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