Novel platinum(IV) complexes conjugated with a wogonin derivative as multi-targeted anticancer agents
Novel platinum(IV) complexes conjugated with a wogonin derivative as multi-targeted anticancer agents
复制标题
与汉黄芩素衍生物缀合的新型铂（IV）络合物作为多靶点抗癌剂
DOI：
10.1016/j.bmc.2017.03.007
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发表时间：
2017
影响因子：
3.5
通讯作者：
Gou Shaohua
中科院分区：
文献类型：
--
作者：
Qin Xiaodong;Xu Gang;Chen Feihong;Fang Lei;Gou Shaohua
铂类化合物如顺铂和奥沙利铂是临床上的主流化疗方案。汉黄素是一种具有广泛生物活性的天然产物，目前正处于中国抗癌药物的I期临床试验阶段。本文报道了一系列新颖的铂(IV)配合物，它们通过连接基将汉黄藤素衍生物(化合物3)连接到轴向位置。在与铂(IV)络合物连接后，汉黄连甲素衍生物提供了多种抗癌作用，特别是在化合物10中，这是一种含有汉黄连甲素和顺铂单元的融合。化合物10不仅继承了顺铂的遗传毒性，而且从汉黄连素衍生物中获得了环氧合酶抑制活性。进一步的机制研究表明，化合物10引起ROS积聚，降低线粒体膜电位(ΔΨm)，进而激活P53途径。总体而言，研究表明，“一体化”前药可以成为一种有效的策略，以促进铂为基础的药物治疗癌症的抗癌效力。
Platinum-based complexes like cisplatin and oxaliplatin are well known the mainstay of chemotherapy regimens on clinic. Wogonin, a natural product that possesses wide biological activities, is now in phase I clinical test as an anticancer agent in China. Herein reported are a series of novel Pt(IV) complexes that conjugated a wogonin derivative (compound3) to the axial position via a linker group. After being tethered to the platinum(IV) complexes, the wogonin derivative provided multiple anticancer effects, especially in compound10, a fusion containing wogonin and cisplatin units. Compound10not only inherited the genotoxicity from cisplatin, but also obtained the COX inhibitory property from the wogonin derivative. Further mechanistic investigation revealed that compound10caused the accumulation of ROS, decreased the mitochondrial membrane potential (ΔΨm) and then activated the p53 pathway. Overall, the research demonstrates that the “integrative” prodrug can be an effective strategy to promote the anticancer potency of Pt-based drugs for cancer treatment.