High Selectivity in Csp2-Csp2 versus Csp3-O Reductive Elimination from Cycloplatinated(IV) Complexes.

The cycloplatinated(IV) complexes trans-[Pt(p-MeC6H4)(C∧N)(OAc)2(H2O)] (C∧N = benzo[h]quinolate, bhq, 2a, and 2-phenylpyridinate, ppy, 2b) were prepared by reacting the corresponding [Pt(p-MeC6H4)(C∧N)(SMe2)] precursors with PhI(OAc)2 through an oxidative addition (OA) reaction. Thermolysis of 2a at 65 °C generates cis-[Pt(κ1N-10-(p-MeC6H4)-bhq)(OAc)2(H2O)], 3a, which is the product of a Csp2Ar-Csp2bhq reductive elimination (RE). The observed coupling reaction is significantly different from the previously reported analogous thermolysis of trans-[PtMe(C∧N)(OAc)2(H2O)] (C∧N = bhq, 2c, and ppy, 2d) that selectively releases Me-OAc (C-O RE). The density functional theory (DFT) calculations and experimental observations reveal that the Csp2Ar-Csp2bhq coupling reaction occurs through the dissociation of a coordinated water ligand. This in turn is followed by the concomitant bond forming and bond breaking process via a three-center ring transition state, in contrast to the Csp3Me-OAc coupling, which had taken place by an outer sphere SN2 type RE reaction in methyl complexes.

Cycloplatinated(II) Derivatives of Mercaptopurine Capable of Binding Interactions with HSA/DNA.

In this study, two new bis-cyclometalated Pt(II) complexes, [Pt(C^N)(S^N)] [S^N = deprotonated 6-mercaptopurine (6-MP) and C^N = deprotonated 2-phenylpyridine (ppy), 2a; C^N = deprotonated benzo[h]quinoline (bhq), 2b], are synthesized by the reaction of [PtR(SMe2)(C^N)] (R = Me or p-MeC6H4) with 1 equiv of 6-mercaptopurine (6-HMP) at room temperature. The complexes are fully characterized using 1H and 13C NMR spectroscopies, electrospray ionization mass spectrometry, and elemental analysis. Biomolecular interaction of complex 2a with human serum albumin (HSA) is studied by fluorescence, UV-vis, and circular dichroism (CD) spectroscopies. The binding constants (Kb) and number of binding sites (n) are evaluated using the Stern-Volmer equation. The intrinsic fluorescence of protein is quenched by a static quenching mechanism, with a binding constant of Kb ∼ 105 reflecting a high affinity of complex 2a for HSA. The thermodynamic parameters (ΔH°, ΔG°, and ΔS°) indicate that the interaction is a spontaneous process and hydrophobic forces play a main role in the reaction. The displacement experiments demonstrate that the reactive binding sites of HSA to complex 2a are mainly located within its hydrophobic cavity in subdomain IIA (site I). Synchronous fluorescence spectra reveal that complex 2a affected the microenvironment of tryptophan-214 residues in subdomain IIA of HSA. In the case of interaction of complex 2b and HSA, because of overlapping of the emission spectra of complex 2b with HSA, chemometric approaches are applied. The results indicate significant interaction between the tryptophan residue of HSA and complex 2b. Moreover, the binding of Pt(II) complexes 2a and 2b causes a reduction of the α-helix content of HSA, as obtained by far-UV CD spectroscopy. The average binding distance (r) between Pt(II) complexes and HSA is obtained by Förster's resonance energy-transfer theory. Also, a molecular docking simulation reveals that π-π-stacking and hydrophobic interactions between these complexes and HSA are significant. Furthermore, the interactions of platinum complexes, 2, with calf-thymus DNA (CT-DNA) are investigated. The UV-vis results and ethidium bromide competitive studies support an intercalative interaction of both Pt(II) complexes with DNA. The new complexes 2 are also screened for anticancer activities. The results show that complexes 2 exhibit significant anticancer activity against the K562 (chronic myelogenous leukemia) cell line.

