A Comparative Study of Molecular Structure,pKa, Lipophilicity,Solubility, Absorption and Polar Surface Area of Some Antiplatelet Drugs

Theoretical chemistry methods have been used to study the molecular properties of antiplatelet agents (ticlopidine, clopidogrel, prasugrel, elinogrel, ticagrelor and cangrelor) and several thiol-containing active metabolites. The geometries and energies of most stable conformers of these drugs have been computed at the Becke3LYP/6-311++G(d,p) level of density functional theory. Computed dissociation constants show that the active metabolites of prodrugs (ticlopidine, clopidogrel and prasugrel) and drugs elinogrel and cangrelor are completely ionized at pH 7.4. Both ticagrelor and its active metabolite are present at pH = 7.4 in neutral undissociated form. The thienopyridine prodrugs ticlopidine, clopidogrel and prasugrel are lipophilic and insoluble in water. Their lipophilicity is very high (about 2.5–3.5 logP values). The polar surface area, with regard to the structurally-heterogeneous character of these antiplatelet drugs, is from very large interval of values of 3–255 Ų. Thienopyridine prodrugs, like ticlopidine, clopidogrel and prasugrel, with the lowest polar surface area (PSA) values, exhibit the largest absorption. A high value of polar surface area (PSA) of cangrelor (255 Ų) results in substantial worsening of the absorption in comparison with thienopyridine drugs.     

Mechanism of cytotoxicity and cellular uptake of lipophilic inert dinuclear polypyridylruthenium(II) complexes

The accumulation, uptake mechanism, cytotoxicity, cellular localisation of—and mode of cell death induced by—dinuclear ruthenium(II) complexes ΔΔ/ΛΛ‐[{Ru(phen)₂}₂{μ‐bb_n}]⁴⁺ (Rubb_n), where phen is 1,10‐phenanthroline, bb_n is bis[4(4′‐methyl‐2,2′‐bipyridyl)]‐1,n‐alkane (n=2, 5, 7, 10, 12 or 16), and the corresponding mononuclear complexes containing the bb_n ligands, were studied in L1210 murine leukaemia cells. Cytotoxicity increased with linker chain length, and the ΔΔ‐Rubb₁₆ complex displayed the highest cytotoxicity of the series, with an IC₅₀ value of 5 μM , similar to that of carboplatin in the L1210 murine leukaemia cell line. Confocal microscopy and flow cytometry studies indicated that the complexes accumulate in the mitochondria of L1210 cells, with the magnitude of cellular uptake and accumulation increasing with linking chain length in the bb_n bridge of the metal complex. ΔΔ‐Rubb₁₆ entered the L1210 cells by passive diffusion (with a minor contribution from protein‐mediated active transport), inducing cell death via apoptosis. Additionally, metal‐complex uptake in leukaemia cells was approximately 16‐times that observed in healthy B cells highlighting that the bb_n series of complexes may have potential as selective anticancer drugs.     

Platinum(II) Complexes Bearing Triphenylphosphine and Chelating Oximes: Antiproliferative Effect and Biological Profile in Resistant Cells

Platinum(II) complexes of the type [Pt(Cl)(PPh₃){(κ²-N,O)-(1{C(R)=N(OH)-2(O)C₆H₄})}] with R=Me, H, ( 1 and 2 ) were synthesized and characterized. Single-crystal X-ray diffraction confirmed the proposed (SP4-3) configuration for 1 . Study of the antiproliferative activity, performed on a panel of human tumor cell lines and on mesothelial cells, highlighted complex 2 as the more effective. In particular, it showed a remarkable cytotoxicity in ovarian carcinoma cells (A2780) and interestingly, a significant antiproliferative effect on cisplatin resistant cells (A2780cis). Investigation into the intracellular mechanism of action demonstrated that 2 had a lower ability to platinate DNA than did cisplatin, which was taken as reference, and a notably higher uptake in resistant cells. A significant accumulation in mitochondria, along with the ability to induce concentration-dependent mitochondrial membrane depolarization and intracellular reactive oxygen species production, allowed us to propose a mitochondrion-mediated pathway as responsible for the interesting cytotoxic profile of complex 2 .     

Development of an Efficient Dual‐Action GST‐Inhibiting Anticancer Platinum(IV) Prodrug

The cytotoxicity of cisplatin (cDDP) is enhanced when co‐administered with ethacrynic acid (EA), a glutathione S‐transferase (GST) inhibitor. A Pt^IV–EA conjugate containing a cDDP core and two axial ethacrynate ligands (compound 1 ) was shown to be an excellent inhibitor of GST, but did not readily release a Pt^II species to exert a synergistic cytotoxic effect. In this study, a redesigned Pt^IV construct composed of a cDDP core with one axial ethacrynate ligand and one axial hydroxido ligand (compound 2 ) was prepared and shown to overcome the limitations of compound 1 . The EA ligand in 2 is readily released in vitro together with a cytotoxic Pt^II species derived from cisplatin, working together to inhibit cell proliferation in cDDP‐resistant human ovarian cancer cells. The in vitro activity translates well in vivo with 2 , showing effective (～80 %) inhibition of tumor growth in a human ovarian carcinoma A2780 tumor model, while showing considerably lower toxicity than cisplatin, thus validating the new design strategy.     

