Synthesis, Structure, and Cytotoxicity of Oxaliplatin-Based Platinum(IV) Anticancer Prodrugs Bearing One Axial Fluoride,Inorganic Chemistry

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Synthesis, Structure, and Cytotoxicity of Oxaliplatin-Based Platinum(IV) Anticancer Prodrugs Bearing One Axial Fluoride
Inorganic Chemistry ( IF 4.3 ) Pub Date : 2018-06-26 00:00:00 , DOI: 10.1021/acs.inorgchem.8b00706
Zoufeng Xu _{1,

2} , Ho Ming Chan ₁ , Cai Li _{1,

2} , Zhigang Wang _{1,

2} , Man-Kit Tse ₁ , Zixuan Tong ₁ , Guangyu Zhu _{1,

2}

Affiliation

Fluorine plays more and more important roles in drug design and development. In recent years, fluorine-containing organic drugs have already been applied in a broad range of therapeutic areas. Herein, we report our attempt to introduce an axial fluorine ligand to Pt(IV) complexes by oxidizing oxaliplatin with electrophilic fluorinating reagents in different protic solvents. The crystal structure of one representative complex is presented. The fluorinated Pt(IV) complexes are further expanded by functionalization with different anhydrides, and their analogues bearing one different axial ligand (OAc or OH group) are also synthesized. Further investigations show that the axial fluorine atom has dramatic effects on the chemical properties of these prodrugs. These new fluorinated Pt(IV) complexes are proved to be stable in physiological conditions. For most of the fluorinated Pt(IV) complexes, a higher reduction potential indicates its greater tendency to be reduced by ascorbate. Introducing an axial fluorine ligand in Pt(IV) complexes does not lead to the increase of their lipophilicity. Moreover, these new fluorinated Pt(IV) complexes show better cytotoxicity than nonfluorinated analogues which may derive from their higher cellular accumulation in cancer cells. Therefore, the good stability and high cytotoxicity of these fluorinated Pt(IV) prodrugs indicate their great potential as a building block for further functionalization.

中文翻译：

含一轴氟化物的草酸铂基抗癌前药的合成，结构和细胞毒性

氟在药物设计和开发中起着越来越重要的作用。近年来，含氟有机药物已经被广泛应用于治疗领域。在本文中，我们报告了通过在不同质子溶剂中用亲电子氟化试剂氧化奥沙利铂来将轴向氟配体引入Pt（IV）配合物的尝试。介绍了一种代表性复合物的晶体结构。氟化的Pt（IV）配合物通过用不同的酸酐官能化进一步扩展，并且还合成了带有一个不同轴向配体（OAc或OH基团）的类似物。进一步的研究表明，轴向氟原子对这些前药的化学性质具有显着影响。这些新的氟化Pt（IV）配合物在生理条件下被证明是稳定的。对于大多数氟化的Pt（IV）配合物，较高的还原电位表明其被抗坏血酸还原的趋势更大。在Pt（IV）配合物中引入轴向氟配体不会导致其亲脂性增加。此外，这些新的氟化Pt（IV）络合物显示出比非氟化类似物更好的细胞毒性，后者可能是由于它们在癌细胞中的较高细胞蓄积所致。因此，这些氟化的Pt（IV）前药的良好稳定性和高细胞毒性表明它们作为进一步功能化的基础材料具有巨大的潜力。这些新的氟化Pt（IV）络合物显示出比非氟化类似物更好的细胞毒性，后者可能是由于它们在癌细胞中的较高细胞积累所致。因此，这些氟化的Pt（IV）前药的良好稳定性和高细胞毒性表明它们作为进一步功能化的基础材料具有巨大的潜力。这些新的氟化Pt（IV）络合物显示出比非氟化类似物更好的细胞毒性，后者可能是由于它们在癌细胞中的较高细胞积累所致。因此，这些氟化的Pt（IV）前药的良好稳定性和高细胞毒性表明它们作为进一步功能化的基础材料具有巨大的潜力。

更新日期：2018-06-26

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