Here we investigated cytotoxicity and DNA and protein binding of an iodido analog of picoplatin, the cis-ammine-diiodido(2-methylpyridine)platinum(II) complex (I-picoplatin). I-picoplatin (IC50 = 3.7-12.4 μM) outperforms picoplatin (IC50 = 11.8-22.6 μM) in the human cancer cell lines used and shows a greater ability to overcome the cisplatin resistance of A2780 ovarian cancer cells than does picoplatin. I-picoplatin also induces different cell cycle changes (reduced S-phase fraction and an increase in the G2/M phase arrest) in HeLa cervical carcinoma cells compared to both picoplatin and cisplatin. Binding of the metal compound to DNA model systems was investigated by ethidium bromide displacement assay and circular dichroism. Its reactivity with lysozyme (HEWL) and pancreatic RNase A was studied by X-ray diffraction and mass spectrometry experiments. I-picoplatin binds the DNA double helix and is able to retain the 2-methylpyridine ligand and at least one of the two iodido ligands when bound to the two proteins. Various Pt-containing moieties, including one based on the isomerized structure of I-picoplatin, coordinate the His and Met residues. A low-resolution structure of the I-picoplatin/human serum albumin (HSA) adduct has also been solved. The side chains of His146, Met289, and Met329 are the primary binding sites of the I-picoplatin moieties on HSA.

• MeSH
• DNA * metabolism   chemistry   MeSH
• Humans MeSH
• Serum Albumin, Human * metabolism   chemistry   MeSH
• Molecular Structure MeSH
• Muramidase * metabolism   chemistry   MeSH
• Cell Line, Tumor MeSH
• Organoplatinum Compounds * chemistry   pharmacology   chemical synthesis   metabolism   MeSH
• Ribonuclease, Pancreatic * metabolism   chemistry   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents * pharmacology   chemistry   chemical synthesis   metabolism   MeSH
• Drug Screening Assays, Antitumor MeSH
• Protein Binding MeSH
• Binding Sites MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• DNA * MeSH
• Serum Albumin, Human * MeSH
• Muramidase * MeSH
• Organoplatinum Compounds * MeSH
• Ribonuclease, Pancreatic * MeSH
• Antineoplastic Agents * MeSH

The platinum(II) complex [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]2+ (PtII56MeSS, 1) exhibits high potency across numerous cancer cell lines acting by a multimodal mechanism. However, 1 also displays side toxicity and in vivo activity; all details of its mechanism of action are not entirely clear. Here, we describe the synthesis and biological properties of new platinum(IV) prodrugs that combine 1 with one or two axially coordinated molecules of diclofenac (DCF), a non-steroidal anti-inflammatory cancer-selective drug. The results suggest that these Pt(IV) complexes exhibit mechanisms of action typical for Pt(II) complex 1 and DCF, simultaneously. The presence of DCF ligand(s) in the Pt(IV) complexes promotes the antiproliferative activity and selectivity of 1 by inhibiting lactate transporters, resulting in blockage of the glycolytic process and impairment of mitochondrial potential. Additionally, the investigated Pt(IV) complexes selectively induce cell death in cancer cells, and the Pt(IV) complexes containing DCF ligands induce hallmarks of immunogenic cell death in cancer cells.

• MeSH
• Anti-Inflammatory Agents, Non-Steroidal pharmacology   MeSH
• Diclofenac pharmacology   MeSH
• Ligands MeSH
• Cell Line, Tumor MeSH
• Neoplasms * MeSH
• Organoplatinum Compounds pharmacology   MeSH
• Platinum MeSH
• Prodrugs * MeSH
• Antineoplastic Agents * MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1,10-phenanthroline MeSH Browser
• Anti-Inflammatory Agents, Non-Steroidal MeSH
• Diclofenac MeSH
• Ligands MeSH
• Organoplatinum Compounds MeSH
• Platinum MeSH
• Prodrugs * MeSH
• Antineoplastic Agents * MeSH

Helicates and related metallofoldamers, synthesised by dynamic self-assembly, represent an area of chemical space inaccessible by traditional organic synthesis, and yet with potential for discovery of new classes of drug. Here we report that water-soluble, optically pure Fe(ii)- and even Zn(ii)-based triplex metallohelices are an excellent platform for post-assembly click reactions. By these means, the in vitro anticancer activity and most importantly the selectivity of a triplex metallohelix Fe(ii) system are dramatically improved. For one compound, a remarkable array of mechanistic and pharmacological behaviours is discovered: inhibition of Na+/K+ ATPase with potency comparable to the drug ouabain, antimetastatic properties (including inhibition of cell migration, re-adhesion and invasion), cancer stem cell targeting, and finally colonosphere inhibition competitive with the drug salinomycin.

• Publication type
• Journal Article MeSH

2-Amino-5,10-dihydro-5,10-dioxo-4(pyridine-3-yl)-4H-benzo[g]chromene-3-carbonitrile 5, a cytotoxic lawsone derivative, was reacted with [Ru(p-cymene)Cl2]2 to afford a new Ru(II) 'piano-stool' complex 6 which differed from its ligand 5 by a greater selectivity for highly invasive 518A2 melanoma cells over human dermal fibroblasts in MTT cytotoxicity assays, and by inducing senescence rather than apoptosis in the former. DNA is a likely cellular target of complex 6 as it bound, presumably non-covalently, to linear and circular double-stranded DNA in vitro and as ruthenium was found in the lysate of nuclei of treated 518A2 melanoma cells. It also caused a fivefold increase of reactive oxygen species in these cells, originating from a more persistent redox cycling as visualised by cyclic voltammetry.

• Keywords
• Anticancer agents, Lawsone, Melanoma, Naphthoquinone, Ruthenium(II) complex, Senescence,
• MeSH
• Cell Line MeSH
• Coordination Complexes chemistry   pharmacology   MeSH
• DNA, Circular metabolism   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Oxidation-Reduction MeSH
• Cell Proliferation drug effects   genetics   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Ruthenium chemistry   MeSH
• Cellular Senescence drug effects   genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Coordination Complexes MeSH
• DNA, Circular MeSH
• Antineoplastic Agents MeSH
• Reactive Oxygen Species MeSH
• Ruthenium MeSH