Cytotoxic trans-platinum(II) complex with 3-hydroxymethylpyridine: Synthesis, X-ray structure and biological activity evaluation

• New Pt(II) isomers with 3-hydroxymethylpyridine ligands are prepared.
• X-ray structures reveal different patterns of intermolecular connectivity.
• Trans isomer 2 causes more damage to pCMV-NeoBam plasmid DNA than cisplatin.
• In vivo, 2 has equal efficacy on mouse sarcoma (SA-1) tumour growth than cisplatin.
• 2 has less effect on body weight loss in SA-1 sarcoma bearing mice than cisplatin.

To assess the potential cytostatic properties of Pt(II) complexes with 3-hydroxymethylpyridine (3-hmpy) as the only carrier ligand, novel cis-[PtCl2(3-hmpy)2] (1) and trans-[PtCl2(3-hmpy)2] (2) have been prepared. Elemental analysis, FTIR spectroscopy, multinuclear NMR spectroscopy and X-ray crystallography were used to determine their structures. Based on the results obtained with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and clonogenic assay on T24 human bladder carcinoma cells (T24), the most potent compound 2 was further tested for cytotoxicity in human ovarian carcinoma cell lines - cisplatin sensitive (IGROV 1) and its resistant subclone (IGROV 1/RDDP). The cytotoxicity of compound 2 in IGROV 1/RDDP is comparable to cisplatin. Furthermore, compound 2 induced severe conformational changes in plasmid DNA, which resulted in a delayed onset of apoptosis in T24 cells, and higher amounts of Pt in tumours and serum compared to cisplatin. In addition, in vivo antitumour effectiveness was comparable to that of cisplatin with a smaller reduction of animals' body weight, thus demonstrating that it is a promising transplatin analogue which deserves further studies.

The crystal structure of the new compound, trans-[PtCl2(3-hydroxymethylpyridine)2] (2), was determined. In vivo, 2 had equal efficacy on mouse sarcoma (SA-1) tumour growth than cisplatin with less effect on body weight loss in SA-1 tumour bearing mice than cisplatin.Figure optionsDownload as PowerPoint slide