Shrestha Deepak, Kimutai Bett, Chow Christine S
Department of Chemistry, Wayne State University, Detroit, MI, USA.
J Biol Inorg Chem. 2025 Feb;30(1):87-101. doi: 10.1007/s00775-025-02097-x. Epub 2025 Jan 24.
The discovery of cisplatin (cisPt) as an effective anticancer agent was a milestone in the health industry. Despite its success, undesired side effects and acquired resistance still limit the therapeutic usefulness of cisPt. Intrastrand adduct formation at consecutive purines and structural modifications of DNA caused by platinum(II) complexes are important factors for antitumor efficacy. In this study, we examined amino acid-linked platinum(II) complexes, collectively referred to as AAPt, for antiproliferative activity and ability to induce DNA bending. The antiproliferative activity of one AAPt complex tested against a prostate cancer cell line was comparable to that of cisPt, whereas only activity of the AAPt complex was lower in a normal human prostate cell line. Various AAPt analogues were examined for impact on the structures of DNAs with four different purine dinucleotide target sites (GG, AG, GA, and AA) and compared to the parent cisPt. The roles of side-chain identity, chirality, and coordination type (e.g., (N,O) vs. (N,N)) of AAPt complexes are discussed with respect to DNA adduct formation and ability to induce DNA bending. Although the AAPt complexes display different nucleotide preferences (A for AAPt vs. G for cisPt), DNAs containing GG-platinum adducts display a greater degree of bending compared to DNAs with AA-platinum adducts.
顺铂（cisPt）作为一种有效的抗癌药物的发现是健康产业的一个里程碑。尽管取得了成功，但不良副作用和获得性耐药性仍然限制了顺铂的治疗效用。铂（II）配合物导致的连续嘌呤处的链内加合物形成和DNA的结构修饰是抗肿瘤疗效的重要因素。在本研究中，我们研究了统称为AAPt的氨基酸连接铂（II）配合物的抗增殖活性和诱导DNA弯曲的能力。一种针对前列腺癌细胞系测试的AAPt配合物的抗增殖活性与顺铂相当，而在正常人前列腺细胞系中只有AAPt配合物的活性较低。研究了各种AAPt类似物对具有四个不同嘌呤二核苷酸靶位点（GG、AG、GA和AA）的DNA结构的影响，并与母体顺铂进行了比较。就DNA加合物形成和诱导DNA弯曲的能力而言，讨论了AAPt配合物的侧链特性、手性和配位类型（例如，（N，O）与（N，N））的作用。尽管AAPt配合物表现出不同的核苷酸偏好（AAPt偏好A，而顺铂偏好G），但与含有AA - 铂加合物的DNA相比，含有GG - 铂加合物的DNA表现出更大程度的弯曲。
