A non-cross-linking platinum-acridine agent with potent activity in non-small-cell lung cancer.
A non-cross-linking platinum-acridine agent with potent activity in non-small-cell lung cancer.
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DOI：
10.1021/jm800900g
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发表时间：
2008-12-11
影响因子：
7.3
通讯作者：
Bierbach U
中科院分区：
文献类型：
--
作者：
Ma Z;Choudhury JR;Wright MW;Day CS;Saluta G;Kucera GL;Bierbach U
细胞毒性络合物[PtCL(Am)2(ACRAMTU)](NO3)2(1)((Am)2=乙烷-1，2-二胺，EN；ACRAMTU=1-[2-(acridin-9-ylamino)ethyl]-1，3-dimethylthiourea)，是一种双重的铂/插层脱氧核糖核酸结合剂，与临床用铂类药物不同，它不会引起脱氧核糖核酸的交联。在这里，我们证明了硫脲被酰胺基取代后，在体外和体内对H460非小细胞肺癌(NSCLC)的细胞毒性大大增强。合成了两个配合物：4A(Am2=en)和4b(Am=NH3)，其中N-[2-(acridin-9-ylamino)ethyl]-N-methylpropionamidine取代了ACRAMTU。事实证明，络合物4a是一种比络合物1更有效的DNA结合剂，并在未被原型靶向的序列中诱导加合物。化合物4a和4b诱导H460细胞杀伤，IC50值分别为28和26 nM，4b在0.5 mg/kg剂量下使H460小鼠移植瘤的生长速度减慢40%。化合物4b是第一个在非小细胞肺癌中具有良好活性的非交联型铂试剂。
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.