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 * metabolismus   chemie   MeSH
• lidé MeSH
• lidský sérový albumin * metabolismus   chemie   MeSH
• molekulární struktura MeSH
• muramidasa * metabolismus   chemie   MeSH
• nádorové buněčné linie MeSH
• organoplatinové sloučeniny * chemie   farmakologie   chemická syntéza   metabolismus   MeSH
• pankreatická ribonukleasa * metabolismus   chemie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   metabolismus   MeSH
• screeningové testy protinádorových léčiv MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA * MeSH
• lidský sérový albumin * MeSH
• muramidasa * MeSH
• organoplatinové sloučeniny * MeSH
• pankreatická ribonukleasa * MeSH
• protinádorové látky * 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
• antiflogistika nesteroidní farmakologie   MeSH
• diklofenak farmakologie   MeSH
• ligandy MeSH
• nádorové buněčné linie MeSH
• nádory * MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• platina MeSH
• prekurzory léčiv * MeSH
• protinádorové látky * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1,10-phenanthroline MeSH Prohlížeč
• antiflogistika nesteroidní MeSH
• diklofenak MeSH
• ligandy MeSH
• organoplatinové sloučeniny MeSH
• platina MeSH
• prekurzory léčiv * MeSH
• protinádorové látky * 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.

• Publikační typ
• časopisecké články 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.

• Klíčová slova
• Anticancer agents, Lawsone, Melanoma, Naphthoquinone, Ruthenium(II) complex, Senescence,
• MeSH
• buněčné linie MeSH
• komplexní sloučeniny chemie   farmakologie   MeSH
• kruhová DNA metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• oxidace-redukce MeSH
• proliferace buněk účinky léků   genetika   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• ruthenium chemie   MeSH
• stárnutí buněk účinky léků   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• komplexní sloučeniny MeSH
• kruhová DNA MeSH
• protinádorové látky MeSH
• reaktivní formy kyslíku MeSH
• ruthenium MeSH