A non-cross-linking platinum-acridine agent with potent activity in non-small-cell lung cancer

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.