GSK Carbon Neutral Laboratories for Sustainable Chemistry, University of Nottingham, Triumph Road, Nottingham NG7 2TU, U.K.
Department of Chemistry, College of Science, University of Anbar, Anbarshire 31001, Iraq.
J Med Chem. 2024 Feb 22;67(4):2732-2744. doi: 10.1021/acs.jmedchem.3c01874. Epub 2024 Feb 8.
The need for anticancer therapies that overcome metallodrug resistance while minimizing adverse toxicities is targeted, herein, using titanium coordination complexes. Octahedral titanium(IV) ,-[Ti{RN(CH-2-MeO-4-R-CH)}] [R = Et, allyl, -Pr, CHO, F, CH(morpholino), the latter from the formyl derivative; R = Me, Et; not all combinations] are attained from Mannich reactions of commercial 2-methoxyphenols (27-74% overall yield, 2 steps). These crystalline (four X-ray structures) Ti(IV)-complexes are active against MCF-7, HCT-116, HT-29, PANC-1, and MDA-MB-468 cancer cell lines (GI = 0.5-38 μM). Their activity and cancer selectivity (vs nontumor MRC-5 cells) typically exceeds that of cisplatin (up to 16-fold). Proteomic analysis (in MCF-7) supported by other studies (G2/M cell cycle arrest, ROS generation, γH2AX production, caspase activation, annexin positivity, western blot, and kinase screens in MCF-7 and HCT-116) suggest apoptosis elicited by more than one mechanism of action. Comparison of these data to the modes of action proposed for salan Ti(IV) complexes is made.
需要开发能够克服金属药物耐药性，同时将不良反应毒性最小化的抗癌疗法，本文采用钛配位化合物来实现这一目标。八面体钛（IV），-[Ti{RN(CH-2-MeO-4-R-CH)}] [R = Et、allyl、-Pr、CHO、F、CH(morpholino)，后者来自甲酰基衍生物；R = Me、Et；并非所有组合]通过商业 2-甲氧基苯酚的曼尼希反应获得（总收率 27-74%，两步反应）。这些结晶态的 Ti(IV)-配合物对 MCF-7、HCT-116、HT-29、PANC-1 和 MDA-MB-468 癌细胞系具有活性（GI = 0.5-38 μM）。它们的活性和抗癌选择性（与非肿瘤 MRC-5 细胞相比）通常超过顺铂（高达 16 倍）。蛋白组学分析（在 MCF-7 中）以及其他研究（G2/M 细胞周期停滞、ROS 生成、γH2AX 产生、半胱天冬酶激活、 annexin 阳性、western blot 和 MCF-7 和 HCT-116 中的激酶筛选）表明，凋亡是由多种作用机制引起的。将这些数据与 salan Ti(IV) 配合物的作用模式进行了比较。
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