Total Synthesis and Structural Studies of the Antiviral Marine Natural Product Hennoxazole A

A concise synthetic strategy and the structure elucidation of hennoxazole A are presented. A meta-xylene degradation is used to construct the pyran segment, and the preparation of the skipped polyene moiety is accomplished via asymmetric reduction of β-stannyl enone, an SN2 displacement of an allylic trimethylbenzoate with vinyl cuprate, and coupling of a vinyl-zinc reagent with a π-allyl palladium species. The final steps of the convergent total synthesis of (2S,4S,6S,8S,22R)-hennoxazole A involve an amide coupling followed by the construction of the bisoxazole core. The combined use of circular dichroism, total synthesis, and optical rotation serves to unequivocally establish the relative and absolute configuration of the marine natural product. A new empirical CD helicity rule is proposed that allows the assignment of bisallylic stereocenters in acyclic homoconjugated dienes. In addition, an independent proof of the configuration of hennoxazole A is based on an extensive study of van't Hoff's principle of optical superposition. This chiroptical analysis employs the additivity of the molar rotation [Φ] of the individual stereocenters

Winter climate change in alpine tundra: plant responses to changes in snow depth and snowmelt timing

Snow is an important environmental factor in alpine ecosystems, which influences plant phenology, growth and species composition in various ways. With current climate warming, the snow-to-rain ratio is decreasing, and the timing of snowmelt advancing. In a 2-year field experiment above treeline in the Swiss Alps, we investigated how a substantial decrease in snow depth and an earlier snowmelt affect plant phenology, growth, and reproduction of the four most abundant dwarf-shrub species in an alpine tundra community. By advancing the timing when plants started their growing season and thus lost their winter frost hardiness, earlier snowmelt also changed the number of low-temperature events they experienced while frost sensitive. This seemed to outweigh the positive effects of a longer growing season and hence, aboveground growth was reduced after advanced snowmelt in three of the four species studied. Only Loiseleuria procumbens, a specialist of wind exposed sites with little snow, benefited from an advanced snowmelt. We conclude that changes in the snow cover can have a wide range of species-specific effects on alpine tundra plants. Thus, changes in winter climate and snow cover characteristics should be taken into account when predicting climate change effects on alpine ecosystem

Improved Mass Constraints in the MSSM from Vacuum Stability

Using a simple numerical method, we compute the stability of the MSSM vacuum with respect to tunneling. The stability criterion is then used to put restrictions on the mass parameters. These restrictions are necessary conditions for the vacuum stability and compliment the existing sufficiency conditions obtained analytically.Comment: LaTex. 15 pages. 4 postscript figures (uses epsf). Some minor corrections. Enlarged data set. Figures showing data have been improve

Relation between chiral symmetry breaking and confinement in YM-theories

Spectral sums of the Dirac-Wilson operator and their relation to the Polyakov loop are thoroughly investigated. The approach by Gattringer is generalized to mode sums which reconstruct the Polyakov loop locally. This opens the possibility to study the mode sum approximation to the Polyakov loop correlator. The approach is re-derived for the ab initio continuum formulation of Yang-Mills theories, and the convergence of the mode sum is studied in detail. The mode sums are then explicitly calculated for the Schwinger model and SU(2) gauge theory in a homogeneous background field. Using SU(2) lattice gauge theory, the IR dominated mode sums are considered and the mode sum approximation to the static quark anti-quark potential is obtained numerically. We find a good agreement between the mode sum approximation and the static potential at large distances for the confinement and the high temperature plasma phase.Comment: 17 pages, 10 figures, typos corrected, references added, final version to appear in PR

Supplementary material for the article: Ajdačić, V.; Nikolić, A.; Kerner, M.; Wipf, P.; Opsenica, I. M. Reevaluation of the Palladium/Carbon-Catalyzed Decarbonylation of Aliphatic Aldehydes. Synlett 2018, 29 (13), 1781–1785. https://doi.org/10.1055/s-0037-1610433

