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At least 649 records · Page 36Linked to original sources
PubMed2003

New bivalent PKC ligands linked by a carbon spacer: enhancement in binding affinity.

Protein kinase C (PKC) is known to play an important role in many signal transduction pathways involved in hormone release, mitogenesis, and tumor promotion. In continuation of our efforts to find highly potent activators of PKC for possible use as Alzheimer's disease therapeutics, we designed and synthesized molecules containing two binding moieties (amides of benzolactams or esters of naphthylpyrrolidones) connected by a flexible spacer chain, which could theoretically bind to both the C1a and C1b activator binding domains of the catalytic region or to the C1 domains of two adjacent PKC molecules. The dimers 2a-g of benzolactam showed a 200-fold increase in affinity to PKCalpha and -delta as the spacer length increased from 4 to 20 carbon atoms. Replacement of the oligomethylene chain with an oligoethylene glycol unit (compounds 2h, 2i) showed a 4000- to 7000-fold decrease in affinity to PKCalpha. The dimers of naphthylpyrrolidones 4a-g did not show any marked improvement in binding affinities to PKC in comparison to the monomers synthesized earlier. The dimer of benzolactam 2e did not show much selectivity for PKCalpha, -betaIota, -delta, -epsilon, and -gamma. The high binding affinity of compounds 2d-g to PKCs gives us the impetus to design additional molecules that would retain this enhanced activity and would also show selectivity for the PKC isoforms.

Binding Sites↗
PubMed2003

Synthesis, in vitro affinity, and efficacy of a bis 8-ethynyl-4H-imidazo[1,5a]- [1,4]benzodiazepine analogue, the first bivalent alpha5 subtype selective BzR/GABA(A) antagonist.

The synthesis and in vitro affinity of the alpha5beta3gamma2 (alpha5) subtype selective BzR/GABA(A) antagonist 7 is described. This ligand is selective for alpha5 subtypes in vitro and is a potent antagonist of the effects of diazepam only at alpha5beta3gamma2 subtypes (oocytes). Ligands such as 7 will be important in the determination of which physiological function(s) are subserved by this GABA(A) alpha5 subtype.

Animals↗
PubMed2006

Flavonoid dimers as bivalent modulators for P-glycoprotein-based multidrug resistance: synthetic apigenin homodimers linked with defined-length poly(ethylene glycol) spacers increase drug retention and enhance chemosensitivity in resistant cancer cells.

Much effort has been spent on searching for better P-glycoprotein- (P-gp-) based multidrug resistance (MDR) modulators. Our approach was to target the binding sites of P-gp using dimers of dietary flavonoids. A series of apigenin-based flavonoid dimers, linked by poly(ethylene glycol) chains of various lengths, have been synthesized. These flavonoid dimers modulate drug chemosensitivity and retention in breast and leukemic MDR cells with the optimal number of ethylene glycol units equal to 2-4. Compound 9d bearing four ethylene glycol units increased drug accumulation in drug-resistant cells and enhanced cytotoxicity of paclitaxel, doxorubicin, daunomycin, vincristine, and vinblastine in drug-resistant breast cancer and leukemia cells in vitro, resulting in reduction of IC50 by 5-50 times. This compound also stimulated P-gp's ATPase activity by 3.3-fold. Its modulating activity was presumably by binding to the substrate binding sites of P-gp and disrupting drug efflux.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Serotonin dimers: application of the bivalent ligand approach to the design of new potent and selective 5-HT(1B/1D) agonists.

