Abstract

The search for more effective platinum anticancer drugs has led to the design, synthesis, and preclinical testing of hundreds of new platinum complexes. This search resulted in the recognition and subsequent FDA approval of the third-generation Pt(II) anticancer drug, [Pt(1,2-diaminocyclohexane)(oxalate)], oxaliplatin, as an effective agent in treating colorectal and gastrointestinal cancers. Another promising example of the class of anticancer platinum(II) complexes incorporating the Pt(1,n-diaminocycloalkane) moiety is kiteplatin ([Pt(cis-1,4-DACH)Cl₂], DACH = diaminocyclohexane). We report here our progress in evaluating the role of the cycloalkyl moiety in these complexes focusing on the synthesis, characterization, evaluation of the antiproliferative activity in tumor cells and studies of the mechanism of action of new [Pt(cis-1,3-diaminocycloalkane)Cl₂] complexes wherein the cis-1,3-diaminocycloalkane group contains the cyclobutyl, cyclopentyl, and cyclohexyl moieties. We demonstrate that [Pt(cis-1,3-DACH)Cl₂] destroys cancer cells with greater efficacy than the other two investigated 1,3-diamminocycloalkane derivatives, or cisplatin. Moreover, the investigated [Pt(cis-1,3-diaminocycloalkane)Cl₂] complexes show selectivity toward tumor cells relative to non-tumorigenic normal cells. We also performed several mechanistic studies in cell-free media focused on understanding some early steps in the mechanism of antitumor activity of bifunctional platinum(II) complexes. Our data indicate that reactivities of the investigated [Pt(cis-1,3-diaminocycloalkane)Cl₂] complexes and cisplatin with glutathione and DNA binding do not correlate with antiproliferative activity of these platinum(II) complexes in cancer cells. In contrast, we show that the higher antiproliferative activity in cancer cells of [Pt(cis-1,3-DACH)Cl₂] originates from its highest hydrophobicity and most efficient cellular uptake.

Graphic abstract

中文翻译：

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[Pt（cis-1,3-diaminocycloalkane）Cl2]类似物的合成，在癌细胞中的抗增殖活性和DNA相互作用研究。

摘要

寻找更有效的铂类抗癌药物已导致数百种新的铂类复合物的设计，合成和临床前测试。该搜索结果导致第三代Pt（II）抗癌药[Pt（1,2-二氨基环己烷）（草酸盐）]，奥沙利铂被认可并获得FDA的批准，它是治疗结肠直肠和胃肠道癌的有效药物。引入Pt（1，n-二氨基环烷烃）部分的抗癌铂（II）配合物类别的另一个有希望的例子是凯铂（[Pt（顺式-1,4 -DACH）Cl ₂]，DACH ＝二氨基环己烷）。我们在这里报告我们在评估环烷基部分在这些复合物中的作用方面的进展，重点是合成，表征，评估肿瘤细胞中抗增殖活性以及研究新的[Pt（顺式-1,3-二氨基环烷烃）的作用机理。）Cl ₂ ]配合物，其中顺式-1，3-二氨基环烷烃基包含环丁基，环戊基和环己基部分。我们证明[Pt（顺-1,3-DACH）Cl ₂ ]破坏癌细胞比其他两个研究的1,3-二氨基环烷衍生物或顺铂更大的功效。此外，研究的[Pt（顺式-1,3-二氨基环烷烃）Cl ₂相对于非致瘤性正常细胞，复合物显示出对肿瘤细胞的选择性。我们还在无细胞培养基中进行了一些机理研究，重点是了解双功能铂（II）配合物的抗肿瘤活性机制中的一些早期步骤。我们的数据表明，所研究的[Pt（顺式-1,3-二氨基环烷烃）Cl ₂ ]复合物和顺铂与谷胱甘肽和DNA结合的反应性与这些铂（II）复合物在癌细胞中的抗增殖活性无关。相反，我们显示[Pt（顺-1,3-DACH）Cl ₂ ]在癌细胞中较高的抗增殖活性源自其最高的疏水性和最有效的细胞摄取。

图形摘要