Luminescent cyclometalated platinum compounds with N, P, and O boolean AND O ligands: Density-functional theory studies and analysis of the anticancer potential

Luminescent platinum cyclometalated complexes are species of interest mainly due to their applications in the optoelectronic and biological fields, especially with regard to their anticancer activity. Given this level of interest, a series of cyclometalated (2-[2 '-thienyl]pyridinate, thpy and 2-[2,4-difluorophenyl]pyridinate, dfppy) platinum complexes with N-donor, PTA (1,3,5-triaza-7-phosphaadamantane) or chrysin-derived ligands (incorporating piperidine, HL1, or morpholine, HL2, fragments) were synthesized. The complexes are luminescent with tunable emission wavelengths. Aggregation in solution was observed for [Pt(dfppy)L1], 5. Density-functional theory (DFT) studies provided descriptions of the highest occupied molecular orbital (HOMO) and least unoccupied molecular orbital (LUMO) characteristics and their influence on the photophysical properties. The orbitals of 5-6 were different in nature to those of 1-4. Time-dependent DFT (TD-DFT) calculations showed that for 1-4 the excited states S-1 and T-1 reflect metal-to-ligand charge transfer (MLCT) and ligand-centered (LC) (C boolean AND N) contributions while for 5-6 these states are an LC transition centered on L1 or L2. The speciation in DMSO and DMSO/H2O was evaluated. Biological studies showed that [Pt(thpy)Cl(Hthpy)], 1, [Pt(dfppy)Cl(Hdfppy)], 2, and 5 exert significant cytotoxic activity against human cervical (HeLa) and lung (A549) carcinoma cells. The cytotoxicity of 1 increased 2.84-fold upon irradiation (blue). Microscopy assays on 5 showed that this compound accumulates in cytoplasmic organelles, preferentially in mitochondria. Mitochondrial metabolism was disrupted by the activity of the complexes, leading to a decline in the adenosine triphosphate (ATP) cellular content. Overall, the results show an alternative anticancer activity for complexes 1, 2, and 5, which could be of great interest for the treatment of tumors with acquired resistance to conventional DNA-targeted anticancer drugs.