Origami paper analytical assay based on metal complex sensor for rapid determination of blood cyanide concentration in fire survivors.

Cyanide-based blood poisoning can seriously damage fire victims and cause death if not detected quickly. Previous conventional methods require laboratory equipment, which are expensive and increase the duration of the analysis. Here, a simple origami based microfluidic device was introduced for point of need detection of blood cyanide concentration in people involved in fire. The device is made of four layers of paper. Each layer was in the size of 1 × 1 cm folded on each other. In this work, the blood sample was acidified by trichloroacetic acid to separate cyanide from methaemoglobin in the form of HCN gas. The produced gas released into borate buffer to recover free cyanide ions which interacted with the Pt complex ([Pt(p-MeC6H4)2(phen)]) used as a receptor in this study. Optimized conditions were applied to have a suitable interaction causing the color of the receptor to change from yellow to colorless. The color changes were recorded by a smartphone, and the sensor response was calculated by the routine image analysis software. The assay was capable of determining cyanide ions at different concentrations in the range of 1.0 to 100.0 µmol L-1. The detection limit of these determination was equal to 0.4 µmol L-1. The assay responses were not affected by the interfering species. As a practical analysis, the proposed sensor was applied to determine cyanide ions in the blood sample of 20 studied fire survivors and 10 controls with high accuracy.

Comparative study on the interaction of two binuclear Pt (II) complexes with human serum albumin: Spectroscopic and docking simulation assessments.

Human serum albumin (HSA) principally tasks as a transport carrier for a vast variety of natural compounds and pharmaceutical drugs. In the present study, two structurally related binuclear Pt (II) complexes containing cis, cis-[Me2Pt (µ-NN) (µ-dppm) PtMe2] (1), and cis, cis-[Me2Pt(µ-NN)(µ dppm) Pt((CH2)4)] (2) in which NN=phthalazine and dppm=bis (diphenylphosphino) methane were used to investigate their interaction with HSA, using UV-Vis absorption spectroscopy, fluorescence, circular dichroism and molecular dynamic analyses. The spectroscopic results suggest that upon binding to HSA, the binuclear Pt (II) complexes could effectively induce structural alteration of this protein. These complexes can bind to HSA with the binding affinities of the following order: complex 2>complex 1. Moreover, the thermodynamic parameters of binding between these complexes and HSA suggested the existence of entropy-driven spontaneous interaction, which mostly dominated with the hydrophobic forces. The ANS fluorescence results also indicated that two binuclear Pt (II) complexes were competing for the binding to the hydrophobic regions on HSA. In addition, competitive displacement assay and docking simulation study revealed that complexes 1 and 2 bind to the drug binding sites II and I on HSA, respectively. Furthermore, complex 2, with the higher binding affinity for HSA, shows more denaturing effect on this protein. Considering the protein structural damages in the pathway of harmful side effects of platinum drugs, complex 1 with the moderate binding affinity and low denaturing effect might be of high significance.

Anticancer activity assessment of two novel binuclear platinum (II) complexes.

In the current study, two binuclear Pt (II) complexes, containing cis, cis-[Me2Pt (µ-NN) (µ-dppm) PtMe2] (1), and cis,cis-[Me2Pt(µ-NN)(µ dppm) Pt((CH2)4)] (2) in which NN=phthalazine and dppm=bis (diphenylphosphino) methane were evaluated for their anticancer activities and DNA/purine nucleotide binding properties. These Pt (II) complexes, with the non-classical structures, demonstrated a significant anticancer activity against Jurkat and MCF-7 cancer cell lines. The results of ethidium bromide/acridine orange staining and Caspase-III activity suggest that these complexes were capable to stimulate an apoptotic mechanism of cell death in the cancer cells. Using different biophysical techniques and docking simulation analysis, we indicated that these complexes were also capable to interact efficiently with DNA via a non-intercalative mechanism. According to our results, substitution of cyclopentane (in complex 2) with two methyl groups (in complex 1) results in significant improvement of the complex ability to interact with DNA and subsequently to induce the anticancer activity. Overall, these binuclear Pt (II) complexes are promising group of the non-classical potential anticancer agents which can be considered as molecular templates in designing of highly efficient platinum anticancer drugs.

