Design and synthesis of functionalized piperazin-1yl-(E)-stilbenes as inhibitors of 17α-hydroxylase-C17,20-lyase (Cyp17)

The synthesis of steroid hormones is critical to human physiology and improper regulation of either the synthesis of these key molecules or activation of the associated receptors can lead to disease states. This has led to intense interest in developing compounds capable of modulating the synthesis of steroid hormones. Compounds capable of inhibiting Cyp19 (Aromatase), a key enzyme in the synthesis of estrogens, have been successfully employed as breast cancer therapies, while inhibitors of Cyp17 (17α-hydroxylase-17,20-lyase), a key enzyme in the synthesis of glucocorticoids, mineralocorticoids and steroidal sex hormones, are a key component of prostate cancer therapy. Inhibition of CYP17 has also been suggested as a possible target for the treatment of Cushing Syndrome and Metabolic Syndrome. We have identified two novel series of stilbene based CYP17 inhibitors and demonstrated that exemplary compounds in these series have pharmacokinetic properties consistent with orally delivered drugs. These findings suggest that compounds in these classes may be useful for the treatment of diseases and conditions associated with improper regulation of glucocorticoids synthesis and glucocorticoids receptor activation.     

Flexible pivoting of dynamin pleckstrin homology domain catalyzes fission: insights into molecular degrees of freedom

The neuronal dynamin1 functions in the release of synaptic vesicles by orchestrating the process of GTPase-dependent membrane fission. Dynamin1 associates with the plasma membrane–localized phosphatidylinositol-4,5-bisphosphate (PIP₂) through the centrally located pleckstrin homology domain (PHD). The PHD is dispensable as fission (in model membranes) can be managed, even when the PHD-PIP₂ interaction is replaced by a generic polyhistidine- or polylysine-lipid interaction. However, the absence of the PHD renders a dramatic dampening of the rate of fission. These observations suggest that the PHD-PIP₂–containing membrane interaction could have evolved to expedite fission to fulfill the requirement of rapid kinetics of synaptic vesicle recycling. Here, we use a suite of multiscale modeling approaches to explore PHD–membrane interactions. Our results reveal that 1) the binding of PHD to PIP₂-containing membranes modulates the lipids toward fission-favoring conformations and softens the membrane, and 2) PHD associates with membrane in multiple orientations using variable loops as pivots. We identify a new loop (VL4), which acts as an auxiliary pivot and modulates the orientation flexibility of PHD on the membrane—a mechanism that we believe may be important for high-fidelity dynamin collar assembly. Together, these insights provide a molecular-level understanding of the catalytic role of PHD in dynamin-mediated membrane fission.     

Identification of potent,selective and orally bioavailable phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone analogues as RORγt inverse agonists

An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.     

Effect of retinol deficiency and curcumin or turmeric feeding on brain Na+−K+ adenosine triphosphatase activity

The effect of retinol deficiency and curcumin and turmeric feeding on brain microsomal Na⁺-K⁺ ATPase activity was investigated. The brain Na⁺–K⁺ ATPase activity registered an increase of 148.5% as compared to the control group. Upon treating retinol deficient rats with curcumin or turmeric, the abnormally elevated activity showed a decrease of 36.9 and 47.1%, respectively, when compared to the retinol deficient group. An increase in V_max by 67% and K_m by 66% for ATP was observed in the retinol deficient group. Curcumin or turmeric fed retinol-deficient groups reduced the V_max by 25 and 33%, while K_m was reduced by 25 and 31%, respectively, compared to the retinol deficient group. Arrhenius plot of Na⁺–K⁺ ATPase showed a typical bi-phasic pattern in all the groups. Cholesterol: Phospholipid ratio showed a decrease in the retinol-deficient group by 67.8%, which showed a marked increase in curcumin or turmeric treated groups. Detergents could increase the Na⁺–K⁺ ATPase activity more in the control group than in the retinol deficient groups. Curcumin or turmeric improved the detergent action on the enzyme. Subsequent freezing and thawing over a period of 30 min decreased the enzyme activity by 22.8% in the retinol deficient group compared to 15.9% decrease in the control group. Curcumin or turmeric treated groups showed a decrease in the enzyme activity by 22.0 and 19.2%, respectively, when compared to the zero time in each group. In the presence of concanavalin-A (Con-A) there was only 52.4% stimulation in the enzyme activity in retinol deficient groups, compared to 108.0% in the control group. Curcumin or turmeric treated retinol-deficient groups showed a stimulation in the presence of con-A by 70 and 99.5%, respectively.     

Diurnal variations in intervertebral disc height affect spine flexibility,intradiscal pressure and contact compressive forces in the facet joints

Diurnal changes of intervertebral disc height are caused by high compressive loading during the day, which expulses fluid from the disc, and by osmotic pressure, which imbibes fluid into the disc at low loading. The aim of the present study was to determine the magnitude of diurnal changes in spine flexibility, intradiscal pressures and contact forces in the facet joints. A validated osseoligamentous finite element model of the lumbar spine was used to determine these quantities for morning and evening situations. Disc height varied by 10% for these two situations. Spine flexibility and facet joint forces were markedly higher in the evening than in the morning. Intradiscal pressures were higher in the morning than in the evening. The different spine flexibilities in the morning and evening should be taken into account during kinematical measurements. Predicted facet joint forces may be used for the designing and pre-clinical testing of artificial facet joint replacements.     

Experimental Analysis of a Gossip-Based Service for Scalable, Distributed Failure Detection and Consensus

Gossip protocols and services provide a means by which failures can be detected in large, distributed systems in an asynchronous manner without the limits associated with reliable multicasting for group communications. Extending the gossip protocol such that a system reaches consensus on detected faults can be performed via a flat structure, or it can be hierarchically distributed across cooperating layers of nodes. In this paper, the performance of gossip services employing flat and hierarchical schemes is analyzed on an experimental testbed in terms of consensus time, resource utilization and scalability. Performance associated with a hierarchically arranged gossip scheme is analyzed with varying group sizes and is shown to scale well. Resource utilization of the gossip-style failure detection and consensus service is measured in terms of network bandwidth utilization and CPU utilization. Analytical models are developed for resource utilization and performance projections are made for large system sizes.     

Synthesis of Some New N-Substituted Imidazole Derivatives and Their In Vitro Antibacterial Investigation

Russian Journal of Bioorganic Chemistry - Here we reported the synthesis of N-substituted imidazole derivatives (VIa–o) that involves Suzuki coupling reaction between...