Rational Design of Near-Infrared-Absorbing Pt(II)-Chelated Azadipyrromethene Dyes as a New Generation of Photosensitizers for Synergistic Phototherapy.

Pt(II) photosensitizers are emerging as novel Pt anticancer agents for cancer photodynamic therapy (PDT) to avoid uncontrollable toxicity of cisplatin. However, the application of Pt(II) photosensitizers is limited by tumor hypoxia and the poor penetration depth of excitation light. To overcome these drawbacks, exploiting the next generation of Pt anticancer agents is of urgent need. According to theoretical calculations, novel near-infrared (NIR)-absorbing Pt(II)-chelated azadipyrromethene dyes (PtDP-X, where X = N, C, and S) were designed. Importantly, spin-orbit coupling of the Pt atom could promote the intersystem crossing of a singlet-to-triplet transition for converting oxygen to singlet oxygen (1O2), and the azadipyrromethene skeleton could provide a strong photothermal effect. As expected, PtDP-X exhibited intense NIR absorption and synergistic PDT and photothermal effects with low dark cytotoxicity. Furthermore, water-soluble and biocompatible PtDP-N nanoparticles (PtDP-N NPs) were prepared that achieved effective tumor cell elimination with low side effects under 730 nm light irradiation in vitro and in vivo. This pioneering work could push the exploitation of NIR-absorbing metal-chelated azadipyrromethene dyes, so as to promote the positive evolution of phototherapy agents.

Anticancer drug impact on DNA - a study by neutron spectroscopy coupled with synchrotron-based FTIR and EXAFS.

Complementary structural and dynamical information on drug-DNA interplay has been achieved at a molecular level, for Pt/Pd-drugs, allowing a better understanding of their pharmacodynamic profile which is crucial for the development of improved chemotherapeutic agents. The interaction of two cisplatin-like dinuclear Pt(ii) and Pd(ii) complexes with DNA was studied through a multidisciplinary experimental approach, using quasi-elastic neutron scattering (QENS) techniques coupled with synchrotron-based extended X-ray absorption fine structure (SR-EXAFS) and Fourier-Transform Infrared Spectroscopy-Attenuated Total Reflectance (SR-FTIR-ATR). DNA extracted from drug-exposed human triple negative breast cancer cells (MDA-MB-231) was used, with a view to evaluate the effect of the unconventional antineoplastic agents on this low prognosis type of cancer. The drug impact on DNA's dynamical profile, via its hydration layer, was provided by QENS, a drug-triggered enhanced mobility having been revealed. Additionally, an onset of anharmonicity was detected for dehydrated DNA, at room temperature. Far- and mid-infrared measurements allowed the first simultaneous detection of the drugs and their primary pharmacological target, as well as the drug-prompted changes in DNA's conformation that mediate cytotoxicity. The local environment of the absorbing Pd(ii) and Pt(ii) centers in the drugs' adducts with adenine, guanine and glutathione was attained by EXAFS.

Evolution of 1, 3, 5-trisubstituted bipyrazole scaffold based platinum(II) complexes as a biological active agent.

Square planar mononuclear platinum(II) complexes having general formula [Pt(Ln)Cl2], (where, Ln = L1-4) were synthesized with neutral bidentate heterocyclic 1,3,5-trisubstituted bipyrazole based ligands. The synthesized compounds were characterized by physicochemical method such as TGA, molar conductance, micro-elemental analysis and magnetic moment, and spectroscopic method such as, FT-IR, UV-vis, 1H NMR, 13C NMR and mass spectrometry. Biological applications of the compounds were carried out using in vitro brine shrimp lethality bioassay, in vitro antimicrobial study against five different pathogens, and cellular level cytotoxicity against Schizosaccharomyces pombe (S. Pombe) cells. Pt(II) complexes were tested for DNA interaction activities using electronic absorption titration, viscosity measurements study, fluorescence quenching technique and molecular docking assay. Binding constants (Kb) of ligands and complexes were observed in the range of 0.23-1.07 × 105 M-1 and 0.51-3.13 × 105 M-1, respectively. Pt(II) complexes (I-IV) display an excellent binding tendency to biomolecule (DNA) and possess comparatively high binding constant (Kb) values than the ligands. The DNA binding study indicate partial intercalative mode of binding in complex-DNA. The gel electrophoresis activity was carried out to examine DNA nuclease property of pUC19 plasmid DNA.

