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一类新型金(I)NHC 配合物,对过表达 BCL-2 的多药耐药白血病细胞具有促凋亡和再致敏作用。

A New Class of Gold(I) NHC Complexes with Proapoptotic and Resensitizing Properties towards Multidrug Resistant Leukemia Cells Overexpressing BCL-2.

机构信息

Department of Human Medicine, MSH Medical School Hamburg, Am Kaiserkai 1, 20457 Hamburg, Germany.

Department of Pediatric Hematology/Oncology, Helios Kliniken Schwerin, Wismarsche Str. 393-397, 19055 Schwerin, Germany.

出版信息

J Med Chem. 2024 Sep 12;67(17):15494-15508. doi: 10.1021/acs.jmedchem.4c01117. Epub 2024 Aug 28.

Abstract

From previous studies, it is evident that metal-organic gold(I) complexes have antiproliferative activities. The aim of this study is not only to find new anticancer agents but also to overcome existing cytostatic resistance in cancer cells. The synthesis and medicinal evaluation of two cationic 1,3-disubstituted gold(I) bis-tetrazolylidene complexes and are reported. To determine apoptosis-inducing properties of the complexes, DNA fragmentation was measured using propidium iodide staining followed by flow cytometry. Gold(I) complex targets explicitly malignant cells, effectively inhibiting their growth and selectively inducing apoptosis without signs of necrosis. Even in cells resistant to common treatments such as doxorubicin, it overcomes multidrug resistance and sensitizes existing drug-resistant cells to common cytostatic drugs. It is assumed that gold(I) complex involves the mitochondrial pathway in apoptosis and targets members of the BCL-2 family, enhancing its potential as a therapeutic agent in cancer treatment.

摘要

从先前的研究中可以明显看出,金属有机金(I)配合物具有抗增殖活性。本研究的目的不仅是寻找新的抗癌剂,而且还要克服癌细胞中现有的细胞抑制耐药性。本文报道了两种阳离子 1,3-二取代金(I)双四唑基配合物[Au(btz)(phen)]Cl(1)和[Au(btz)(Me-phen)]Cl(2)的合成和药用评价。为了确定配合物诱导细胞凋亡的特性,使用碘化丙啶染色后通过流式细胞术测量 DNA 片段化。金(I)配合物 靶向明确的恶性细胞,有效抑制其生长并选择性诱导凋亡,而没有坏死的迹象。即使在对常见治疗方法(如多柔比星)耐药的细胞中,它也能克服多药耐药性,并使现有的耐药细胞对常见细胞毒性药物敏感。假设金(I)配合物 涉及细胞凋亡的线粒体途径,并靶向 BCL-2 家族成员,从而增强其作为癌症治疗中治疗剂的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57e6/11403678/eab08bf4c0e2/jm4c01117_0006.jpg

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