ctc-[Pt(NH3)(2)(cinnamate)(valproate)Cl-2] is a highly potent and low-toxic triple action anticancer prodrug

作者全名："Li, Yang; Shi, Shan; Zhang, Shurong; Gan, Zongjie; Wang, Xin; Zhao, Xudong; Zhu, Yijian; Cao, Meiting; Wang, Xiaoyue; Li, Wei"

作者地址："[Li, Yang; Shi, Shan; Zhang, Shurong; Gan, Zongjie; Wang, Xin; Zhao, Xudong; Zhu, Yijian; Cao, Meiting; Wang, Xiaoyue; Li, Wei] Chongqing Med Univ, Sch Pharm, Dept Med Chem, Chongqing 400016, Peoples R China; [Li, Yang; Shi, Shan; Zhang, Shurong; Gan, Zongjie; Li, Wei] Chongqing Med Univ, Chongqing Res Ctr Pharmaceut Engn, Chongqing 400016, Peoples R China"

通信作者："Li, W (corresponding author), Chongqing Med Univ, Sch Pharm, Dept Med Chem, Chongqing 400016, Peoples R China.; Li, W (corresponding author), Chongqing Med Univ, Chongqing Res Ctr Pharmaceut Engn, Chongqing 400016, Peoples R China."

来源：DALTON TRANSACTIONS

ESI学科分类：CHEMISTRY

WOS号：WOS:000680102000001

JCR分区：Q1

影响因子：4

年份：2021

卷号：50

期号：32

开始页：11180

结束页：11188

文献类型：Article

关键词：　

摘要："Pt(iv) prodrugs have gained tremendous attention due to their indisputable advantages compared to cisplatin. Herein, new Pt(iv) derivatives with cinnamic acid at the first axial position, and inhibitor of matrix metalloproteinases-2 and -9, histone deacetylase, cyclooxygenase or pyruvate dehydrogenase at the second axial position are constructed to develop multi-action prodrugs. We demonstrate that Pt(iv) prodrugs are reducible and have superior antiproliferative activity with IC50 values at submicromolar concentrations. Notably, Pt(iv) prodrugs exhibit highly potent anti-tumour activity in an in vivo breast cancer model. Our results support the view that a triple-action Pt(iv) prodrug acts via a synergistic mechanism, which involves the effects of CDDP and the effects of axial moieties, thus jointly leading to the death of tumour cells. These findings provide a practical strategy for the rational design of more effective Pt(iv) prodrugs to efficiently kill tumour cells by enhancing their cellular accumulation and tuning their canonical mechanism."

基金机构："Chongqing Municipality Education Commission [KJ1400212]; Municipal Science and Technology Committee of Chongqing [CSTC2014jcyjA0019]; School of Pharmacy, Chongqing Medical University"

基金资助正文："This work was supported by the Chongqing Municipality Education Commission (KJ1400212), the Municipal Science and Technology Committee of Chongqing (CSTC2014jcyjA0019), and the School of Pharmacy, Chongqing Medical University."