Epigenetic drug discovery: targeting DNA methyltransferases.

Epigenetic modification of DNA leads to changes in gene expression. DNA methyltransferases (DNMTs) comprise a family of nuclear enzymes that catalyze the methylation of CpG dinucleotides, resulting in an epigenetic methylome distinguished between normal cells and those in disease states such as cancer. Disrupting gene expression patterns through promoter methylation has been implicated in many malignancies and supports DNMTs as attractive therapeutic targets.

A dinuclear iron(II) complex, [(TPyA)FeII(THBQ(2-))FeII(TPyA)](BF4)2 [TPyA = tris(2-pyridylmethyl)amine; THBQ(2-) = 2,3,5,6-tetrahydroxy-1,4-benzoquinonate] exhibiting both spin crossover with hysteresis and ferromagnetic exchange.

Dinuclear [(TPyA)FeII(THBQ(2-))FeII(TPyA)](BF4)2 (1) possesses hydrogen bonding interactions that form a 1-D chain, and pi-pi interactions between the 1-D chains that give rise to a 2-D supramolecular-layered structure, inducing hysteresis in the spin crossover behavior; 1 has shown spin crossover behavior around 250 K with thermal hysteresis and ferromagnetic interactions at low temperature.

Molecular discrimination of type-I over type-II methionyl aminopeptidases.

Two residues that are conserved in type-I methionyl aminopeptidases (MetAPs) but are absent in all type-II MetAPs are the cysteine residues (Escherichia coli MetAP-I: C59 and C70) that reside at the back of the substrate recognition pocket. These Cys residues are 4.4 A apart and do not form a disulfide bond.

A concerted mechanism for the transfer of the thiophosphinoyl group from aryl dimethylphosphinothioate esters to oxyanionic nucleophiles in aqueous solution.

Earlier work on the hydrolysis of aryl phosphinothioate esters has led to contradictory mechanistic conclusions. To resolve this mechanistic ambiguity, we have measured linear free energy relationships (beta(nuc) and beta(lg)) and kinetic isotope effects for the reactions of oxyanions with aryl dimethylphosphinothioates. For the attack of nucleophiles on 4-nitrophenyl dimethylphosphinothioate, beta(nuc) = 0.

Design, new synthesis, and calcilytic activity of substituted 3H-pyrimidin-4-ones.

Design, new synthesis, structure-activity relationship studies and calcium receptor antagonist (calcilytic) properties of novel 3H-pyrimidin-4-ones are described.

A comparison of phosphonothioic acids with phosphonic acids as phosphatase inhibitors.

Phosphorothioates, analogues of phosphate esters in which a sulfur replaces an oxygen atom in the phosphoryl group, are competent surrogate substrates for a number of phosphatases. In some cases the thio analogues show similar binding (as estimated by K(m)) while other phosphatases show quite different K(m) values for phosphate compared to phosphorothioate esters. On this basis it was hypothesized that there might be different inhibitory tendencies by the nonhydrolyzable analogues, phosphonothioic acids compared with phosphonic acids.