Synthesis and Evaluation of Series of Diazine-Bridged Dinuclear Platinum(II) Complexes through in Vitro Toxicity and Molecular Modeling: Correlation between Structure and Activity of Pt(II) Complexes

Abstract

Polynuclear Pt(II) complexes are a novel class of promising anticancer agents with potential clinical significance. A series of pyrazine (pz) bridged dinuclear Pt(II) complexes with general formulas {[Pt(L)Cl]2(μ-pz)}(2+) (L, ethylenediamine, en; (±)-1,2-propylenediamine, 1,2-pn; isobutylenediamine, ibn; trans-(±)-1,2-diaminocyclohexane, dach; 1,3-propylenediamine, 1,3-pd; 2,2-dimethyl-1,3-propylenediamine, 2,2-diMe-1,3-pd) and one pyridazine (pydz) bridged {[Pt(en)Cl]2(μ-pydz)}(2+) complex were prepared. The anticancer potential of these complexes were determined through in vitro cytotoxicity assay in human fibroblasts (MRC5) and two carcinoma cell lines (A375 and HCT116), interaction with double stranded DNA through in vitro assay, and molecular docking study. All complexes inhibited cell proliferation with inhibitory concentrations in the 0.5-120 μM range. While {[Pt(1,3-pd)Cl]2(μ-pz)}(2+) showed improved activity and {[Pt(en)Cl]2(μ-pydz)}(2+) showed comparable activity to that of clinically relevant cisplatin, {[Pt(en)Cl]2(μ-pydz)}(2+) was less toxic in an assay with zebrafish (Danio rerio) embryos, causing no adverse developmental effects. The in vitro cytotoxicity of all diazine-bridged dinuclear Pt(II) complexes is discussed in correlation to their structural characteristics.

Synthesis, spectroscopic and X-ray characterization of various pyrazine-bridged platinum(II) complexes: 1H NMR comparative study of their catalytic abilities in the hydrolysis of methionine- and histidine-containing dipeptides

“…The NMR chemical shifts for complexes 1 and 2 have been previously reported [9] and here these spectral data have been repeated and discussed in comparison with those for the uncoordinated diamine ligands and complex 3. All chemical shifts for the uncoordinated diamine X and pz ligands generally agree with the literature values [16].…”

A new class of platinum(ii) complexes with the phosphine ligand pta which show potent anticancer activity

“…64 This semi-empirical level of theory has already been successfully applied to metal complex geometry optimization in similar docking studies. 65,66 All geometry optimization calculations were performed using the Gaussian 09 molecular package. 67 As a model to study the interaction between the metal complex and DNA the structure of the B-DNA dodecamer d(CGCGAATTCGCG) 2 (PDB:1BNA) was used.…”

“…69 MVD has been successfully applied in docking studies of metal complexes in DNA. 65,70 Hydrogen bonds, and hydrophilic and hydrophobic interactions between the studied complexes and DNA were calculated. The binding site was computed with a grid resolution of 0.3 Å.…”

Novel heteronuclear Pt (II)‐L‐Zn (II) complexes: synthesis, interactions with biomolecules, cytotoxic properties. Two metals give promising antitumor activity?

“…[ 29 ] Some complexes with pyrazine as linker such as {[Pt(1,3‐pd)Cl] 2 ( μ ‐pz)} 2+ showed improved activity while with linker pyradizine {[Pt (en)Cl] 2 ( μ ‐pydz)} 2+ showed comparable activity to that of clinically relevant cisplatin. [ 30 ] The new isomeric azine‐bridged complexes ([{ cis ‐Pt (NH 3 ) 2 Cl} 2 ( μ ‐pzn)]Cl 2 (pzn = pyrazine) and its corresponding nitrate salt, [{ cis ‐Pt (NH 3 ) 2 Cl} 2 ( μ ‐pmn)]Cl 2 (pmn = pyrimidine), and [{ cis ‐Pt (NH 3 ) 2 Cl}2( μ ‐pdn)](NO 3 ) 2 (pdn = pyridazine) show lower cytotoxicity than cisplatin for the human tumor cell lines except for the IGROV cell line (ovarian cancer). [ 31 ]…”