Photochemical activity of the thiosemicarbazone Dp44mT and its complexes with copper(ii) and zinc(ii) ions†

Abstract

Photosensitivity is among the most frequently reported adverse drug reactions. In this study, the photochemical behavior of the experimental anticancer ligand di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and its chelate complexes with copper(II) and zinc(II) ions were investigated using laser flash photolysis (LFP), electron paramagnetic resonance (EPR) with spin traps, chemically induced dynamic nuclear polarization (CIDNP), and high-resolution liquid chromatography-mass spectrometry (LC-MS) techniques. MTT assay demonstrated a reduction in cell viability when cells were irradiated in the presence of Dp44mT and its complexes with Cu(II). LFP analysis revealed the formation of transient absorption upon excitation of Dp44mT solutions by UVA light (355 nm). This absorption featured an intense band peaking at ∼400 nm and a broad, structureless absorption in the visible region. The intermediate absorption spectra of the Dp44mT complexes with Cu(II) and Zn(II) ions were characterized by the absence of an intense intermediate absorption band near 400 nm. The spectra and lifetime of this intermediate were independent of the presence of oxygen, indicating the absence of the singlet oxygen generation. CIDNP experiments showed that the photoreaction of Dp44mT with model electron acceptors, such as quinones, proceeds via proton-coupled electron transfer, leading to the formation of an S-centered neutral radical. It was found that complex formation of Dp44mT with zinc and copper ions stabilizes the thiosemicarbazone, which leads to inhibition of the formation of free radical species and increase Dp44mT photostability. Dp44mT and its chelate complexes did not exhibit electron acceptor properties in reaction with the amino acid derivative N-acetyl-L-tryptophan. EPR experiments with the TMIO spin trap showed the redox activity of the Dp44mT chelate complex with Cu(II) ions in the Fenton reaction under UV-A light (366 nm), which are correlated with its photocytotoxicity. Chromatography-mass spectrometry data were used to propose a photoconversion pathway for Dp44mT and identify its primary photodegradation products. The Dp44mT photocytotoxicity is probably explained by the toxicity of secondary products formed during the photodegradation of Dp44mT. These results provide insight into the possible photodegradation pathways of Dp44mT, highlighting the role of photodegradation products in its biological activity.