Höfer Doris, Varbanov Hristo P, Hejl Michaela, Jakupec Michael A, Roller Alexander, Galanski Mathea S, Keppler Bernhard K
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria.
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria; Research Platform "Translational Cancer Therapy Research", University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria.
J Inorg Biochem. 2017 Sep;174:119-129. doi: 10.1016/j.jinorgbio.2017.06.005. Epub 2017 Jun 16.
The impact of the equatorial coordination sphere on the reduction behavior (i.e. rate of reduction) of platinum(IV) complexes with axial carboxylato ligands was studied. Moreover, the influence of equatorial ligands on the stability, lipophilicity and cytotoxicity of platinum(IV) compounds was evaluated. For this purpose, a series of platinum(IV) complexes featuring axial carboxylato ligands (succinic acid monoesters) was synthesized; anionic carboxylato (OAc, oxalate) and halido (Cl, Br, I) ligands served as leaving groups and am(m)ine carrier ligands were provided by monodentately (isopropylamine, ammine+cyclohexaneamine) or bidentately (ethane-1,2-diamine) coordinating am(m)ines. All platinum(IV) products were fully characterized based on elemental analysis, high resolution mass spectrometry and multinuclear (H, C, N, Pt) NMR spectroscopy as well as by X-ray diffraction in some cases. The rate of reduction in the presence of ascorbic acid was determined by NMR spectroscopy and the lipophilicity of the complexes was investigated by analytical reversed phase HPLC measurements. Cytotoxic properties were studied by means of a colorimetric microculture assay in three human cancer cell lines derived from cisplatin sensitive ovarian teratocarcinoma (CH1/PA-1) as well as cisplatin insensitive colon carcinoma (SW480) and non-small cell lung cancer (A549).
研究了赤道配位层对具有轴向羧基配体的铂（IV）配合物还原行为（即还原速率）的影响。此外，还评估了赤道配体对铂（IV）化合物稳定性、亲脂性和细胞毒性的影响。为此，合成了一系列具有轴向羧基配体（琥珀酸单酯）的铂（IV）配合物；阴离子羧基（乙酸根、草酸根）和卤代（氯、溴、碘）配体作为离去基团，单齿（异丙胺、氨+环己胺）或双齿（乙二胺）配位的氨（胺）配体作为载体配体。所有铂（IV）产物均通过元素分析、高分辨率质谱和多核（氢、碳、氮、铂）核磁共振光谱进行了全面表征，部分情况下还通过X射线衍射进行了表征。通过核磁共振光谱测定了抗坏血酸存在下的还原速率，并通过反相高效液相色谱分析测量研究了配合物的亲脂性。通过比色微培养试验研究了三种人类癌细胞系的细胞毒性特性，这三种细胞系分别来自顺铂敏感的卵巢畸胎癌（CH1/PA-1）以及顺铂不敏感的结肠癌（SW480）和非小细胞肺癌（A549）。
