Diclofenac conjugates with biocides through silver(I) ions (CoMeD's); Development of a reliable model for the prediction of anti-proliferation of NSAID's-silver formulations

The conjugation of diclofenac (DICLH), a Non-Steroidal Anti-inflammatory Drug (NSAID), with biocides such as dimethyl sulfoxide (DMSO) and triphenylphosphine (TPP), through silver(I) ions, results into the chemical [Ag-n(DICL)(n)(L)(m)](k) (L = DMSO and n = 2, m = 2, k = infinite (1); L = TPP and n = 1, m = 2, k = 1 (2)). The compounds were characterized by m.p., FT-IR, UV-vis and H-1 NMR spectroscopic techniques. The crystal and molecular structures of 1-2 were determined by X-ray crystallography. The in vitro cytotoxic activity of 1 2 against the human breast adenocarcinoma cancer cells MCF-7 (hormone dependent) and MDA-MB-231 (hormone independent) reveals that the 1 inhibits the MCF-7 rather than the MDA-MB-231 cells, suggesting hormone mimetic behaviour. Compound 2 inhibits both cancerous cell lines, stronger than cisplatin. Both compounds inhibit MCF-7 cells migration. Compounds 1-2, exhibit, lower toxicity against fetal lung fibroblast (MRC-5) cells than cisplatin. Their genotoxicity was evaluated on MRC-5 cells. The molecular mechanism of 1-2 against MCF-7 cells was clarified by (i) their cell cycle arrest study (ii) their mitochondrial membrane permeability (iii) their binding affinity towards Calf Thymus (CT)-DNA and (iv) their inhibitory activity against the enzyme lipoxygenase (LOX). Regression analysis of the data obtained for [Ag(NSAID)(Ar3P)(m)] (NSAID = p-hydroxy-benzoic acid (p-HO-BZAH), salicylic acid (SALH(2)), aspirin (ASPH), naproxen (NAPRH), nimesulide (NIMH); L = TPP, Tri(p-tolyl)phosphine (TPTP), Tri(o-tolyl)phosphine (TOTP), Tri(m-tolyl)phosphine (TMTP); m = 2 or 3) and [Ag(DICL)(2)(DMSO)(2)](k) (k = infinite) was performed. Considering the biological results (IC50) as dependent variable a theoretical equation is obtained for these compounds. The calculated IC50 values are compared satisfactorily with the corresponding experimental inhibitory activity of the complexes.