研究动态
Articles below are published ahead of final publication in an issue. Please cite articles in the following format: authors, (year), title, journal, DOI.

手性SPINOL基Pt(II)金属环对免疫原性细胞凋亡的影响。

Chiral SPINOL-Based Pt(II) Metallacycles For Immunogenic Cell Death.

发表日期:2023 Sep 06
作者: Lu Zhu, Wenjing Du, Yanrong Li, Ding Li, Wei Wei, Jing Zhao, Xiuxiu Wang
来源: BIOMEDICINE & PHARMACOTHERAPY

摘要:

手性的Pt(II)金属有机络合物在非线性光学和手性催化等领域具有独特的潜力。然而,手性的Pt(II)金属环在生物反应中的研究仍然相对不足。在本研究中,我们设计并合成了两种手性的Pt(II)金属环1和2,通过手性的1,1'-螺环辛二醚-7,7'-二醇 (SPINOL)衍生配体和顺式-Pt(PEt3)2(OTf)2 (90°Pt)的配位驱动自组装反应得到。通过1H NMR、31P{1H} NMR、ESI-TOF-MS和X射线晶体学对其结构进行了详细表征,并利用紫外-可见吸收光谱、荧光光谱和圆二色性 (CD) 光谱研究了其光物理性质。然后,我们进一步测试了这两种手性金属环在体外的抗肿瘤活性。金属环1和2表现出强烈的细胞毒性,尤其对A549细胞。金属环1和2通过破坏线粒体功能、抑制谷胱甘肽 (GSH)/谷胱甘肽二硫化物 (GSSG)水平和失活超氧化物歧化酶 (SOD)导致活性氧 (ROS)的大量积累。过高的ROS进而触发细胞凋亡,细胞损伤相关分子样式 (DAMPs)的释放进一步诱导免疫原性细胞死亡 (ICD)。据我们所知,这是首个能够诱导免疫原性细胞死亡的Pt(II)金属环的实例,为未来癌症治疗中免疫调节型铂系药物的设计和构建提供了新的策略。
The incorporation of chirality endows Pt(II)-based metal-organic complexes (MOCs) with unique potentials in several fields such as nonlinear optics and chiral catalysis. However, the exploration of chiral Pt(II) metallacycles in biological responses remains underdeveloped. Herein, we designed and synthesized two chiral Pt(II) metallacycles 1 and 2 via the coordination-driven self-assembly of chiral 1,1'-spirobiindane-7,7'-diol (SPINOL)-derived ligands and cis-Pt(PEt3)2(OTf)2 (90°Pt). Their structures were well characterized by 1H NMR, 31P{1H} NMR, ESI-TOF-MS, and X-ray crystallography, and their photophysical properties were investigated by UV-vis absorption, fluorescence, and circular dichroism (CD) spectroscopies. Then, the antitumor activity of the two chiral metallacycles in vitro was further tested. Complexes 1 and 2 exhibited strong cytotoxicity, especially toward the A549 cells. The destruction of the mitochondrial function, the inhibition of the glutathione (GSH)/glutathione disulfide (GSSG) level, and the inactivation of superoxide dismutase (SOD) induced by complexes 1 and 2 led to the massive accumulation of reactive oxygen species (ROS). The overloaded ROS then triggered apoptotic cell death, and the release of damage-associated molecular patterns (DAMPs) further induced immunogenic cell death (ICD). To the best of our knowledge, this is the first example of Pt(II)-based metallacycles that can induce immunogenic cell death, providing a new strategy for the future design and construction of immune-modulating platinum agents in cancer therapy.