.forename: Sudhir K
authors.initials: SK
authors.lastname: Singh
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wu
authors.forename: Abhijit
authors.initials: A
authors.lastname: Ray
authors.forename: Jin-Ming
authors.initials: JM
authors.lastname: Yang
authors.forename: Tsai-Kun
authors.initials: TK
authors.lastname: Li
authors.forename: Angela
authors.initials: A
authors.lastname: Liu
authors.forename: Leroy F
authors.initials: LF
authors.lastname: Liu
authors.forename: Edmond J
authors.initials: EJ
authors.lastname: LaVoie
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D001372:Aza Compounds; D002911:Chrysenes; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D004247:DNA