Platinum(iv) anticancer prodrugs - hypotheses and facts.

In this manuscript we focus on Pt(iv) anticancer prodrugs. We explore the main working hypotheses for the design of effective Pt(iv) prodrugs and note the exceptions to the common assumptions that are prevalent in the field. Special attention was devoted to the emerging class of "dual action" Pt(iv) prodrugs, where bioactive ligands are conjugated to the axial positions of platinum in order to obtain orthogonal or complementary effects that will increase the efficacy of killing the cancer cells. We discuss the rationale behind the design of the "dual action" prodrugs and the results of the pharmacological studies obtained. Simultaneous release of two bioactive moieties inside the cancer cells often triggers several processes that together determine the fate of the cell. Pt(iv) complexes provide many opportunities for applying new concepts in targeting, synergistic cell killing and exploiting novel nanodelivery systems.

In Situ Biosynthesis of Fluorescent Platinum Nanoclusters: Toward Self-Bioimaging-Guided Cancer Theranostics.

Among the noble-metal clusters, very few reports about platinum clusters were used as bioimaging probes of tumors except as a reducing catalyst. It is first established herein that the biocompatible platinum nanoclusters are spontaneously biosynthesized by cancerous cells (i.e., HepG2 (human hepatocarcinoma), A549 (lung cancer), and others) rather than noncancerous cells (i.e., L02 (human embryo liver cells)) when incubated with micromolar chloroplatinic acid solutions. These in situ biosynthesized platinum nanoclusters could be readily realized in a biological environment and emit a bright fluorescence at 460 nm, which could be further utilized to facilitate an excellent cancer-cell-killing efficiency when combined with porphyrin derivatives for photothermal treatment. This raises the possibility of providing a promising and precise bioimaging strategy for specific fluorescent self-biomarking of tumor locations and realizing fluorescence imaging-guided photothermal therapy of tumors.

Materials and fractal designs for 3D multifunctional integumentary membranes with capabilities in cardiac electrotherapy.

Advanced materials and fractal design concepts form the basis of a 3D conformal electronic platform with unique capabilities in cardiac electrotherapies. Fractal geometries, advanced electrode materials, and thin, elastomeric membranes yield a class of device capable of integration with the entire 3D surface of the heart, with unique operational capabilities in low power defibrillation. Co-integrated collections of sensors allow simultaneous monitoring of physiological responses. Animal experiments on Langendorff-perfused rabbit hearts demonstrate the key features of these systems.

Trifolium-like Platinum Nanoparticle-Mediated Photothermal Therapy Inhibits Tumor Growth and Osteolysis in a Bone Metastasis Model.

Bone metastasis is a frequent and fatal complication of cancer that lacks effective clinical treatment. Photothermal therapy represents a new strategy for the destruction of multiple cancers. In this study, trifolium-like platinum nanoparticles (TPNs) with small size and excellent photothermal conversion property are prepared via a facile and green method. TPNs show minimal cytotoxicity on normal cell lines and kill cancer cells upon exposure to a near-infrared light. These nanoparticles effectively inhibit tumor growth and prevent osteolysis in a bone metastasis model. This study offers a promising strategy in the treatment of bone metastasis.

A platinum(II) complex of liriodenine from traditional Chinese medicine (TCM): Cell cycle arrest, cell apoptosis induction and telomerase inhibition activity via G-quadruplex DNA stabilization.

