ABSTRACT
Two zinc(ii)-NSAID complexes [(phendione)ZnII(NPR)2(H2O)2] (1) and [(phendione)ZnII(MFN)2] (2) (HNPR = naproxen and HMFN = mefenamic acid) of 1,10-phenanthroline-5,6-dione (phendione) were isolated and characterized to evaluate their potential as anti-cancer agents. Each of the complexes contains two equivalents of NSAID per zinc(ii)-phendione unit. The complexes are stable in solution under cell culture conditions. Cytotoxic assay on the human breast cancer cell line (MDA-MB-231) reveals that the anti-proliferative activity of phendione is retained in both the complexes. The anti-inflammatory properties of NSAIDs are also preserved in the metal complexes as evident from the PGE2 assay. Both 1 and 2 exhibit selective COX-1 inhibition at a low concentration. Furthermore, the zinc(ii)-naproxen complex (1) disrupts the intercellular bridges displaying in vitro delay in cellular migration and down-regulation of EMT-related genes. The mechanistic studies indicate that the ternary complexes are more active compared to cisplatin and have the potential to overcome cisplatin resistance in MDA MB 231 cells. These findings demonstrate that the zinc(ii)-NSAID complexes are worthy of further in vivo studies for their promising anti-tumor potential.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Phenanthrolines/pharmacology , Zinc/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Density Functional Theory , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Phenanthrolines/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured , Zinc/chemistryABSTRACT
The ability of two iron(II) complexes, [(TpPh2)FeII(benzilate)] (1) and [(TpPh2)(FeII)2(NPP)3] (2) (TpPh2 = hydrotris(3,5-diphenylpyrazol-1-yl)borate, NPP-H = α-isonitrosopropiophenone), of a monoanionic facial N3 ligand in the O2-dependent oxidation of oximes is reported. The mononuclear complex 1 reacts with dioxygen to decarboxylate the iron-coordinated benzilate. The oximate-bridged dinuclear complex (2), which contains a high-spin (TpPh2)FeII unit and a low-spin iron(II)-oximate unit, activates dioxygen at the high-spin iron(II) center. Both the complexes exhibit the oxidative transformation of oximes to the corresponding carbonyl compounds with the incorporation of one oxygen atom from dioxygen. In the oxidation process, the oxime units are converted to nitric oxide (NO) or nitroxyl (HNO). The iron(II)-benzilate complex (1) reacts with oximes to afford HNO, whereas the iron(II)-oximate complex (2) generates NO. The results described here suggest that the oxidative transformation of oximes to NO/HNO follows different pathways depending upon the nature of co-ligand/reductant.Graphic abstract.
Subject(s)
Ferrous Compounds/chemistry , Nitric Oxide/chemistry , Oximes/chemistry , Oxygen/chemistry , Coordination Complexes/chemistry , Heme/chemistry , Ligands , Oxidation-ReductionABSTRACT
Zinc(ii)-NSAID complexes supported by NO-donating 1,10-phenanthrolinefuroxan exhibit anti-inflammatory activities through selective inhibition of the COX-2 pathway. The strategy represents a general procedure to convert non-selective or COX-1 selective NSAIDs to selective COX-2 inhibitors.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase 2/metabolism , Nitric Oxide Donors/pharmacology , Oxadiazoles/pharmacology , Zinc/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Cyclooxygenase 1/metabolism , Dinoprostone/antagonists & inhibitors , Interferon-gamma/pharmacology , Ligands , Lipopolysaccharides/pharmacology , Mice , Nitric Oxide Donors/chemistry , Oxadiazoles/chemistry , RAW 264.7 Cells , Zinc/chemistryABSTRACT
The catalytic reactivity of an iron(ii) complex [(TPA)Fe(II)(CH3CN)2](2+) (1) (TPA = tris(2-pyridylmethyl)amine) towards oxygenative aromatic C-C bond cleavage of catechol and 2-aminophenol is presented. Complex 1 exhibits catalytic and regioselective C-C bond cleavage of 3,5-di-tert-butylcatechol (H2DBC) to form intradiol products, whereas it catalyzes extradiol-type C-C bond cleavage of 2-amino-4,6-di-tert-butylphenol (H2AP). The catalytic reactions are found to be pH-dependent and the complex exhibits maximum turnovers at pH 5 in acetonitrile-phthalate buffer. An iron(iii)-catecholate complex [(TPA)Fe(III)(DBC)](+) (2) is formed in the ring cleavage of catechol. In the extradiol-type cleavage of H2AP, an iron(iii)-2-iminobenzosemiquinonate complex [(TPA)Fe(III)(ISQ)](2+) (3) (ISQ = 4,6-di-tert-butyl-2-iminobenzosemiquinonate radical anion) is observed in the reaction pathway. This work shows the importance of the nature of 'redox non-innocent' substrates in governing the mode of ring fission reactivity.
