Lead identification of benzimidazolone and azabenzimidazolone arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists

A knowledge-based library of 2,3-dichlorophenylsulfonyl derivatives of commercially available aryl amines was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. Hits were required to be more potent than an existing indazole series, have better physicochemical properties (c log P 116 μg/mL), and be stable to acid and light. The benzimidazol-2-one core was identified as a hit suitable for further investigation. Substitution at N1 with small alkyl groups was tolerated; however, these analogues were inactive in the whole blood assay (pA2 <5). Azabenzimidazolone analogues were all found to be active, with compound 38 exhibiting whole blood activity of 6.1, low molecular weight (389) and chrom log D7.4 (2.4), high LE (0.43), and solubility (152 μg/mL). In addition, 38 had human serum albumin binding of around 93% and met all the criteria for progression to lead optimisation

Hyperspectral Image Classification via Information Theoretic Dimension Reduction

Hyperspectral images (HSIs) are one of the most successfully used tools for precisely and potentially detecting key ground surfaces, vegetation, and minerals. HSIs contain a large amount of information about the ground scene; therefore, object classification becomes the most difficult task for such a high-dimensional HSI data cube. Additionally, the HSI’s spectral bands exhibit a high correlation, and a large amount of spectral data creates high dimensionality issues as well. Dimensionality reduction is, therefore, a crucial step in the HSI classification pipeline. In order to identify a pertinent subset of features for effective HSI classification, this study proposes a dimension reduction method that combines feature extraction and feature selection. In particular, we exploited the widely used denoising method minimum noise fraction (MNF) for feature extraction and an information theoretic-based strategy, cross-cumulative residual entropy (CCRE), for feature selection. Using the normalized CCRE, minimum redundancy maximum relevance (mRMR)-driven feature selection criteria were used to enhance the quality of the selected feature. To assess the effectiveness of the extracted features’ subsets, the kernel support vector machine (KSVM) classifier was applied to three publicly available HSIs. The experimental findings manifest a discernible improvement in classification accuracy and the qualities of the selected features. Specifically, the proposed method outperforms the traditional methods investigated, with overall classification accuracies on Indian Pines, Washington DC Mall, and Pavia University HSIs of 97.44%, 99.71%, and 98.35%, respectively

Effect of Weave Type Variation on Tensile and Tearing Strength of Woven Fabric

Among the functional properties of fabric, Tear &amp; Tensile strength has the paramount importance and weave variation has a significant effect on this. The effect of a weave on the strength of the fabric is discussed in this research. For this purpose, five weave variations on a piece of fabric were woven having the same construction by using the Air Jet loom. Titan 5 Universal Tester was used for testing and previous works took under consideration. These results are presented in this paper with numeric value tables and graphs

2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis

A number of potent 2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine CCR4 antagonists binding to the extracellular allosteric site were synthesised. (R)-N-(2,4-Dichlorobenzyl)-2-(2-(pyrrolidin-2-ylmethyl)-2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine (R)-(18a) has high affinity in both the [125I]-TARC binding assay with a pKi of 8.8, and the [35S]-GTPγS functional assay with a pIC50 of 8.1, and high activity in the human whole blood actin polymerisation assay (pA2 = 6.7). The most potent antagonists were also investigated for their ability to induce endocytosis of CCR4 and were found to internalise about 60% of the cell surface receptors, a property which is not commonly shared by small molecule antagonists of chemokine receptors

HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins

Small molecule-induced protein degradation is an attractive strategy for the development of chemical probes. One method for inducing targeted protein degradation involves the use of PROTACs, heterobifunctional molecules that can recruit specific E3 ligases to a desired protein of interest. PROTACs have been successfully used to degrade numerous proteins in cells, but the peptidic E3 ligase ligands used in previous PROTACs have hindered their development into more mature chemical probes or therapeutics. We report the design of a novel class of PROTACs that incorporate small molecule VHL ligands to successfully degrade HaloTag7 fusion proteins. These HaloPROTACs will inspire the development of future PROTACs with more drug-like properties. Additionally, these HaloPROTACs are useful chemical genetic tools, due to their ability to chemically knock down widely used HaloTag7 fusion proteins in a general fashion

A Modular Strategy for the Synthesis of Macrocycles and Medium-Sized Rings via Cyclization/Ring Expansion Cascade Reactions

Macrocycles and medium-sized rings are important in many scientific fields and technologies but are hard to make using current methods, especially on a large scale. Outlined herein is a strategy by which functionalized macrocycles and medium-sized rings can be prepared using cyclization/ring expansion (CRE) cascade reactions, without resorting to high dilution conditions. CRE cascade reactions are designed to operate exclusively via kinetically favorable 5-7-membered ring cyclization steps; this means that the problems typically associated with classical end-to-end macrocyclization reactions are avoided. A modular synthetic approach has been developed to facilitate the simple assembly of the requisite linear precursors, which can then be converted into an extremely broad range of functionalized macrocycles and medium-sized rings using one of nine CRE protocols

Syntheses of difluorinated carbasugar phosphates from trifluoroethanol

Difluorinated cyclohexene diols (prepd. from trifluoroethanol) can be elaborated to racemic analogs of phosphorylated sugars via regioselective protection and phosphorylation of the exposed C-1 hydroxyl group. Cis-diol protection was achieved using stannylene methodol., though the regioselectivity depended on the orientation of the Me group at C-5. UpJohn dihydroxylation is effective with the phosphotriester in place and global deprotection to the tetrol monophosphates I (R1 = OH, R2 = H; R1 = H, R2 = OH) is efficient