Supplementary material for: [https://doi.org/10.1055/s-0037-1610433]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2192

Toward a Molecular Understanding of the Interaction of Dual Specificity Phosphatases with Substrates: Insights from Structure-Based Modeling and High Throughput Screening

Dual-specificity phosphatases (DSPs) are important, but poorly understood, cell signaling enzymes that remove phosphate groups from tyrosine and serine/threonine residues on their substrate. Deregulation of DSPs has been implicated in cancer, obesity, diabetes, inflammation, and Alzheimer’s disease. Due to their biological and biomedical significance, DSPs have increasingly become the subject of drug discovery high-throughput screening (HTS) and focused compound library development efforts. Progress in identifying selective and potent DSP inhibitors has, however, been restricted by the lack of sufficient structural data on inhibitor-bound DSPs. The shallow, almost flat, substrate binding sites in DSPs have been a major factor in hampering the rational design and the experimental development of active site inhibitors. Recent experimental and virtual HTS studies, as well as advances in molecular modeling, provide new insights into the potential mechanisms for substrate recognition and binding by this important class of enzymes. We present herein an overview of the progress, along with a brief description of applications to two types of DSPs: Cdc25 and MAP kinase phosphatase (MKP) family members. In particular, we focus on combined computational and experimental efforts for designing Cdc25B and MKP-1 inhibitors and understanding their mechanisms of interactions with their target proteins. These studies emphasize the utility of developing computational models and methods that meet the two major challenges currently faced in structure-based in silico design of lead compounds: the conformational flexibility of the target protein and the entropic contribution to the selection and stabilization of particular bound conformers

A Targeted Library Screen Reveals a New Inhibitor Scaffold for Protein Kinase D

Protein kinase D (PKD) has emerged as a potential therapeutic target in multiple pathological conditions, including cancer and heart diseases. Potent and selective small molecule inhibitors of PKD are valuable for dissecting PKD-mediated cellular signaling pathways and for therapeutic application. In this study, we evaluated a targeted library of 235 small organic kinase inhibitors for PKD1 inhibitory activity at a single concentration. Twenty-eight PKD inhibitory chemotypes were identified and six exhibited excellent PKD1 selectivity. Five of the six lead structures share a common scaffold, with compound 139 being the most potent and selective for PKD vs PKC and CAMK. Compound 139 was an ATP-competitive PKD1 inhibitor with a low double-digit nanomolar potency and was also cell-active. Kinase profiling analysis identified this class of small molecules as pan-PKD inhibitors, confirmed their selectivity again PKC and CAMK, and demonstrated an overall favorable selectivity profile that could be further enhanced through structural modification. Furthermore, using a PKD homology model based on similar protein kinase structures, docking modes for compound 139 were explored and compared to literature examples of PKD inhibition. Modeling of these compounds at the ATP-binding site of PKD was used to rationalize its high potency and provide the foundation for future further optimization. Accordingly, using biochemical screening of a small number of privileged scaffolds and computational modeling, we have identified a new core structure for highly potent PKD inhibition with promising selectivity against closely related kinases. These lead structures represent an excellent starting point for the further optimization and the design of selective and therapeutically effective small molecule inhibitors of PKD. © 2012 Tandon et al

Effect of temperature, age and lifespan extending interventions on Caenorhabditis elegans models of amyloid beta pathology

