Synthesis and DNA Interactions Study of Novel Fluorinated Pyridinium Platinum (IV) Complexes with Tumor Targeting Activity,ChemistrySelect

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Synthesis and DNA Interactions Study of Novel Fluorinated Pyridinium Platinum (IV) Complexes with Tumor Targeting Activity
ChemistrySelect ( IF 1.9 ) Pub Date : 2024-03-14 , DOI: 10.1002/slct.202400511
Yusheng Peng ₁ , Pengmin Shi ₂ , Changli Wang ₃ , Tangli Wei ₁ , Jing Yang ₁ , Xiali Liao ₁ , Bo Yang ₁ , Chuanzhu Gao ₁

Affiliation

Picoplatin can effectively circumvent cisplatin‐induced resistance through the “steric hindrance effect” of its structure, but there are still problems such as toxicity and side effects, so the search for safer, more efficient platinum analogs is crucial. Here we report three fluorinated pyridine‐containing Pt(IV) complexes employing biotin as an axial ligand to provide targeting functionality. Lipid solubility studies showed that all the synthesized complexes possessed improved lipid‐water partition coefficients, which are beneficial for transmembrane transport of drugs. The DNA binding activity of the compounds was studied using UV titration, fluorescence titration, and PicoGreen staining, demonstrating the presence of potential intercalation and electrostatic interaction binding modes. It probably attributable to planar π‐π interactions provided by the aromatic pyridine ligands. Meanwhile, molecular docking studies showed that the introduction of axial biotin molecules allowed the complexes to effectively target cancer cells, which was simultaneously confirmed by the results of cellular uptake studies. And another docking result showed that the Pt(IV) complexes binds to DNA by minor groove binding. The synthesized complexes exhibited similar cytotoxicity to cisplatin in five cell lines (SW480, HCT116, HepG2, A549 and LO2), with complex 3 being superior to the parent drug, picoplatin.

中文翻译：

具有肿瘤靶向活性的新型氟化吡啶铂(IV)配合物的合成及DNA相互作用研究

吡铂通过其结构的“位阻效应”可以有效规避顺铂引起的耐药，但仍存在毒性和副作用等问题，因此寻找更安全、更高效的铂类似物至关重要。在这里，我们报道了三种含氟化吡啶的 Pt(IV) 配合物，采用生物素作为轴向配体来提供靶向功能。脂溶性研究表明，所有合成的复合物都具有改善的脂水分配系数，有利于药物的跨膜转运。使用紫外滴定、荧光滴定和 PicoGreen 染色研究了化合物的 DNA 结合活性，证明了潜在嵌入和静电相互作用结合模式的存在。这可能归因于芳香吡啶配体提供的平面 π-π 相互作用。同时，分子对接研究表明，轴向生物素分子的引入使得复合物能够有效靶向癌细胞，这同时得到细胞摄取研究结果的证实。另一项对接结果表明，Pt(IV)复合物通过小沟结合与DNA结合。合成的复合物在五种细胞系（SW480、HCT116、HepG2、A549 和 LO2）中表现出与顺铂相似的细胞毒性，其中复合物 3 优于母体药物吡铂。

更新日期：2024-03-14

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