Multitarget Thiol-Activated Tetrapyridyl Gold(Ⅲ)Complexes for Hypoxic Cancer Therapy  

作　　者：Xue-Quan Zhou Selda Abyar Imma Carbo-Bague Lan Wang Sebastian Türck Maxime ASiegler Uttara Basu Ingo Ott Rongfang Liu Adriaan PIJzerman Sylvestre Bonnet 

机构地区：[1]Institute of Biopharmaceutical and Health Engineering,Tsinghua Shenzhen International Graduate School(SIGS),Tsinghua University,Shenzhen 518055 [2]Leiden Institute of Chemistry,Leiden University,2333 CC Leiden [3]Department of Chemistry,Simon Fraser University,Burnaby,British Columbia V5A 1S6 [4]Institute of Medicinal and Pharmaceutical Chemistry,Technische Universität Braunschweig,38106 Braunschweig [5]Department of Chemistry,Johns Hopkins University,Baltimore,Maryland 21218 [6]Division of Drug Discovery&Safety,Leiden Academic Centre for Drug Research,Leiden University,2333 CC Leiden

出　　处：《CCS Chemistry》2024年第3期783-797,共15页中国化学会会刊（英文）

基　　金：the China Scholarship Council for a personal financial grant(no.201606200045);supported by the European Research Council via a Starting Grant;Dutch Research Council(NWO)for a VICI grant to S.Bonnet.

摘　　要：Gold complexes have emerged as promising anticancer metallodrugs due to their efficient thioredoxin reductase(TrxR)inhibition,which disturbs the redox balance of cancer cells.However,in this model,the role of the ligand(s)coordinated to gold is often overlooked.In this work,we present a series of tetrapyridyl Au(Ⅲ)complexes that exhibit thiol-induced release of a Au(Ⅰ)ion and a tetrapyridyl ligand.The formation of a free Au(Ⅰ)center is responsible for the expected TrxR inhibition.Additionally,the released ligand,which was visible in cells due to its intense blue fluorescence,showed excellent binding properties to the hERG potassium channel.Moreover,these ligands ended up in the lysosomes,resulting in significant lysosome damage.Altogether,the Au(Ⅲ)complexes presented in this work showed broad-spectrum anticancer properties,both in hypoxic 2D monolayers and 3D tumor spheroids.We suggest that the interaction of the released Au(Ⅰ)center and the tetrapyridyl ligand with two different protein targets may combine into prodrugs that overcome hypoxia-induced drug deactivation.

关 键 词：anticancer Au(Ⅲ)complexes enzyme inhibtion potassium channel affinity lysosome damage cell imaging PRODRUG 

分 类 号：O62[理学—有机化学]