Liriodenine (L), an antitumor active ingredient from the traditional Chinese medicine (TCM), Zanthoxylum nitidum, afforded a platinum(II) complex (1) of L, cis-[PtCl2(L)(DMSO)], which previously reported for its in vitro antitumor activity and intercalative binding with DNA. In this study, complex 1 was further discussed for its antitumor mechanism and structure-activity relationship, comparing with L and cisplatin. Towards the most sensitive BEL-7404 human hepatoma cells, complex 1 significantly induced cell cycle arrest at both G2/M phase and S phase. It suggests that double helix DNA is not the simplex intracellular target for 1. On the other hand, the BEL-7404 cells incubated with 1 and stained by Hoechst 33258 and AO/EB showed typical cell apoptosis in dose-dependent manner. The BEL-7404 cells incubated with 1 and stained by JC-1 were also characteristic for cell apoptosis on the loss of mitochondrial membrane potential. Furthermore, the G-quadruplex DNA binding property of complex 1 was also investigated by spectroscopic analyses, fluorescent indicator displacement (FID) assay and fluorescence resonance energy transfer (FRET) assay. The results indicated that 1 stabilized the human telomeric G4-HTG21 DNA better than L. The telomerase inhibition ratio of 1 ((62.50±0.03)%), which was examined by telomerase polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA), was much higher than L ((21.77±0.01)%). It can be ascribed to the better G4-HTG21 DNA stabilization of 1 than L. The results suggested that the nuclei, mitochondria and telomerase via G-quadruplex DNA stabilization all should be key targets for the antitumor mechanism of 1, in which the central platinum(II) played a key role.

Plant-mediated synthesis of platinum nanoparticles and its bioreductive mechanism.

Pt nanoparticles (PtNPs) were biologically synthesized by reducing Na2PtCl4 with Cacumen Platycladi Extract (CPE). The effects of reaction temperature, initial Pt(II) concentration, and CPE percentage on Pt(II) conversion and the size distribution of the PtNPs were studied. The results showed that the Pt(II) conversion rate reached 95.9% and that PtNPs measuring 2.4±0.8nm were obtained under the following conditions: reaction temperature, 90°C; CPE percentage, 70%; initial Pt(II) concentration, 0.5mM; reaction time, 25h. In addition, the bioreduction of Pt(II) was attributed to reducing sugars and flavonoids rather than proteins. The elucidation of bioreductive mechanism of Pt(II) ions was achieved by investigating the changes that occurred in the reducing sugar, flavonoid and protein concentrations in the plant extract, leading to a good insight into the formation mechanism of such biosynthesized PtNPs.

Structure, solution chemistry, antiproliferative actions and protein binding properties of non-conventional platinum(II) compounds with sulfur and phosphorus donors.

Twelve Pt(II) complexes with cis-PtP(2)S(2) pharmacophores (where P(2) refers to two monodentate or one bidentate phosphane ligand and S(2) is a dithiolato ligand) were prepared, characterized and evaluated as potential antiproliferative agents. The various compounds were first studied from the structural point of view; afterward, their solubility properties as well as their solution behaviour were analyzed in detail. Antiproliferative properties were specifically evaluated against A2780 human ovarian carcinoma cells, either resistant or sensitive to cisplatin. For comparison purposes similar studies were carried out on four parent cis-dichloro bisphosphane Pt(II)complexes. On the whole, the cis-PtP(2)S(2) compounds displayed significant antiproliferative properties while the cis-PtP(2)Cl(2) (cis-dichloro bisphosphane Pt(II)) compounds revealed quite poor biological performances. To gain further insight into the molecular mechanisms of these bisphosphane Pt(II) compounds, the reactions of selected complexes against the model protein cytochrome c were investigated by ESI-MS and their adduct formation explored. A relevant reactivity with cyt c was obtained only for cis-PtP(2)Cl(2) compounds, whereas cis-PtP(2)S(2) compounds turned out to be nearly unreactive. The obtained results are interpreted and discussed in the frame of the current knowledge of anticancer platinum compounds and their structure-activity-relationships. The observation of appreciable antiproliferative effects for the relatively inert cis-PtP(2)S(2) compounds strongly suggests that these compounds will undergo specific activation within the cellular environment.

Molecular interaction fields (MIFs) to predict lipophilicity and ADME profile of antitumor Pt(II) complexes.

