Locations associated with Glacier Size Equilibrium Variability inside Key Asia

A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized linker. Several of these dual inhibitors were highly potent (IC50 less then 10 nM) and selective against PI3Kγ, δ and HDAC6 enzymes and exhibited good antiproliferative activity against multiple cancer cell lines. The lead compound 48c, induced necrosis in several mutant and FLT3-resistant AML cell lines and primary blasts from AML patients, while showing no cytotoxicity against normal PBMCs, NIH3T3, and HEK293 cells. Target engagement of PI3Kδ and HDAC6 by 48c was demonstrated in MV411 cells using the cellular thermal shift assay (CETSA). Compound 48c showed good pharmacokinetics properties in mice via intraperitoneal (ip) administration and provides a means to examine the biological effects of inhibiting these two important enzymes with a single molecule, either in vitro or in vivo.An efficient method is described for generating a fragmented, permutationally invariant polynomial basis to fit electronic energies and, if available, gradients for large molecules. The method presented rests on the fragmentation of a large molecule into any number of fragments while maintaining the permutational invariance and uniqueness of the polynomials. The new approach improves on a previous one reported by Qu and Bowman by avoiding repetition of polynomials in the fitting basis set and speeding up gradient evaluations while keeping the accuracy of the PES. The method is demonstrated for CH3-NH-CO-CH3 (N-methylacetamide) and NH2-CH2-COOH (glycine).Human dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, is a target for the treatment of rheumatoid arthritis and multiple sclerosis and is re-emerging as an attractive target for cancer therapy. Here we describe the optimization of recently identified tetrahydroindazoles (HZ) as DHODH inhibitors. Several of the HZ analogues synthesized in this study are highly potent inhibitors of DHODH in an enzymatic assay, while also inhibiting cancer cell growth and viability and activating p53-dependent transcription factor activity in a reporter cell assay. Furthermore, we demonstrate the specificity of the compounds toward the de novo pyrimidine synthesis pathway through supplementation with an excess of uridine. We also show that induction of the DNA damage marker γ-H2AX after DHODH inhibition is preventable by cotreatment with the pan-caspase inhibitor Z-VAD-FMK. Additional solubility and in vitro metabolic stability profiling revealed compound 51 as a favorable candidate for preclinical efficacy studies.A catalytic sequence for the diastereo- and enantioselective preparation of homoallylic alcohols with an adjacent quaternary (stereo)center is reported. The one-pot process relies on the use of a single (achiral or chiral) iridium complex to catalyze the concomitant isomerization of primary allylic alcohols and homoallylboronates into (chiral) aldehydes and allylboronates, respectively. In the same flask, a chiral Brønsted acid is added next to engage the isomerization products into a stereocontrolled allylboration reaction. Structural variations have been performed on both the allylic alcohols and the homoallylboronates. This mild process affords an array of stereochemically congested and complex chiral secondary homoallylic alcohols in high yield, excellent diastereoselectivity, and usually high enantioselectivity.Removal of trace chlorobutane (CB) isomers is highly desired to produce high grade 1-chlorobutane (1-CB) and 2-chlorobutane (2-CB). Here, we report that nonporous adaptive crystals (NACs) of perethylated pillar[5]arene (EtP5) and pillar[6]arene (EtP6) effectively remove trace CB isomers. EtP5 NACs can remove trace 1-CB (2%) from 2-CB to improve its purity from 98.0% to 99.9%, while EtP6 NACs can remove trace 2-CB from 1-CB to improve its purity from 98.0% to 99.9%. The adsorption of trace CB isomers results in the formation of new CB-loaded crystal structures, whose thermostability is higher than their corresponding isomer-loaded structures. This determines the selectivity of NACs toward the trace CB isomers. Reversible transformations between nonporous guest-free and guest-loaded structures make EtP5 and EtP6 highly recyclable.The Burkholderia cepacia complex is a group of closely related bacterial species with large genomes that infect immunocompromised individuals and those living with cystic fibrosis. Some of these species are found more frequently and cause more severe disease than others, yet metabolomic differences between these have not been described. Furthermore, our understanding of how these species respond to antibiotics is limited. PEG300 We investigated the metabolomics differences between three most prevalent Burkholderia spp. associated with cystic fibrosis B. cenocepacia, B. multivorans, and B. dolosa in the presence and absence of the antibiotic trimethoprim. Using a combination of supervised and unsupervised metabolomics data visualization and analysis tools, we describe the overall differences between strains of the same species and between species. Specifically, we report, for the first time, the role of the pyomelanin pathway in the metabolism of trimethoprim. We also report differences in the detection of known secondary metabolites such as fragin, ornibactin, and N-acylhomoserine lactones and their analogs in closely related strains. Furthermore, we highlight the potential for the discovery of new secondary metabolites in clinical strains of Burkholderia spp. The metabolomics differences described in this study highlight the personalized nature of closely related Burkholderia strains.The search for alternatives to bioaccumulative perfluoroalkyl acids (PFAAs) is ongoing. New, still highly fluorinated alternatives are produced in hopes of reducing bioaccumulation. To better estimate this bioaccumulative behavior, we performed dialysis experiments and determined membrane/water partition coefficients, Kmem/w, of six perfluoroalkyl carboxylic acids (PFCAs), three perfluoroalkanesulfonic acids, and four alternatives. We also investigated how passive permeation might influence the uptake kinetics into cells, measuring the passive anionic membrane permeability Pion through planar lipid bilayers for six PFAAs and three alternatives. Experimental Kmem/w and Pion were both predicted well by the COSMO-RS theory (log RMSE 0.61 and 0.46, respectively). Kmem/w values were consistent with the literature data, and alternatives showed similar sorption behavior as PFAAs. Experimental Pion values were high enough to explain observed cellular uptake by passive diffusion with no need to postulate the existence of active uptake processes.