Department of Chemistry, City University of Hong Kong, 83 Tat Chee Ave., Kowloon Tong, Hong Kong SAR, P. R. China.
City University of Hong Kong, Shenzhen Research Institute, Shenzhen, P. R. China.
Angew Chem Int Ed Engl. 2018 Jul 16;57(29):9098-9102. doi: 10.1002/anie.201804314. Epub 2018 Jun 14.
Recently, Pt prodrugs have attracted much attention as the next generation of platinum-based antineoplastic drug candidates. Here we report the discovery and evaluation of monochalcoplatin, a monocarboxylated Pt prodrug that is among the most cytotoxic Pt prodrugs to date. Compared with its dicarboxylated counterpart chalcoplatin, monochalcoplatin accumulates astonishingly effectively and rapidly in cancer cells, which is not ascribed to its lipophilicity. The prodrug is quickly reduced, causes DNA damage, and induces apoptosis, resulting in superior cytotoxicity with IC values in the nanomolar range in both cisplatin-sensitive and -resistant cells; these IC values are up to 422-fold higher than that of cisplatin. A detailed mechanistic study reveals that monochalcoplatin actively enters cells through a transporter-mediated process. Moreover, monochalcoplatin shows significant antitumor activity in an in vivo colorectal tumor model. Our study implies a practical strategy for the design of more effective Pt prodrugs to conquer drug resistance by tuning both cellular uptake pathways and activation processes.
最近，Pt 前药作为下一代基于铂的抗肿瘤候选药物引起了广泛关注。在这里，我们报告了单羧酸铂的发现和评估，这是迄今为止最具细胞毒性的 Pt 前药之一。与其二羧酸化的对应物卡铂相比，单羧酸铂在癌细胞中惊人地有效和快速地积累，这并不是因为它的亲脂性。该前药被迅速还原，导致 DNA 损伤并诱导细胞凋亡，导致在顺铂敏感和耐药细胞中具有优异的细胞毒性，IC 值在纳摩尔范围内；这些 IC 值比顺铂高 422 倍。详细的机制研究表明，单羧酸铂通过转运体介导的过程主动进入细胞。此外，单羧酸铂在体内结直肠肿瘤模型中表现出显著的抗肿瘤活性。我们的研究为设计更有效的 Pt 前药提供了一种实用策略，通过调节细胞摄取途径和激活过程来克服耐药性。