A series of serotonin dimers of formula 4 in which two serotonin moeities are linked together through their 5-hydroxyl residue has been prepared and evaluated as 5-HT(1B/1D) receptor agonists. Binding experiments at cloned human 5-HT(1B), 5-HT(1D), and 5-HT(1A) receptors show that all of these dimers are very potent ligands at 5-HT(1B/1D) receptors with increased binding selectivity vs the 5-HT(1A) receptor when compared to serotonin. Studies of inhibition of the forskolin-stimulated c-AMP formation mediated by the human 5-HT(1B) receptor (formerly the 5-HT(1Dbeta) receptor) demonstrate that all of these serotonin dimers behave as full agonists. Among them, the piperazide derivatives of bis-serotonin, 4g,j, were also identified as very potent agonists in contracting the New Zealand white rabbit saphenous vein (pD2 = 7.6 in each case compared to 5.8 for sumatriptan). Results analysis supports the hypothesis that the important increase in potency of the serotonin dimers can be attributed to the presence of two serotonin pharmacophores in the same molecule, while the enhanced selectivity for 5-HT(1B/1D) receptor subtypes may be due to the position of the spacer attachment to serotonin.

Animals↗
PubMed2001

2,6-Dichloro-9-thiabicyclo[3.3.1]nonane: a privileged, bivalent scaffold for the display of nucleophilic components.

The title compound, the condensation product of sulfur dichloride and 1,5-cyclooctadiene, is a reliable acceptor of a wide variety of heteroatom nucleophiles, sometimes in reversible fashion. Optical resolution of the core structure has been achieved and preserved in succeeding transformations. The high reactivity and reliable stereochemical control afforded by this system illustrates the power of neighboring-group participation by the sulfur center.

Alkanes↗
PubMed2005

Single-step syntheses of 2-amino-7-chlorothiazolo[5,4-d]pyrimidines: intermediates for bivalent thiazolopyrimidines.

[reaction: see text] A single-step process for the preparation of 2-amino-7-chlorothiazolo[5,4-d]pyrimidines, 2, was achieved by the reaction of the commercially available 4,6-dichloro-5-aminopyrimidine 1 with isothiocyanates. This mild reaction accommodates a variety of functionalized isothiocyanates and proceeds in good to excellent yields. The utility of such intermediates is exemplified by subsequent reaction with alkyl or arylamine nucleophiles to afford novel, differentially functionalized 2,7-diaminothiazolo[5,4-d]pyrimidines, 3.

Molecular Structure↗
PubMed2006

Statistical associating fluid theory coupled with restrictive primitive model extended to bivalent ions. SAFT2: 1. Single salt + water solutions.

Statistical associating fluid theory coupled with the restricted primitive model is extended to multivalent ions by relaxing the range of the square-well width parameter, which leads to a new dispersion term approximation and calls for a new set of salt and ion parameters. This new approximation, referred to as SAFT2, requires a single set of parameters derived from the salt (mean ionic) activity coefficients and liquid densities of single-salt solutions for five cations (Li(+), Na(+), K(+), Ca(2+), Mg(2+)), six anions (Cl(-), Br(-), I(-), NO(3)(-), SO(4)(-2), HCO(3)(-)), and 24 salts. These parameters, in turn, are shown to predict the osmotic coefficients for single salt + water solutions.

Journal Article↗
PubMed2006

Statistical associating fluid theory coupled with restrictive primitive model extended to bivalent ions. SAFT2: 2. Brine/seawater properties predicted.

Statistical associating fluid theory coupled with restricted primitive model (SAFT2) represents the properties of aqueous multiple-salt solutions, such as brine/seawater. The osmotic coefficients, densities, and vapor pressures are predicted without any additional parameters using the salt hydrated diameters obtained for single-salt solutions. For a given ion composition of brine, the predicted vapor pressure, osmotic coefficient, activity of water, and density are found to agree with the experimental data.

Journal Article↗
PubMed1997

Physicochemical characterization of nedocromil bivalent metal salt hydrates. 3. Nedocromil calcium.

