title: A non-cross-linking platinum-acridine agent with potent activity in non-small-cell lung cancer.
abstract: The cytotoxic complex, [PtCl(Am)2(ACRAMTU)](NO3)2 (1) ((Am)2 = ethane-1,2-diamine, en; ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea), is a dual platinating/intercalating DNA binder that, unlike clinical platinum agents, does not induce DNA cross-links. Here, we demonstrate that substitution of the thiourea with an amidine group leads to greatly enhanced cytotoxicity in H460 non-small-cell lung cancer (NSCLC) in vitro and in vivo. Two complexes were synthesized: 4a (Am2 = en) and 4b (Am = NH3), in which N-[2-(acridin-9-ylamino)ethyl]-N-methylpropionamidine replaces ACRAMTU. Complex 4a proves to be a more efficient DNA binder than complex 1 and induces adducts in sequences not targeted by the prototype. Complexes 4a and 4b induce H460 cell kill with IC(50) values of 28 and 26 nM, respectively, and 4b slows tumor growth in a H460 mouse xenograft study by 40% when administered at a dose of 0.5 mg/kg. Compound 4b is the first non-cross-linking platinum agent endowed with promising activity in NSCLC.
authors.affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, USA.
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Ma
authors.forename: Jayati Roy
authors.initials: JR
authors.lastname: Choudhury
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Wright
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Day
authors.forename: Gilda
authors.initials: G
authors.lastname: Saluta
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Kucera
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bierbach
mesh_terms: D000166:Acridines / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004247:DNA / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010984:Platinum / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C539553:chloro((1-(2-acridin-9-ylamino)ethyl)-1,3-dimethylthiourea)(ethane-1,2-diamine)platinum(II); D010984:Platinum; D004247:DNA; C114062:BBR 3464