Water‐Soluble Platinum(II) Complexes Featuring 2‐Alkyl‐2H‐tetrazol‐5‐ylacetic Acids: Synthesis, Characterization, and Antiproliferative Activity

Abstract

2‐R‐2H‐Tetrazol‐5‐ylacetic acids (abbreviated as 2‐R‐taa; R = Me, iPr, tBu) react with K2[PtCl4] in 1 m HCl in H2O at r.t. furnishing trans‐platinum(II) complexes trans‐[PtCl2(2‐R‐taa)2] (1–3), whereas cis‐isomeric species cis‐[PtCl2(2‐R‐taa)2] (R = iPr, 4; tBu, 5) are isolated at lower temperature (4–6 °C). In the presence of EtOH in the reaction mixture, esterification of the tetrazol‐5‐ylacetoxy group of 2‐tBu‐taa leads to trans‐[PtCl2(ethyl 2‐tert‐butyl‐2H‐tetrazol‐5‐ylacetate)2] (6). Complexes 1–6 were characterized by elemental analyses (CHN), HRESI+‐MS, 1H, 13C{1H}, 195Pt{1H} NMR and IR spectroscopy, differential scanning calorimetry/thermogravimetry (DSC/TG), and X‐ray diffraction (for 1·H2O, 2, 3·2H2O, 4, 5·2H2O, and 6). The generation of the tetrazole‐based complexes in solution (1 m DCl in D2O, 25 °C) was studied by 1H NMR spectroscopy and HPLC‐MS. The obtained data indicate the initial formation of anionic [PtCl3(2‐R‐taa)]– complexes that are subsequently converted into disubstituted isomeric platinum(II) species cis‐ and trans‐[PtCl2(2‐R‐taa)2]. By contrast to cis‐ and trans‐[PtCl2(2‐R‐taa)2] that were inactive in two human cancer models in vitro (IC50 > 100 µm), complex 6 demonstrated noticeable antiproliferative effects in HT‐29 colon and MCF‐7 breast carcinoma cell lines with IC50 values of 14.2 ± 1.1 and 5.8 ± 1.2 µm, respectively.