In vitro anticancer active cis-Pt(II)-diiodido complexes containing 4-azaindoles

Abstract

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)2I2] (1), cis-[PtI2(ip4aza)2] (2), cis-[Pt(4aza)I2(NH3)] (3) and cis-[PtI2(ip4aza)(NH3)] (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 14 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 14 induce different cell cycle perturbations as compared with cisplatin, thus suggesting a different mechanism of their antitumor action.

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Acknowledgements

The authors gratefully thank the National Program of Sustainability I (LO1305) of the Ministry of Education, Youth and Sports of the Czech Republic and Palacký University in Olomouc (a Grant No. PrF_2018_011) for financial support. The authors also thank Ms. Kateřina Kubešová and Ms. Marta Rešová for performing the in vitro cytotoxicity experiments and preparation of the samples for cellular accumulation and flow cytometry experiments, Dr. Bohuslav Drahoš for recording the ESI–MS and NMR spectra, Dr. Alena Klanicová for performing FTIR spectroscopy and Mrs. Pavla Richterová for carrying out elemental analyses. The authors also thank Mr. Ivan Saksa for his help with the syntheses of the studied compounds.

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Štarha, P., Trávníček, Z., Vančo, J. et al. In vitro anticancer active cis-Pt(II)-diiodido complexes containing 4-azaindoles. J Biol Inorg Chem 24, 257–269 (2019). https://doi.org/10.1007/s00775-019-01643-8

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Keywords

  • Platinum(II) complexes
  • 4-Azaindole
  • Iodido
  • Cytotoxicity
  • In vitro