Promoting C-C Bond Coupling of Benzyne and Methyl Ligands in Electron-Deficient (triphos)Pt-CH3+ Complexes.

In situ generated benzyne reacts at room temperature with (triphos)Pt-CH3+ to form a five-coordinate π-complex (2) that is isolable and stable in solution. Thermolysis of 2 at 60 °C generates (triphos)Pt(o-tolyl)+ (3), which is the product of formal migratory insertion of CH3- onto the coordinated benzyne. The reaction of 2 with the acid Ph2NH2+ yields toluene at room temperature over the course of 8 h, while the same reaction with 3 only proceeds to 40% conversion over 2 days. These data indicate that the protonolysis of 2 does not proceed by CH3 migration onto benzyne to form 3 followed by protodemetalation. Instead, the data suggest either that protonation of 2 is first and is followed by H migration to yield a PtIVPh(Me) dication or that this latter species is generated by direct protonolysis of coordinated benzyne prior to reductive elimination of toluene.

DNA binding and anticancer activity of novel cyclometalated platinum (II) complexes.

This study describes anticancer activity and DNA binding properties of two cyclometalated platinum (II) complexes with non-leaving lipophilic ligands; deprotonated 2-phenylpryidine (ppy): C1 and deprotonated benzo[h] quinolone (bhq): C2. Both complexes demonstrate significant anticancer activity and were capable to stimulate Caspase-III activity in Jurkat cancer cells. The results of Acridine orange/Ethidium bromide(AO/EtB), along with those of Caspase-III activity suggest that these complexes can induce apoptosis in the cancer cells. Moreover, C1 with flexible chemical structure indicates considerably higher anticancer activity than C2 which possesses a higher structural rigidity. Additionally, C2 represents a complex which is in part inducing cancer cell death due to the cell injury (necrosis). The absorption spectra of DNA demonstrate a hypochromic effect in the presence of increasing concentration of these complexes, reflecting DNA structural alteration after drug binding. Also, EtB competition assay and docking results revealed partial intercalation and DNA groove binding for the metal complexes. Overall, from the therapeutic point of view, ppy containing platinum complex (C1) is a favored anticancer agent, because it induces signaling cell death (apoptosis) in cancer cells, and lacks the necrotic effect.

DNA Binding and Anticancer Activity of Novel Cyclometalated Platinum (II) Complexes.

This study describes anticancer activity and DNA binding properties of two cyclometalated platinum (II) complexes with non-leaving lipophilic ligands; deperotonated 2-phenylpryidine (ppy): C1 and deperotonated benzo[h]quinolone (bhq): C2. Both complexes demonstrate significant anticancer activity and were capable to stimulate Caspase-III activity in Jurkat cancer cells. The results of Acridine orange/Ethidium bromide(AO/EtB), along with those of Caspase-III activity suggest that these complexes can induce apoptosis in the cancer cells. Moreover, C1 with flexible chemical structure indicates considerably higher anticancer activity than C2 which possesses a higher structural rigidity. Additionally, C2 represents a complex which is in part inducing cancer cell death due to the cell injury (necrosis). The absorption spectra of DNA demonstrate a hypochromic effect in the presence of increasing concentration of these complexes, reflecting DNA structural alteration after drug binding. Also, EtB competition assay and docking results revealed partial intercalation and DNA groove binding for the metal complexes. Overall, from the therapeutic point of view, ppy containing platinum complex (C1) is a favored anticancer agent, because it induces signaling cell death (apoptosis) in cancer cells, and lacks the necrotic effect.