New Apoptosis Inducers Containing Anti-inflammatory Drugs and Pnictogen Derivatives: A New Strategy in the Development of Mitochondrial Targeting Chemotherapeutics.

{[Ag ₈ (Mef) ₈ (μ ₂ - S,O -DMSO) ₂ (μ ₂ - O -DMSO) ₂ ( O -DMSO) ₈ ]·2(H ₂ O)} ( 1 ), [Ag(Mef)(tpP) ₂ ] ( 2 ), [Ag(Mef)(tpAs) ₃ ] ( 3 ), and {2 [Ag(Mef)(tpSb) ₃ ] (DMSO)} ( 4 ) were obtained by the conjugation of mefenamic acid (MefH), a nonsteroidal anti-inflammatory drug (NSAID), with a mitochondriotropic derivative of pnictogen tpE (tp = triphenyl group; E = P, As, and Sb) through silver(I). Their hydrophilicity was adjusted by their dispersion into sodium lauryl sulfate (SLS), forming SLS@ 1 - 4 . 1 - 4 and SLS@ 1 - 4 were characterized by their spectral data and X-ray crystallography. They inhibit the proliferation of human breast adenocarcinoma cells MCF-7 (hormone-dependent (HD)) and MDA-MB-231 (hormone-independent (HI)). X-ray fluorescence reveals the Ag cellular uptake. The in vitro and in vivo nongenotoxicity was confirmed with micronucleus (MN), Artemia salina , and Allium cepa assays. Their mechanism of action was studied by cell morphology, DNA fragmentation, acridine orange/ethidium bromide (AO/EB) staining, cell cycle arrest, mitochondrial membrane permeabilization tests, DNA binding affinity, and LOX inhibitory activity and was rationalized by regression analysis.