Picoplatin-based complexes with the bioactive orotate and 5-fluoroorotate ligands: Synthesis, DFT calculations, structure, spectroscopic characterization and in vitro cytotoxicity

Abstract

Two novel, sterically hindered platinum(II) complexes Pt(Oro)(NH3)(2-pic), 1, and Pt(5-FOro)(NH3)(2-pic), 2, were synthesized by connecting the cis-[Pt(NH3)(2-picoline)]2+ fragment of picoplatin (new anticancer agent, being currently under clinical trials) with the chelating orotate or 5-fluoroorotate bioactive ligands. The complexes were characterized in depth using IR, Raman and multinuclear (1H, 13C, 19F, 195Pt) NMR spectroscopy, high resolution mass spectrometry (ESI-TOF), elemental analysis and thermogravimetry. The experimental vibrational spectroscopic studies combined with the theoretical (DFT) calculations were indispensable to elucidate the molecular structures of these complexes. A complete assignment of the IR and Raman spectra was made on the basis of the calculated potential energy distribution (PED). The spectroscopic (FT-IR and NMR) data have shown that of two possible isomers of each complex, just one isomer (A) exists in the solid state and in DMSO solution. Interestingly, the DFT calculations with the PBE0 and B3LYP methods have revealed that the other isomer (B) with the intramolecular NH⋅⋅⋅O hydrogen bond is more stable than A, in the gas phase. It is concluded that during the synthesis the steric and kinetic effects of the 2-picoline ligand play the dominant role, therefore, the isomer A is formed. The antiproliferative activity of 1, 2 and 5-fluoroorotic acid (3) was evaluated in vitro against several human cancer cell lines. The studied compounds exhibited larger IC50 values, in comparison to cisplatin, however 1, 2 and picoplatin showed much lower toxicity against the normal cell lines as compared with cisplatin. Complex 2 was significantly more potent than 1, 3 and picoplatin against HT-29 (human colorectal adenocarcinoma).