化学
吡啶
钌
联吡啶
配体(生物化学)
激发态
电子转移
亲脂性
立体化学
光化学
药物化学
结晶学
受体
催化作用
有机化学
晶体结构
生物化学
物理
核物理学
作者
Lindsey Paul,Khuslen Enkhbold,Sydney Robinson,Than Than Aye,Chung Yh,Daniel J. Harrison,Julie A. Pollock,Michael Norris
标识
DOI:10.1016/j.jinorgbio.2022.111930
摘要
Photoactivated chemotherapy (PACT) has emerged as a promising strategy to selectively target cancer cells by using light irradiation to generate cytotoxic complexes in situ through a mechanism involving ligand-loss. Due to their rich optical properties and excited state chemistry, Ru polypyridyl complexes have attracted significant attention for PACT. However, studying PACT is complicated by the fact that many of these Ru complexes can also undergo excited-state electron transfer to generate 1 O 2 species. In order to deconvolute the biological roles of possible photo-decomposition products without the added complication of excited-state electron transfer chemistry, we have developed a methodology to systematically investigate each product individually, and assess the structure-function relationship. Here, we synthesized a series of eight distinct Ru polypyridyl complexes: Ru-Xa ([Ru(NN) 3 ] 2+ ), Ru-Xb ([Ru(NN) 2 py 2 ] 2+ ), and Ru-Xc ([Ru(NN)(OH 2 ) 2 ] 2+ ) where NN = 2,2′-bipyridine, 4,4′-dimethyl-2,2′-bipyridine, or dimethyl 2,2′-bipyridine-4,4′-dicarboxylate and py = pyridine. The cytotoxicity of these complexes was investigated in two cell lines amenable to PACT: H23 (breast cancer) and T47D (lung cancer). We confirmed that light irradiation of Ru-Xa and Ru-Xb complexes generate Ru-Xc complexes through UV–visible spectroscopy, and observed that the Ru-Xc complexes are the most toxic against the cancer cell lines. In addition, we have shown that ligand release and biological activity including bovine serum albumin (BSA) binding, lipophilicity, and DNA interaction are altered when different groups are appended to the bipyridine ligands. We believe that the methodology presented here will enhance the development of more potent and selective PACT agents moving forward. Light-initiated ligand loss in Ru polypyridyl complexes can lead to several degradants which have been proposed as cytotoxic agents in cancer therapies. We test these degradants to gain insight into which are cytotoxic, and how systematic structural changes influence their properties. • Photo-degradants independently synthesized and tested for cytotoxicity. • Ru fragments show toxicity towards lung and breast cancer cells. • Ligand release and biological activity altered by functional groups of ligands. • Protocol decouples light-induced effects from chemical toxicity of degradants.
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