催化剂表面积的表征及其在催化剂研究中的应用

介绍了用１７５０比表面测定仪表征催化剂的表面积的方法,具有快速、准确、自动的优点。同时将比表面积与催化剂的研究有机地关联起来,其数据是反应条件下催化剂的老化、积炭、烧结、抗污染等方面研究的一个主要依据,有助于催化剂的应用和研究。     

Blends of polypropylene with poly(cis‐butadiene) rubber. II. Small‐angle X‐ray scattering studies of the phase structure of immiscible blends of polypropylene with poly(cis‐butadiene) rubber

Pressed films of the blends of polypropylene (PP) with poly(cis‐butadiene) rubber (PcBR) were studied by IR spectra, small‐angle X‐ray scattering, and scanning electron microscopy. The problem of the interaction between different macromolecules in the blends of PP/PcBR is discussed by melt‐mixing at a temperature of 210°C using IR. X‐ray scattering from the relation of the phase was analyzed using Porod's law, and the interface layer thickness was calculated. The immiscibility of the blends of PP/PcBR was proved. The structure parameters, the correlation distance a_c, average chord lengths l?, and radius of gyration R?_g were obtained by the Debye–Buech statistical theory of scattering. Porod's index was calculated and the shape of the dispersed phase is discussed in relation to Porod's index in the blends. The morphology and structure of the blends were investigated by scanning electron microscopy. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 83: 2088–2094, 2002     

Bis(dipyridophenazine)(2‐(2′‐pyridyl)pyrimidine‐4‐carboxylic acid)ruthenium(II) Hexafluorophosphate: A Lesson in Stubbornness

Ruthenium complexes are currently considered to be among the most promising alternatives to platinum anticancer drugs. In this work, thirteen structural analogues and organelle/receptor‐targeting peptide bioconjugates of a cytotoxic bis(dppz)‐Ru^II complex [Ru(dppz)₂(CppH)](PF₆)₂ ( 1 ) were prepared, characterized, and assessed for their cytotoxicity and cellular localization (CppH=2‐(2′‐pyridyl)pyrimidine‐4‐carboxylic acid; dppz=dipyrido[3,2‐a:2′,3′‐c]phenazine). It was observed that structural modifications (lipophilicity, charge, and size‐based) result in the cytotoxic potency of 1 being compromised. Confocal microscopy studies revealed that unlike 1 , the screened complexes/bioconjugates do not have a preferential accumulation in mitochondria. The results of this important structure–activity relationship strongly support our initial hypothesis that accumulation in mitochondria is crucial for 1 to exert its cytotoxic action.     

Platinum(II) as Bifunctional Linker in Antibody–Drug Conjugate Formation: Coupling of a 4‐Nitrobenzo‐2‐oxa‐1,3‐diazole Fluorophore to Trastuzumab as a Model

The potential of platinum(II) as a bifunctional linker in the coordination of small molecules, such as imaging agents or (cytotoxic) drugs, to monoclonal antibodies (mAbs) was investigated with a 4‐nitrobenzo‐2‐oxa‐1,3‐diazole (NBD) fluorophore and trastuzumab (Herceptin?) as a model antibody. The effect of ligand and reaction conditions on conjugation efficiency was explored for [Pt(en)(L‐NBD)Cl](NO₃) (en=ethylenediamine), with L=N‐heteroaromatic, N‐alkyl amine, or thioether. Conjugation proceeded most efficiently at pH 8.0 in the presence of NaClO₄ or Na₂SO₄ in tricine or HEPES buffer. Reaction of N‐coordinated complexes (20 equiv) with trastuzumab at 37 °C for 2 h, followed by removal of weakly bound complexes with excess thiourea, afforded conjugates with an NBD/mAb ratio of 1.5–2.9 that were stable in phosphate‐buffered saline at room temperature for at least 48 h. In contrast, thioether‐coordinated complexes afforded unstable conjugates. Finally, surface plasmon resonance analysis showed no loss in binding affinity of trastuzumab after conjugation.     

Surface characterization and study of Langmuir films of poly(4‐vinylpyridine) quaternized with n‐alkylbromide

The surface behaviour of poly(4‐vinylpyridine)s (P4VP) quaternized with four different alkyl chains (pentyl, hexyl, octyl and decy bromide) were studied. Surface pressure–area isotherms (π–A) at the air–water interface were determined. Depending on the length of the side‐chains, the π–A isotherms show a plateau region. An extensive plateau is observed for n > 6. The plateau pressures are similar for n = 8 and n = 10. The monolayers are stable and exhibit hysteresis phenomena. Brewster angle microscopy (BAM) is used to monitor the monolayer topography of the polymer on water subphase. To obtain information about the surface energy (SE) and the degree of hydrophobicity of these systems, we have estimated the critical surface tension, γ_c, and the dispersion force and polar contributions to SE, γ_D and γ_P, respectively, by measurements of the contact angle (CA) of water and bromobenzene on the polymer surface. The results obtained are depend on the length of the alkyl lateral chain of the functionalized polymers. © 2001 Society of Chemical Industry     