A crystalline pentahydrate and a crystalline 8/3 hydrate of nedocromil calcium (NC) were prepared. The relationships between these solid phases and the nature of the water interactions in their structures were studied through characterization by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Karl Fischer titrimetry (KFT), hot-stage microscopy (HSM), ambient- or variable-temperature powder X-ray diffraction (PXRD), Fourier-transform infrared (FTIR) spectroscopy, solid-state nuclear magnetic resonance (SSNMR) spectroscopy, water uptake at various relative humidities (RH), intrinsic dissolution rate (IDR) and solubility measurements. The solubility and intrinsic dissolution rate of the pentahydrate in water at 25 degrees C are approximately 17% greater than the corresponding values for the 8/3 hydrate, corresponding to a greater Gibbs free energy of only 380 J.mol-1 (91 cal.mol-1) for the pentahydrate. The results of DSC, TGA, and FTIR and SSNMR spectroscopy indicate that the water of hydration is more loosely bound in the pentahydrate than in the 8/3 hydrate. On increasing the temperature in open-pan DSC and TGA, the water in the pentahydrate is released in four steps (three steps in crimped pans), whereas the water in the 8/3 hydrate is released in three steps (three steps also in crimped pans). These three stepwise dehydrations are fundamentally explained by their different water environments in the crystal structure of the 8/3 hydrate, which was determined by single-crystal XRD [crystal data: triclinic, space group P1, a = 13.2381(3) A, b = 13.3650(2) A, c = 17.8224(2) A, alpha = 68.202(1) degrees, beta = 86.894(1) degrees, gamma = 82.969(1) degrees, Z = 6]. The asymmetric unit contains three nedocromil anions and three calcium cations associated with eight water molecules. The nedocromil anions act as polyfunctional ligands to the Ca2+ ions, coordinating through both the carbonyl oxygen and the carboxylate oxygen atoms. The molecular conformations of the three nedocromil anions in the asymmetric unit are almost identical. However, the crystal structure contains two different calcium environments, one of which has the Ca2+ ion hydrated by four water molecules in the equatorial plane and by two carbonyl oxygens in its axial coordination sites. In the second environment, the Ca2+ ion has four carboxylate oxygen atoms in its equatorial plane and two water molecules in its axial coordination sites. Two of the carboxylate ligands are twisted out of the tricyclic ring, and the other two carboxylate ligands are nearly coplanar with the tricyclic ring. All of the eight water molecules in the 8/3 hydrate are linked to calcium and carboxylate ions and none are linked to other water molecules.

Calcium↗
PubMed2003

Bivalent transition-state analogue inhibitors of human glyoxalase I.

A new class of competitive inhibitors of homodimeric human glyoxalase I has been created by cross-linking two molecules of the transition-state analogue S-(N-4-chlorophenyl-N-hydroxycarbamoyl)glutathione (CHG) through their gamma-glutamyl-NH(2) groups with poly-beta-alanyl tethers of differing length: [CHG(beta-ala)n](2) suberate diamide (n = 1-7). The strongest inhibitors of this antitumor target enzyme likely bind simultaneously to the active site on each subunit to give K(i) values as small as 0.96 nM (n = 6). [structure: see text]

Animals↗
PubMed2003

Bivalent effects of MK-801 on ethanol-induced sensitization do not parallel its effects on ethanol-induced tolerance.

The relationship between the effects of the N-methyl-D-aspartate (NMDA) antagonist MK-801 on acute responses to ethanol and its ability to block ethanol sensitization and tolerance was examined in DBA/2J mice. Cross-sensitization between these drugs was also studied. Repeated administration of 0.1 mg/kg MK-801 with ethanol potentiated, whereas 0.25 mg/kg attenuated, sensitization to ethanol's locomotor stimulant effects; rearing was similarly affected. There was evidence for cross-sensitization between ethanol and 0.25 mg/kg MK-801. MK-801 potentiated ethanol's ataxic effects in the grid test, but had no effect on tolerance to this effect. MK-801's effects on ethanol sensitization appeared to be related to its own behavioral effects, rather than NMDA receptor blockade per se. Further, these studies demonstrate dissociation between ethanol sensitization and tolerance.

Animals↗