Alzheimer’s disease (AD) is an age-related neurodegenerative disease that accounts for 60-70% of all dementia cases worldwide. The hallmark of AD is neuronal death precipitated by accrual of intercellular amyloid (Aβ) aggregates and intracellular neurofibrillary (NFT) Tau tangles. AD risk factors include age, genetics and environment. Despite intense research, the genetic and biochemical underpinnings of AD are poorly understood, and no drugs have been discovered for curing the disease. In this project, we aimed to study the impact of temperature, age and longevity-promoting interventions on two Caenorhabditis elegans transgenic strains modeling aspects of Aβ pathophysiology, by expressing full length human (1-42 amino acids) Aβ peptide in muscles or neurons. Since AD is an age-related disease, we first examined how age influenced the dynamics of Aβ-mediated phenotypes, followed by the impact of an additional stress modality- high temperature. As previously reported, worms expressing Aβ in muscles exhibited full body paralysis and mobility defects at high temperatures of 25 °C. Contrarily, the animals expressing Aβ in neurons did not show any paralysis but underwent distinct mobility defects under temperature stress. Surprisingly, we discovered that in both models the extent of pathology was only moderately aggravated by increasing age alone, or upon combining age and temperature stressors. Since aging is the biggest risk factor for AD, we also asked if genetic or chemical interventions known to increase lifespan could impact the phenotypes of the worm Aβ models. We found that a known lifespan-extending drug, promethazine•HCl, significantly delayed the onset of paralysis and mobility defects in the Aβ (muscle) model on day 1 of the animal. Similarly, we found that two known lifespan extending transcription factors, DAF-16 and NHR-49, also played an important role in alleviating Aβ phenotypes on day 1 and influenced the ability of promethazine•HCl to retard Aβ pathology. Overall, in characterizing an in vivo worm platform for identifying drugs and genes that impact AD, we have delineated the interlinked effects of age, temperature and genetic environment on Aβ pathology

Mitotic slippage in non-cancer cells induced by a microtubule disruptor, disorazole C1

<p>Abstract</p> <p>Background</p> <p>Disorazoles are polyene macrodiolides isolated from a myxobacterium fermentation broth. Disorazole C₁was newly synthesized and found to depolymerize microtubules and cause mitotic arrest. Here we examined the cellular responses to disorazole C₁in both non-cancer and cancer cells and compared our results to vinblastine and taxol.</p> <p>Results</p> <p>In non-cancer cells, disorazole C₁induced a prolonged mitotic arrest, followed by mitotic slippage, as confirmed by live cell imaging and cell cycle analysis. This mitotic slippage was associated with cyclin B degradation, but did not require p53. Four assays for apoptosis, including western blotting for poly(ADP-ribose) polymerase cleavage, microscopic analyses for cytochrome C release and annexin V staining, and gel electrophoresis examination for DNA laddering, were conducted and demonstrated little induction of apoptosis in non-cancer cells treated with disorazole C₁. On the contrary, we observed an activated apoptotic pathway in cancer cells, suggesting that normal and malignant cells respond differently to disorazole C₁.</p> <p>Conclusion</p> <p>Our studies demonstrate that non-cancer cells undergo mitotic slippage in a cyclin B-dependent and p53-independent manner after prolonged mitotic arrest caused by disorazole C₁. In contrast, cancer cells induce the apoptotic pathway after disorazole C₁treatment, indicating a possibly significant therapeutic window for this compound.</p

XJB-5-131-mediated improvement in physiology and behaviour of the R6/2 mouse model of Huntington's disease is age- and sex- dependent.

We have reported that the radical scavenger XJB-5-131 attenuates or reverses progression of the disease phenotype in the HdhQ(150/150) mouse, a slow onset model of HD. Here, we tested whether XJB-5-131 has beneficial effects in R6/2 mice, a severe early onset model of HD. We found that XJB-5-131 has beneficial effects in R6/2 mice, by delaying features of the motor and histological phenotype. The impact was sex-dependent, with a stronger effect in male mice. XJB-5-131 treatment improved some locomotor deficits in female R6/2 mice, but the effects were, in general, greater in male mice. Chronic treatment of male R6/2 mice with XJB-5-1-131 reduced weight loss, and improved the motor and temperature regulation deficits, especially in male mice. Treatment with XJB-5-131 had no effect on the lifespan of R6/2 mice. Nevertheless, it significantly slowed somatic expansion at 90 days, and reduced the density of inclusions. Our data show that while treatment with XJB-5-131 had complex effects on the phenotype of R6/2 mice, it produced a number of significant improvements in this severe model of HD