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.

Synthesis and evaluation of platinum complexes with potential antitumor activity

“…Besides, the design of new platinum-based anti-cancer agents might help to overcome cisplatin resistance. The search for new platinum complex is an ever present issue because of the potential of this class of compounds as antitumor agents (Hildebrandt et al, 2016;Lakomska et al, 2016;Pollak, Goddard, Porschke, 2016;Popova et al, 2016;Rehm et al, 2016;Wang et al, 2016).…”