Optimization of Antiproliferative Properties of Triimine Copper(II) Complexes

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL Journal of Medicinal Chemistry Pub Date : 2024-11-04 DOI:10.1021/acs.jmedchem.4c0180610.1021/acs.jmedchem.4c01806

Katarzyna Choroba, Bartosz Zowiślok, Sławomir Kula, Barbara Machura, Anna M. Maroń*, Karol Erfurt, Cristiana Marques, Sandra Cordeiro, Pedro V. Baptista and Alexandra R. Fernandes*,

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Abstract

Cu(II) complexes with 2,2′:6′,2″-terpyridines (terpy) and 2,6-bis(thiazol-2-yl)pyridines (dtpy) with 1- or 2-naphtyl and methoxy-naphtyl were synthesized to elucidate the impact of the triimine core, naphtyl linking mode, and presence of methoxy groups on the antiproliferative activity of [CuCl₂(Lⁿ)]. Their antiproliferative effect was analyzed in ovarian (A2780) and colorectal (HCT116) carcinomas and colorectal carcinoma resistant to doxorubicin (HCT116-DoxR) cell lines and in normal human fibroblasts. Among all complexes, the 1- and 2-naphtyl substituted terpy Cu(II) complexes (Cu1a and Cu1b) showed the strongest cytotoxicity, namely, in HCT116-DoxR 2Dcells and were also capable of inducing the loss of cell viability in 3D HCT116-DoxR spheroids. Their intracellular localization, capability to increase reactive oxygen species (ROS), and interaction with DNA (nonintercalative mode) trigger oxidative DNA cleavage leading to cell death by apoptosis and autophagy. Cu1a and Cu1b do not show in vivo toxicity in a chicken embryo and can interact with bovine serum albumin (BSA).

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优化三亚胺铜(II)配合物的抗增殖特性

研究人员合成了 2,2′:6′,2″-三吡啶（terpy）和 2,6-双（噻唑-2-基）吡啶（dtpy）与 1 或 2-萘基和甲氧基-萘基的 Cu(II) 配合物，以阐明三亚甲基核心、萘基连接方式和甲氧基的存在对 [CuCl2(Ln)] 抗增殖活性的影响。研究分析了它们在卵巢癌（A2780）、结直肠癌（HCT116）、对多柔比星耐药的结直肠癌（HCT116-DoxR）细胞系以及正常人成纤维细胞中的抗增殖作用。在所有复合物中，1-萘基和 2-萘基取代的萜铜(II)复合物（Cu1a 和 Cu1b）在 HCT116-DoxR 2D 细胞中显示出最强的细胞毒性，在三维 HCT116-DoxR 球体内也能诱导细胞丧失活力。它们在细胞内的定位、增加活性氧（ROS）的能力以及与 DNA 的相互作用（非交联模式）会引发 DNA 氧化裂解，导致细胞凋亡和自噬。Cu1a 和 Cu1b 对鸡胚胎没有体内毒性，并能与牛血清白蛋白（BSA）相互作用。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.