A Non-Cross-Linking Platinum−Acridine Agent with Potent Activity in Non-Small-Cell Lung Cancer

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• 作者：Zhidong Ma ; Jayati Roy Choudhury ; Marcus W. Wright ; Cynthia S. Day ; Gilda Saluta ; Gregory L. Kucera ; Ulrich Bierbach
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：December 11, 2008
• 年：2008
• 卷：51
• 期：23
• 页码：7574-7580
• 全文大小：231K
• 年卷期：v.51,no.23(December 11, 2008)
• ISSN：1520-4804

文摘

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 IC₅₀ 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.