Novel copper complex inhibits the proteasome in skin squamous cell carcinoma induced by DMBA in mice

Abstract

The proteasomal system is becoming a target for the treatment of several diseases, especially in cancer therapy. The present study aims to develop a novel copper complex that inhibits the proteasome in skin squamous cell carcinoma. New molecules based on the copper complex were synthesized for the first time to assess their potential as proteasome inhibitors, specifically targeting squamous cell carcinoma induced by 7,12-dimethylbenz(a)anthracene (DMBA) in mouse models. Fourier Transform Infrared (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), nuclear magnetic resonance (NMR), and energy dispersive X-ray analysis (EDX) were carried out to characterize this new copper complex. Notably, the presence of a papilloma (skin tumor) was confirmed by histopathological analysis. Subsequent investigation included the quantification of proteasome levels using a sandwich ELISA test, and the catalytic activity of the 20S proteasome was determined by measuring the fluorescence emitted after the cleavage of 7-amino-4-methylcoumarin (AMC). Hence, X-ray crystallography indicates that all Cu atoms are five-coordinated in a square-pyramidal configuration and biological activity of copper Schiff base complex, which exhibits high proteasome inhibitory activities with particular selectivity of β5 subunit. The pharmacokinetic properties (ADMET) of the copper complex named Cu(L1) showed encouraging results with very low toxicity, distribution, and absorption. Structure-activity relationship (SAR) information obtained from Cu(L1) demonstrated its selectivity and potent inhibition for β5 subunit. In this regard, this copper complex has emerged as a novel therapy for skin cancer.

Keywords: ADMET; Cancer treatment; Copper complex; Docking; Inhibitors; Proteasome; Skin cancer.