PURPOSE: To describe a computational tool to calculate molecular descriptors of potential application in ADME virtual screening of antitumor Pt(II) drug candidates. METHODS: The multistep computational procedure consists in (a) building and optimization (PM3) of the 3D structures of the investigated complexes, (b) parametrization of Pt(II) and its implementation in GRID, (c) GRID calculations and extraction of the information content with VolSurf and BIOCUBE4mf, and (d) PLS analysis to look for the correlation between experimental data and the molecular descriptors. RESULTS: The following results were obtained: (a) the calibration of the GRID force field to take into account the platinum di-cation, (b) solid PLS models between log k30 and log kw with VolSurf descriptors which highlight the main structural differences between the two chromatographic parameters, (c) the prediction of virtual (of each conformer) log k30 and log kw, and (d) the identification of the main descriptors governing VD(ss) of drugs in clinical use. CONCLUSION: The study suggests a strategy to identify good Pt(II) complexes prior to their synthesis to eliminate as soon as possible drug candidates with unfavorable PK profile.

Potential new inorganic antitumour agents from combining the anticancer traditional Chinese medicine (TCM) liriodenine with metal ions, and DNA binding studies.

Liriodenine (), an active component of the anticancer traditional Chinese medicine (TCM), was isolated from Zanthoxylum nitidum. Its reactions with Pt(II) and Ru(II) afforded three metal complexes: cis-[PtCl2(L)] (), cis-[PtCl2(L)(DMSO)] (), and cis-[RuCl2(L)(DMSO)2].1.5H2O (), the crystal structures of , and were determined by single-crystal X-ray diffraction methods. These complexes were fully characterized by elemental analysis, IR spectrophotometry, 1H and 13C NMR spectroscopies, and ES mass spectrometry. The in vitro cytotoxicity of and complexes against 11 human tumour cell lines was assayed. The metal-based compounds exhibit enhanced cytotoxicity vs. free , suggesting that these compounds display synergy in the combination of metal ions and liriodenine. The binding properties of and its complexes to ct-DNA were investigated through UV-vis, fluorescence, CD spectra, viscosity and agarose gels electrophoretic measurements.

Theoretical study of pyrazolate-bridged dinuclear platinum(II) complexes: interesting potential energy curve of the lowest energy triplet excited state and phosphorescence spectra.

Four kinds of 3,5-dialkylpyrazolate(R2pz)-bridged dinuclear platinum(II) complexes [Pt2(mu-R2pz)2(dfppy)2] (dfppy=2-(2,4-difluorophenyl)pyridine; R2pz=pyrazolate in 1, 3,5-dimethylpyrazolate in 2, 3-methyl-5- tert-butylpyrazolate in 3, and 3,5-bis(tert-butyl)pyrazolate in 4) were theoretically investigated by the DFT(B3PW91) method. The Stokes shift of their phosphorescence spectra was discussed on the basis of the potential energy curve (PEC) of the lowest energy triplet excited state (T1). This PEC significantly depends on the bulkiness of substituents on pz. In 1 and 2, bearing small substituents on pz, one local minimum is present in the T1 state besides a global minimum. The local minimum geometry is similar to the S0-equilibrium one. The T1 state at this local minimum is characterized as the pi-pi* excited state in dfppy, where the dpi orbital of Pt participates in this excited state through an antibonding interaction with the pi orbital of dfppy; in other words, this triplet excited state is assigned as the mixture of the ligand-centered pi-pi* excited and metal-to-ligand charge transfer excited state ((3)LC/MLCT). The geometry of the T1-global minimum is considerably different from the S0-equilibrium one. The T1 state at the global minimum is characterized as the triplet metal-metal-to-ligand charge transfer ((3)MMLCT) excited state, which is formed by the one-electron excitation from the dsigma-dsigma antibonding orbital to the pi* orbital of dfppy. Because of the presence of the local minimum, the geometry change in the T1 state is suppressed in polystyrene at room temperature (RT) and frozen 2-methyltetrahydrofuran (2-MeTHF) at 77 K. As a result, the energy of phosphorescence is almost the same in these solvents. In fluid 2-MeTHF at RT, on the other hand, the geometry of the T1 state easily reaches the T1-global minimum. Because the T1-global minimum geometry is considerably different from the S0-equilibrium one, the phosphorescence occurs at considerably low energy. These are the reasons why the Stokes shift is very large in fluid 2-MeTHF but small in polystyrene and frozen 2-MeTHF. In 3 and 4, bearing bulky tert-butyl substituents on pz, only the T1-global minimum is present but the local minimum is not. The electronic structure of this T1-global minimum is assigned as the (3)MMLCT excited state like 1 and 2. Though frozen 2-MeTHF suppresses the geometry change of 3 and 4 in the T1 state, their geometries moderately change in polystyrene because of the absence of the T1-local minimum. As a result, the energy of phosphorescence is moderately lower in polystyrene than in frozen 2-MeTHF. The T1-global minimum geometry is much different from the S0-equilibrium one in 3 but moderately different in 4, which is interpreted in terms of the symmetries of these complexes and the steric repulsion between the tert-butyl group on pz and dfppy. Thus, the energy of phosphorescence of 3 is much lower in fluid 2-MeTHF than in frozen 2-MeTHF like 1 and 2 but that of 4 is moderately lower; in other words, the Stokes shift in fluid 2-MeTHF is small only in 4.

