Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that serves as an important regulator of a broad range of cellular functions. It has been linked to Alzheimer's disease as well as various other diseases, including mood disorders, type 2 diabetes, and cancer. There is considerable evidence indicating that GSK-3β in the central nervous system plays a role in the production of abnormal, hyperphosphorylated, microtubule-associated tau protein found in neurofibrillary tangles associated with Alzheimer's disease.

Design, Structure-Activity Relationships, and In Vivo Evaluation of Potent and Brain-Penetrant Imidazo[1,2-]pyridazines as Glycogen Synthase Kinase-3β (GSK-3β) Inhibitors.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates numerous cellular processes, including metabolism, proliferation, and cell survival. Due to its multifaceted role, GSK-3 has been implicated in a variety of diseases, including Alzheimer's disease, type 2 diabetes, cancer, and mood disorders. GSK-3β has been linked to the formation of the neurofibrillary tangles associated with Alzheimer's disease that arise from the hyperphosphorylation of tau protein.

A Carbon Electrode Functionalized by a Tricopper Cluster Complex: Overcoming Overpotential and Production of Hydrogen Peroxide in the Oxygen Reduction Reaction.

A study of the oxygen reduction reaction (ORR) on a screen printed carbon electrode surface mediated by the tricopper cluster complex Cu (7-N-Etppz(CH OH)) dispersed on electrochemically reduced carbon black, where 7-N-Etppz(CH OH) is the ligand 3,3'-(6-(hydroxymethyl)-1,4-diazepane-1,4-diyl)bis(1-(4-ethyl piperazin-1-yl)propan-2-ol), is described. Onset oxygen reduction potentials of about 0.92 V and about 0.

Electrochemical Hydroxylation of C-C n-Alkanes by Recombinant Alkane Hydroxylase (AlkB) and Rubredoxin-2 (AlkG) from Pseudomonas putida GPo1.

An unprecedented method for the efficient conversion of C-C linear alkanes to their corresponding primary alcohols mediated by the membrane-bound alkane hydroxylase (AlkB) from Pseudomonas putida GPo1 is demonstrated. The X-ray absorption spectroscopy (XAS) studies support that electrons can be transferred from the reduced AlkG (rubredoxin-2, the redox partner of AlkB) to AlkB in a two-phase manner. Based on this observation, an approach for the electrocatalytic conversion from alkanes to alcohols mediated by AlkB using an AlkG immobilized screen-printed carbon electrode (SPCE) is developed.

Mechanistic Study of the Stereoselective Hydroxylation of [2- H ,3- H ]Butanes Catalyzed by Cytochrome P450 BM3 Variants.

Engineered bacterial cytochrome P450s are noted for their ability in the oxidation of inert small alkanes. Cytochrome P450 BM3 L188P A328F (BM3 PF) and A74E L188P A328F (BM3 EPF) variants are able to efficiently oxidize n-butane to 2-butanol. Esterification of the 2-butanol derived from this reaction mediated by the aforementioned two mutants gives diastereomeric excesses (de) of -56±1 and -52±1 %, respectively, with the preference for the oxidation occurring at the C-H bond.

Natural flavonoids silymarin and quercetin improve the brain distribution of co-administered P-gp substrate drugs.

P-glycoprotein (P-gp), a well known efflux transporter in the blood brain barrier inhibits the uptake of substrate drugs into brain. The main aim of this study is to evaluate the effect of natural product based P-gp inhibitors on brain penetration of various CNS drugs which are P-gp substrates. In this study, we have evaluated the inhibitory effects of natural bioflavonoids (quercetin and silymarin) on P-gp by using digoxin and quinidine as model P-gp model substrate drugs.

Regioselective hydroxylation of C(12)-C(15) fatty acids with fluorinated substituents by cytochrome P450 BM3.

We demonstrate herein that wild-type cytochrome P450 BM3 can recognize non-natural substrates, such as fluorinated C12 -C15 chain-length fatty acids, and show better catalysis for their efficient conversion. Although the binding affinities for fluorinated substrates in the P450 BM3 pocket are marginally lower than those for non-fluorinated substrates, spin-shift measurements suggest that fluoro substituents at the ω-position can facilitate rearrangement of the dynamic structure of the bulk-water network within the hydrophobic pocket through a micro desolvation process to expel the water ligand of the heme iron that is present in the resting state. A lowering of the Michaelis-Menten constant (Km ), however, indicates that fluorinated fatty acids are indeed better substrates compared with their non-fluorinated counterparts.

Fenofibrate but not fenofibric acid inhibits 11beta-hydroxysteroid dehydrogenase 1 in C2C12 myotubes.

Fibrates and WY-14643 are widely used as lipid-lowering drugs via modulation of peroxisome proliferator-activated receptor alpha (PPAR α) for the treatment of a wide range of metabolic disorders. Here, to address the question whether PPAR α agonists can affect the enzymatic activity of 11beta-hydroxysteroid dehydrogenase1 (11β-HSD1), we tested fibrates and WY-14643 for the inhibition of cellular 11β-HSD1 activity in C2C12 myotubes. Only fenofibrate but not fenofibric acid, an active agonist of PPAR α, exerted a potent inhibitory activity in the cell based assay, showing an IC(50) of 1.

Discovery of cyclicsulfonamide derivatives as 11 beta-hydroxysteroid dehydrogenase 1 inhibitors.

A new series of cyclic sulfonamide derivatives was synthesized and evaluated for their ability to inhibit 11beta-HSD1. Cyclic sulfonamides with phenylacetyl substituents at the 2-position showed nanomolar inhibitory activities. Among them, compound 4e exhibited a good in vitro inhibitory activity and selectivity toward human 11beta-HSD2.

New clerodane diterpenoids from the aerial parts of Pulicaria wightiana.

Two new ent-clerodane-type diterpenoids, compounds 1 and 2, were isolated from the aerial parts of Pulicaria wightiana, together with three known constituents. Their structures were established based on spectroscopic data, and their antibacterial activities were evaluated (Table 2).

An efficient one-pot synthesis of polyhydroquinolines at room temperature using HY-zeolite.

An efficient one-pot synthesis of polyhydroquinolines by four-component coupling reactions of aldehydes, ethyl acetoacetate, dimedone and ammonium acetate in the presence of HY-zeolite at ambient temperature has been achieved. The conversions took shorter times to form the products in excellent yields. HY-zeolite can be recovered and reused.

New lathyrane and podocarpane diterpenoids from Jatropha curcas.

Chemical investigation on Jatropha curcas resulted in the isolation of twenty constituents among which four diterpenoids were unknown and six compounds, tetradecyl-(E)-ferulate, 3-O-(Z)-coumaroyl oleanolic acid, heudelotinone, epi-isojatrogrossidione, 2alpha-hydroxy-epi-isojatrogrossidione, and 2-methyanthraquinone had not been reported earlier from this species. The structures of the new compounds were established by extensive studies of their 1D- and 2D-NMR spectra.