Mitochodriotropic Agents Conjugated with NSAIDS Through Metal Ions Against Breast Cancer Cells

Abstract

Two copper(I) polymorphs of formula [Cu(SALH)(TPP)3] (1a and 1b) were prepared by the conjugation of the Non-Steroidal Anti-Inflammatory Drug (NSAID) salicylic acid (SALH2) with the mitochondriotropic agent triphenylphosphine (TPP) via metal ion. For comparison their isomorph [Ag(SALH)(TPP)3] (2) was prepared. The conjugates 1a, 1b and 2 were characterized by melting point (m.p.), Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy, Ultraviolet-Visible (UV-Vis) spectroscopy and nuclear magnetic resonance (1H-,31P-NMR). The crystal structure of 1a, 1b and of 2 were confirmed by X-ray diffraction crystallography (XRD). The ex vivo binding affinity of 1a, 1b and 2 towards the CT (calf thymus)-DNA was studied by UV, fluorescence, viscosity and DNA Thermal Denaturation studies. The inhibitory activity of 1a, 1b and 2 against lipoxygenase (LOX) (an enzyme which is mainly located in the mitochondrion) was determined. The in vitro activity of 1a, 1b and 2 was evaluated against human breast cancer cell lines MCF-7 (hormone depended (HD)) and MDA-MB 281 (hormone independent (HI)) cells. The 1a, 1b and 2 inhibit stronger the cancer cells than cisplatin. The molecular mechanism of action of 1a, 1b and 2 was suspected by the MCF-7 cells morphology and confirmed by DNA fragmentation, Acridine Orange/Ethidium Bromide (AO/EB) Staining and mitochondrial membrane permeabilization tests. Differences in the in vitro activity of 1a and 1b against cell lines are observed.

Keywords: Inorganic Biochemistry, Polymorphs, Copper(I) and Silver(I) complexes, NSAIDs, mitochodriotropic agents, Antiproliferative activity