Incorporation of two modified nucleosides allows selective platination of an oligonucleotide making it suitable for duplex cross-linking.

Platinated oligonucleotides are promising tools for the control of gene expression, since they may target and cross-link nucleic acid chains. Here we describe a method for the preparation of platinated oligonucleotides that has proved able to selectively cross-link complementary sequences, making use of 5-methylcytidine analogs with thioether or imidazole groups attached to the 4-position. These nucleoside analogs were derivatized as phosphoramidites and introduced in oligonucleotide chains using standard phosphite triester chemistry. Different oligonucleotide sequences containing either one or two analogs appending from the 5'-end were synthesized and used in preliminary platination studies. The reaction of transplatin with oligonucleotides containing the thioether-modified nucleobase was fast, but generally afforded unstable adducts and complex reaction mixtures. The imidazole-containing oligonucleotides reacted with transplatin much more slowly, in particular at slightly basic pH, and it was found that the imidazole-modified cytosine was less reactive than the natural nucleobases. In contrast, transplatin selectively reacted with the thioether and imidazole groups of oligonucleotides containing the two cytosine analogs in neighboring positions, even in the presence of the four nucleobases and particularly three guanines, affording platinated oligonucleotides suitable for cross-linking.

Construction of double-stranded metallosupramolecular polymers with a controlled helicity by combination of salt bridges and metal coordination.

We describe the construction of the first double-stranded metallosupramolecular helical polymers. We designed and synthesized a supramolecular duplex comprised of complementary m-terphenyl-based strands bearing a chiral amidine or achiral carboxylic acid together with two pyridine groups at the four ends. Supramolecular polymerization of the duplex with cis-PtPh2(DMSO)2 in 1,1,2,2-tetrachloroethane produced the double-stranded metallosupramolecular polymer with a controlled helicity of which the two complementary metallostrands are intertwined through the amidinium-carboxylate salt bridges. The structures and hydrodynamic dimensions of the metallosupramolecular polymers were characterized by 1H NMR, diffusion-ordered NMR, dynamic light scattering, absorption, and CD measurements. The polymeric structure was also visualized by atomic force microscopy.

Genosensor based on a platinum(II) complex as electrocatalytic label.

Voltammetric genosensors on streptavidin-modified screen-printed carbon electrodes (SPCEs) for the detection of virulence nucleic acid determinants of pneumolysin (ply) and autolysin (lytA) genes, exclusively present on the genome of the human pathogen Streptococcus pneumoniae, were described. The oligonucleotide probes were immobilized on electrochemically pretreated SPCEs through the streptavidin/biotin reaction. After that, the hybridization reaction was carried out with labeled complementary targets on the electrode surface. The ply and lytA targets were labeled using the universal linkage system, which consists of the use of a platinum(II) complex that acts as coupling agent between targets and a, usually fluorescent, molecule label. In this case, the platinum(II) complex acts as a label itself because the analytical signal is achieved by measuring chronoamperometrically the current generated by the hydrogen evolution catalyzed by platinum. In nonstringent experimental conditions, these genosensors can detect 24.5 fmol of 20-mer oligonucleotide target and discriminate between a complementary oligo and an oligo with a three-base mismatch. In presence of 25% formamide in the hybridization buffer, a single-base mismatch on the oligonucleotide target can be detected.

