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探索雷洛昔芬为基础的金属药物:一种多功能载体,结合了铂(II)、钯(II)和镍(II)二氯化物和硼酸盐,用于治疗三阴性乳腺癌。

Exploring Raloxifene-Based Metallodrugs: A Versatile Vector Combined with Platinum(II), Palladium(II) and Nickel(II) Dichlorides and Carborates against Triple-Negative Breast Cancer.

机构信息

new address, Institute for Drug Discovery, Leipzig University, Leipzig, Brüderstraße 34, 04103, Germany.

Faculty of Chemistry and Mineralogy, Leipzig University, Johannisallee 29, Leipzig, 04103, Germany.

出版信息

ChemMedChem. 2024 Jul 15;19(14):e202400006. doi: 10.1002/cmdc.202400006. Epub 2024 Jun 5.

Abstract

Triple-negative breast cancer (TNBC) poses challenges in therapy due to the absence of target expression such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Frequently, the treatment of TNBC involves the combination of several therapeutics. However, an enhanced therapeutic effect can be also achieved within a single molecule. The efficacy of raloxifene can be improved by designing a raloxifene-based hybrid drug bearing a 2,2'-bipyridine moiety (2). Integration of platinum(II), palladium(II), and nickel(II) complexes into this structure dramatically changed the cytotoxicity. The platinum(II) dichloride complex 3 did not demonstrate any activity, while palladium(II) and nickel(II) dichloride complexes 4 and 5 exhibited various cytotoxic behavior towards different types of hormone-receptor positive (HR+) cancer and TNBC cell lines. The replacement of the two chlorido ligands in 3-5 with a dicarbollide (carborate) ion [CBH] resulted in reduced activity of compounds 6, 7, and 8. However, the palladacarborane complex 7 demonstrated higher selectivity towards TNBC. Furthermore, the mechanism of action was shifted from cytotoxic to explicitly cytostatic with detectable proliferation arrest and accelerated aging, characterized by senescence-associated phenotype of TNBC cells. This study provides valuable insights into the development of hybrid therapeutics against TNBC.

摘要

三阴性乳腺癌(TNBC)由于缺乏靶标表达,如雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体 2(HER2),在治疗方面带来挑战。通常,TNBC 的治疗涉及几种治疗方法的联合。然而,单一分子也可以实现增强的治疗效果。通过设计一种带有 2,2'-联吡啶部分的雷洛昔芬基杂化药物(2),可以提高雷洛昔芬的疗效。将铂(II)、钯(II)和镍(II)配合物整合到该结构中,显著改变了细胞毒性。铂(II)二氯化物复合物 3 没有表现出任何活性,而钯(II)和镍(II)二氯化物复合物 4 和 5 对不同类型的激素受体阳性(HR+)癌症和 TNBC 细胞系表现出不同的细胞毒性行为。3-5 中两个氯配体被二硼烷(硼酸盐)离子 [CBH]取代,导致化合物 6、7 和 8 的活性降低。然而,钯卡硼烷复合物 7 对 TNBC 表现出更高的选择性。此外,作用机制从细胞毒性转变为明确的细胞静止,可检测到增殖停滞和加速老化,表现为 TNBC 细胞的衰老相关表型。这项研究为开发针对 TNBC 的杂化治疗提供了有价值的见解。

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