Jiang Jia, Cao Bei, Chen Yuting, Luo Hejiang, Xue Jiaying, Xiong Xiaolin, Zou Taotao
Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, P. R. China.
Warshel Institute for Computational Biology, and General Education Division, The Chinese University of Hong Kong, Shenzhen, 518172, P. R. China.
Angew Chem Int Ed Engl. 2022 Apr 11;61(16):e202201103. doi: 10.1002/anie.202201103. Epub 2022 Feb 21.
Spatiotemporally controllable activation of prodrugs within tumors is highly desirable for cancer therapy to minimize toxic side effects. Herein we report that stable alkylgold(III) complexes can undergo unprecedented photo-induced β-hydride elimination, releasing alkyl ligands and forming gold(III)-hydride intermediates that could be quickly converted into bioactive [Au -S] adducts; meanwhile, the remaining alkylgold(III) complexes can photo-catalytically reduce [Au -S] into more bioactive Au species. Such photo-reactivities make it possible to functionalize gold complexes on the auxiliary alkyl ligands without attenuating the metal-biomacromolecule interactions. As a result, the gold(III) complexes containing glucose-functionalized alkyl ligands displayed efficient and tumor-selective uptake; notably, after one- or two-photon activation, the complexes exhibited high thioredoxin reductase (TrxR) inhibition, potent cytotoxicity, and strong antiangiogenesis and antitumor activities in vivo.
在肿瘤内对前药进行时空可控激活对于癌症治疗以最小化毒副作用是非常理想的。在此我们报道，稳定的烷基金（III）配合物可经历前所未有的光诱导β-氢消除反应，释放烷基配体并形成金（III）-氢化物中间体，该中间体可迅速转化为生物活性的[Au -S]加合物；同时，剩余的烷基金（III）配合物可光催化将[Au -S]还原为更具生物活性的金物种。这种光反应性使得在不减弱金属-生物大分子相互作用的情况下，能够在辅助烷基配体上对金配合物进行功能化。结果，含有葡萄糖功能化烷基配体的金（III）配合物表现出高效且肿瘤选择性摄取；值得注意的是，在单光子或双光子激活后，这些配合物在体内表现出高硫氧还蛋白还原酶（TrxR）抑制、强效细胞毒性以及强大的抗血管生成和抗肿瘤活性。