Removal of Hg(II) from acid aqueous solutions by poly(N‐vinylimidazole) hydrogel

Caption of Hg(II) from acid aqueous solution by immersed poly(N‐vinylimidazole) hydrogel particles was studied as a function of pH, counterion, and cation concentration. Fitting parameters to several sorption isotherms have been determined. Their values depend mostly on pH and less, on temperature and counterion, and suggest a large affinity of imidazole groups in the gel and mercury cations. Practically total removal (94.4%) of Hg(II) is achieved at pH = 2, with 10 g of dry gel per liter of solution, when cation concentration was as large as 15,000 ppm (0.075 M). Polymer protonation decreases about fourfold the cation affinity, supporting competitive protonation‐complexation mechanisms. By its side, metal uptake decreases polymer protonation. Thermal stability of loaded gels decreases with respect to metal free hydrogels. Scanning electron micrographs reveal no changes in the gel morphology upon cation binding, but T_g increases significantly with the Hg(II) content of loaded gels and swelling decreases moderately, indicating the role of the cation as ionic crosslinker. Practically total elution of Hg(II) is achieved with 1 M HNO₃ in consecutive loading‐elution cycles. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 79: 1467–1475, 2001     

Platinum(II)‐Catalyzed Allylation of CO and CN Bonds under Hydrogenation Conditions

The nucleophilic addition of allylplatinum to a range of electrophiles including carbonyls, oximes, and hydrazones was examined. Platinum(II) catalysts and allene substrates were subject to hydrogenation conditions to generate nucleophilic allylplatinum complexes without using a stoichiometric amount of toxic and sensitive organometallic reagents. The allylplatinum intermediates reacted with CO and CN bonds to produce the corresponding homoallylic alcohol and amine derivatives in good yield. The Pt‐catalyzed allylation of CN bonds is the first example performed under hydrogenation conditions. A reaction mechanism initiated with the hydrometalation of allenes by Pt H species is proposed based on deuterium labeling studies.     

Highly Enantioselective Cyclopropanation with Co(II)‐Salen Complexes: Control of cis‐ and trans‐Selectivity by Rational Ligand‐Design

Cyclopropanation of styrene derivatives with alkyl α‐diazoacetate in the presence of the second‐generation (salen)cobalt(II) complex 6 proceeded with excellent cis‐ and enantioselectivity. On the other hand, the cyclopropanation in the presence of complex 14 which was designed on the basis of the mechanism of asymmetric induction by complex 6 showed good trans‐ and excellent enantioselectivity.     

Surface immobilization of star‐shaped poly(ethylene oxide) on poly(dimethylsiloxane)

A thin layer of star‐shaped poly(ethylene oxide) (PEO) (starPEO), on the polydimethylsiloxane (PDMS) membrane was prepared by a simple immobilization procedure. Photoreactive molecules were introduced on the surface of the polymeric support to achieve the formation of thin starPEO film from the materials having no functional groups. This novel technique enabled us to immobilize any kind of chemical, especially one that had no functional groups, and readily to control the amount of immobilization. The gas permeation properties of the starPEO‐immobilized PDMS membranes were investigated for pure propane and propylene. The permeance of gases were found to decrease in the starPEO‐immobilized PDMS membranes, although the ideal separation factors for propylene/propane were increased with the loading amount of silver ions, because of the facilitation action of silver ions in the immobilized PEO unit on the PDMS membranes, as propylene carriers. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 83: 2369–2373, 2002     

Surface functionalization of polypropylene by entrapment of polypropylene‐grafted‐poly(ethylene glycol)

A surface functionalization polypropylene was prepared by entrapment a copolymer of polypropylene‐grafted‐poly(ethylene glycol) into polypropylene. The effects of structure of copolymer, contact dies, and content of modifiers were studied. The results of attenuated total reflection infrared spectroscopy(ATR‐FTIR) and contact angle measurements indicated that PP‐g‐PEG could preferably diffuse onto the surface and effectively increase the hydrophilicity of PP. PPw‐g‐PEG with lower PEG contents, lower molecular weight of PPw and PEG had better selective enrichment on the surface of PP blend film. By grafting of PEG‐OH onto the MPP, PP macromolecular surface modifier with better solvent‐resistance than that of PEG can be achieved. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Surface functionalization of poly(lactic acid) film by UV‐photografting of N‐vinylpyrrolidone

The photoinitiated grafting of N‐vinylpyrrolidone (NVP) onto poly(lactic acid) (PLA) film with the use of benzophenone (BP) as the initiator, modified the natural hydrophobic PLA behavior to an hydrophilic film with desirable wettability. The surface photografting parameters‐percent conversion of monomer to overall photopolymerization (Cp), percent conversion of monomer to the photograft polymerization (Cg), and grafting efficiency (Eg) were calculated. The resulting film surface was analyzed using ATR‐FTIR and UV spectroscopy, derivative spectroscopy and water contact angle. Besides, we demonstrated that the grafted polyvinylpyrrolidone chains could easily react with iodine to form a complex as the homopolymer does with antibacterial activity. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008