In-depth study of structure-based drug designing can provide vital leads for the development of novel, clinically active molecules. In this present study, twenty six novel pyrazolo[1,5-a]pyrimidine analogues (6a-6z) were designed using molecular docking studies. The designed molecules were synth...

A series of fused and non fused 1,2,4-triazoles with (2,4-dichlorophenoxy) moiety are prepared utilizing 3-((2,4-dichlorophenoxy)methyl)-4-amino-4H-1,2,4-triazole-5-thiol (3). The latter on reaction with carboxylic acids, ethylchloroformate, ethylcyanoacetate and sodium nitrite gives five member...

Here we report that the widely used protein kinase C inhibitors, bisindolylmaleimide I and IX, are potent inhibitors of glycogen synthase kinase-3 (GSK-3). Bisindolylmaleimide I and IX inhibited GSK-3 in vitro, when assayed either in cell lysates (IC50 360 nM and 6.8 nM, respectively) or in GSK-...

A mild and flexible method for the preparation of bisindolylmaleimides from the corresponding indoles and indole-3-acetimidate esters is described.

The synthesis and biochemical characterization of AX4697, a fluorescent, bisindolylmaleimide-derived probe for PKCα and β, is described. AX4697 was able to quantify changes in PKC expression in drug-treated Jurkat cells and was shown to covalently label PKCα on C619, a residue that sits just ...

Effects of chelerythrine and bisindolylmaleimide I on action potential duration and on voltage-activated K+ and Ca2+ currents in rat ventricular myocytes were studied using perforated patch-clamp technique. The action potentials were markedly prolonged after application of 20 μM chelerythrine o...

Although free radical-mediated necrosis is implicated in many diseases such as neurodegeneration, potent anti-necrotic drugs have not yet been exploited. We found that bisindolylmaleimide I (BMI or GF 109203X), a PKC inhibitor, protected a variety of cells, including neurons, from oxidant-induce...

We investigated the effect of bisindolylmaleimide (I), a widely used protein kinase C (PKC) inhibitor, on the voltage-dependent K+ (Kv) currents of rat mesenteric arterial smooth muscle cells using the whole-cell patch-clamp technique. Bisindolylmaleimide (I) reversibly and dose-dependently inhi...

A series of N-methyl-bisindolylmaleimide derivatives was synthesized and evaluated as cell death inhibitors. N-Methyl-2-[1-(3-aminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)maleimide (21) was the most potent inhibitor of H2O2-induced necrotic death of human leukemia HL60 cells among them.

We devised a screening method for hepatitis C virus (HCV) inhibitors by exploiting the JFH1 viral culture system. The viral RNA released in the medium was adsorbed onto PCR plates, and real-time RT-PCR was performed by directly adding the one-step RT-PCR reaction mixture to the wells. The “tube...

Novel soluble porphyrin–bisindolylmaleimides dyad and pentamer have been prepared conveniently by coupling of amino-porphyrins and bisindolylmaleic anhydride. The bisindolylmaleimide groups function as the antenna to efficiently enhance the intramolecular energy transfer to the porphyrin core. ...

We have used radioligand binding studies to determine the affinities of seven bisindolylmaleimide analogues, six of which are selective inhibitors of protein kinase C, at human muscarinic M1–M4 receptors. The compounds were most potent at M1 receptors, and Ro-31-8220 was the most potent analogu...

Certain N-(naphthalen-2-yl)acetamide and N-(substituted phenyl)acetamide bearing quinolin-2(1H)-one and 3,4-dihydroquinolin-2(1H)-one derivatives have been synthesized and evaluated in vitro for their antiproliferative activities against a panel of human cancer cell lines including nasopharyngea...

Cyclic AMP reverses radiocontrast media–induced apoptosis in LLC-PK1 cells by activating A kinase/PI3 kinase.

PurposeTo investigate the role of extracellular Ca2+ and cyclic 3′-5′ adenosine monophosphate (cAMP), a known second messenger promoting smooth muscle relaxation, in preventing renal vasoconstriction induced by radiographic contrast medium (RCM).

A role for the cyclic AMP (cAMP)-protein kinase A (PKA) transduction cascade in nociceptive processing has been identified. This study examined the effects of intrathecal treatment with the cAMP analogue 8-Bromo-cAMP and the PKA inhibitor H-89 dihydrochloride on nociceptive thresholds to mechani...

We investigated and compared the effects of pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) on cerebral circulation in anesthetized dogs. The intracisternal administration of PACAP-27, PACAP-38, and VIP dilated canine cerebral arteries in a dose...

Tumor necrosis factor-alpha (TNF-α) is a mediator of inflammation and has an important role in human and experimental renal diseases. Pentoxifylline (PTX) has been shown to inhibit cytokine synthesis, including TNF-α. The aim of the present study was to examine the effect of PTX on meglumine a...

A fast stepwise systematic approach for the conversion of conventional reversed-phase high-performance liquid chromatographic (HPLC) assays involving liquid—liquid extraction of biological fluids into fully automated HPLC assays using solid-phase extraction and cartridge exchange is described. ...

The introduction of fluorinated amino acid carrying a CF3 moiety in therapeutical agents and protein engineering requires the accessibility of highly pure chiral samples in order to correctly understand the effect of fluorination on bioactivity. Here we report an easy enzymatic approach for the ...