Prevention of HIV-1 infection by platinum triazines.

To identify and explore the activity of compounds which may act as anti-HIV virucidal agents, we have investigated platinum compounds, especially those containing N-donor aromatic ligands. After screening over 70 related agents, including N-donor aromatic ligands and metal precursors, we have identified a novel class of platinum(II) complexes with 2-pyridyl-1,2,4-triazine derivatives and Pt(II) formulations with these derivatives (ptt compounds) as having the highest anti-HIV activity. The maximum activity was observed when the agents were added immediately post-infection. The ptt agents did not block cell fusion activity of HIV-1 Env proteins in cells bearing CD4X4 or CD4R5 receptors, indicating a lack of interaction with the Env protein. The ptt compounds exhibit low toxicity for human epithelial cells, and are thus promising candidates for use as microbicides or antiviral agents against HIV.

Amorphous Se: a new platform for synthesizing superparamagnetic colloids with controllable surfaces.

We have successfully incorporated iron oxide nanoparticles into monodispersed amorphous selenium (a-Se) colloids by regulating the reaction temperature during the synthesis of a-Se. The surfaces of these a-Se colloids could be coated with conformal and smooth shells made of Pt and SiO2. The Se cores could then be removed by etching with hydrazine. The spherical morphology and superparamagnetism were maintained in all these synthetic steps. The presence of Pt and SiO2 on the outer surfaces of these colloidal particles allows one to control their surface functionalities through the formation of alkanethiolate and siloxane monolayers, respectively.

Biological evaluation of novel estrogen-platinum(II) hybrid molecules on uterine and ovarian cancers-molecular modeling studies.

We have recently reported the synthesis of a series of original 17beta-estradiol-linked platinum(II) hybrid molecules. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent (ER(+) and ER(-)) human uterine and ovarian cancers. The hybrid molecules present higher affinity than that of 17beta-estradiol for the estrogen receptor alpha (ERalpha). The cytotoxicity and the affinity of the hybrid molecules are explained using molecular modeling analysis. This study further confirms that the derivatives made of a 2-(2'-aminoethyl)pyridine ligand displayed superior activity against the cell lines particularly when the connecting arm is 8-10 carbon atoms long. Molecular modeling shows that a long side chain can facilitate the access of the platinum(II) moiety to DNA. The novel compounds also prove to be moderately cytotoxic against platinum resistant endometrial and ovarian cancer cell lines.

Triplex mediated delivery of a platinum complex to a specific DNA target site.

Tethering an ethylene diamine linker to the 5' terminus of an oligothymidine sequence provides a site for complexation with K(2)PtCl(4). Due to the low reactivity of dT toward a platinum source, we chose dT(8) and dT(15) as our initial synthetic targets for platination. Post-synthetic reaction of the platinum reagent with the diamino oligothymidine generates the diamino dichloro platinum-DNA conjugate that can be used for DNA duplex targeting by oligodeoxyncleotide-mediated triplex formation. The dT(8) sequence is not sufficiently long to facilitate triplex formation and Pt-cross-linking, whereas with a dT(15) sequence cross-linking between the third strand and the duplex occurs exclusively with the duplex target strand directly involved in triplex formation. No examples of cross-linking to the complementary target strand, or of cross-linking to both target strands are observed. Most efficient cross-linking occurs when the dinucleotide d(GpG) is present in the target strand and no cross-linking occurs with the corresponding 7-deazaG dinucleotide target. Cross-linking is also observed when dC or dA residues are present in the target strand, or even with a single dG residue, but it is not observed in any cases to dT residues. Triplex formation provides the ability to target specific sequences of double-stranded DNA and the orientational control arising from triplex formation is sufficient to alter the binding preferences of platinum. Conjugates of the type described here offer the potential of delivering a platinum complex to a specific DNA site.