Biologically Active Complexes and Molecular Magnets, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacký University in Olomouc, Šlechtitelů 27, 783 71, Olomouc, Czech Republic.
J Biol Inorg Chem. 2019 Mar;24(2):257-269. doi: 10.1007/s00775-019-01643-8. Epub 2019 Feb 14.
4-Azaindole (1H-pyrrolo[3,2-b]pyridine; 4aza) and its N1-alkylated derivative N1-isopropyl-4-azaindole (1-(propan-2-yl)-1H-pyrrolo[3,2-b]pyridine; ip4aza) have been used for the preparation of the cis-diiodido-platinum(II) complexes cis-[Pt(4aza)I] (1), cis-[PtI(ip4aza)] (2), cis-[Pt(4aza)I(NH)] (3) and cis-[PtI(ip4aza)(NH)] (4). The prepared complexes were thoroughly characterized (e.g., multinuclear NMR spectroscopy and ESI mass spectrometry) and their in vitro cytotoxicity was assessed at human ovarian carcinoma (A2780), cisplatin-resistant ovarian carcinoma (A2780R) and colon carcinoma (HT-29) cell lines, where they showed, in some cases, significantly higher activity than the used reference-drug cisplatin. The results of in vitro cytotoxicity testing at the A2780 and A2780R cells indicated that alkylation of the 4-azaindole moiety at the position of the N1 atom had a positive biological effect, because the ip4aza-containing complexes 2 and 4 showed significantly (p < 0.005) higher cytotoxicity than 4aza-containing analogues 1 and 3. The resistance factors (A2780R/A2780 model) equalled 0.8-1.4, indicating the ability of complexes 1-4 to overcome the acquired resistance of the A2780 cells against cisplatin. Complexes 1 and 2 revealed low toxicity against primary culture of human hepatocytes. The flow cytometry studies of the A2780 cell cycle modification showed that complexes 1-4 induce different cell cycle perturbations as compared with cisplatin, thus suggesting a different mechanism of their antitumor action.
4-氮茚（1H-吡咯并[3,2-b]吡啶；4-氮杂）及其 N1-烷基衍生物 N1-异丙基-4-氮茚（1-（异丙基）-1H-吡咯并[3,2-b]吡啶；ip4aza）已被用于制备顺式-二碘合-铂（II）配合物顺式-[Pt（4aza）I]（1）、顺式-[PtI（ip4aza）]（2）、顺式-[Pt（4aza）I（NH）]（3）和顺式-[PtI（ip4aza）（NH）]（4）。所制备的配合物进行了彻底的表征（例如，多核 NMR 光谱和 ESI 质谱），并在人卵巢癌细胞（A2780）、顺铂耐药卵巢癌细胞（A2780R）和结肠癌细胞（HT-29）系中评估了它们的体外细胞毒性，在某些情况下，它们的活性明显高于所用的参考药物顺铂。在 A2780 和 A2780R 细胞的体外细胞毒性测试结果表明，4-氮茚部分在 N1 原子位置的烷基化具有积极的生物学效应，因为含有 ip4aza 的配合物 2 和 4 表现出明显（p < 0.005）高于含有 4aza 的类似物 1 和 3 的细胞毒性。耐药因子（A2780R/A2780 模型）等于 0.8-1.4，表明配合物 1-4 能够克服 A2780 细胞对顺铂的获得性耐药。配合物 1 和 2 对人原代肝细胞培养物的毒性较低。A2780 细胞周期改变的流式细胞术研究表明，与顺铂相比，配合物 1-4 诱导不同的细胞周期扰动，因此表明其抗肿瘤作用的不同机制。
