A palladium‐catalyzed N−H/B−H double activation of 1,2‐dihydro‐1,2‐benzazaborines proceeded via cycloaddition with vinyl ethylene carbonate to produce polycyclic oxazaborolidines in 31–96 % yield. ...The key step in this process is the release of molecular hydrogen from a borate intermediate. Using a SPINOL‐derived phosphoramidite as a chiral ligand, chiral oxazaborolidines were synthesized in good to high yields with excellent enantioselectivity (up to 95 % ee). The vinyl group of the resulting oxazaborolidine underwent metathesis, Heck reaction, and Wacker oxidation without affecting the oxazaborolidine framework.
Catalytic N−H/B−H double activation of 1,2‐azaborines has been demonstrated. A wide variety of 1,2‐azaborines underwent cycloaddition with vinylethylene carbonate through N−H/B−H bond cleavage to produce unique polycyclic oxazaborolidines under mild conditions. Furthermore, highly enantioselective direct functionalization of 1,2‐azaborines afforded chiral tricyclic oxazaborolidines.
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A matrix metalloproteinase 1 (MMP-1) inhibitor activity cliff was predicted using the SAR Matrix method. Compound 4 was predicted as a highly potent activity cliff partner and found to possess 60 ...times higher inhibitory activity against MMP-1 than the structurally related compound 3. Furthermore, pharmacophore fitting of synthesized compounds indicated that the correctly predicted activity cliff was caused by interactions between the trifluoromethyl group at para position in compound 4 and residue ARG214 of MMP-1.
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A total of 42 trisubstituted carboranes categorised into five scaffolds were systematically designed and synthesized by exploiting the different reactivities of the twelve vertices of o-, m-, and ...p-carboranes to cover all directions in chemical space. Significant inhibitors of hypoxia inducible factor transcriptional activitay were mainly observed among scaffold V compounds (e.g., Vi-m, and Vo), whereas anti-rabies virus activity was observed among scaffold V (Va-h), scaffold II (IIb-g), and scaffold IV (IVb) compounds. The pharmacophore model predicted from compounds with scaffold V, which exhibited significant anti-rabies virus activity, agreed well with compounds IIb-g with scaffold II and compound IVb with scaffold IV. Normalized principal moment of inertia analysis indicated that carboranes with scaffolds I-V cover all regions in the chemical space. Furthermore, the first compounds shown to stimulate the proliferation of the rabies virus were found among scaffold V carboranes.
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Intestinal-type alkaline phosphatase (IAP) is expressed at a high concentration in the brush border membrane of intestinal epithelial cells and is known to be a gut mucosal defense factor. In humans, ...a single gene (ALPI) for IAP has been isolated, and its transcription produces two kinds of alternatively spliced mRNAs (aAug10 and bAug10). Recently, we discovered that vitamin D up-regulated the expression of both types of human IAP alternative splicing variants in Caco-2 cells. However, the functional difference of protein encoded by the mRNA variants has remained elusive. In the present study, we aimed to provide further insight into the characterization and structure of IAP isoforms. To analyze the protein translated from the ALPI gene, we constructed two kinds of cDNA expression plasmids (aAug10 and bAug10), and the transfected cells were homogenized and assayed for alkaline phosphatase (ALP) activity. We also designed the homology-modeled 3D structures of the protein encoded by the mRNA variants (ALPI-aAug10 and ALPI-bAug10). The levels of ALP activity of COS-1 cells transfected with the aAug10 plasmid were increased significantly, while cells transfected with the bAug10 plasmid had undetectable ALP activity. The homology-modeled 3D structures revealed that the variant bAug10 lacks the central N-terminal α-helix and residue corresponding to Asp-42 of ALPI-aAug10 near the active site. This is the first report on the characterization and structure of alternatively spliced transcript variants of the human ALPI gene. Further studies on the regulation of aAug10 and/or bAug10 mRNA expression may identify novel physiological functions of IAP.
Carboranes 1 and 2 were designed and synthesized for hydrophobic tag (HyT)-induced degradation of HaloTag fusion proteins. The levels of the hemagglutinin (HA)-HaloTag2-green fluorescent protein ...(EGFP) stably expressed in Flp-In 293 cells were significantly reduced by HyT13, HyT55, and carboranes 1 and 2, with expression levels of 49, 79, 43, and 65%, respectively, indicating that carborane is an alternative novel hydrophobic tag (HyT) for protein degradation under an intracellular environment. To clarify the mechanism of HyT-induced proteolysis, bovine serum albumin (BSA) was chosen as an extracellular protein and modified with maleimide-conjugated m-carborane (MIC). The measurement of the ζ-potentials and the lysine residue modification with fluorescein isothiocyanate (FITC) of BSA–MIC conjugates suggested that the conjugation of carborane induced the exposure of lysine residues on BSA, resulting in the degradation via ubiquitin E3 ligase-related proteasome pathways in the cell.
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A series of carborane-containing NAMPT inhibitors were designed and synthesized based on the structure of compounds 1 and the NAMPT inhibitory activity was evaluated using NAMPT ...Colorimetric Assay. Among the compounds synthesized, compounds 2b and 2c showed significant NAMPT inhibitory activity with IC50 values of 0.098 ± 0.008 and 0.057 ± 0.001 µM, respectively. Docking simulation of compound 2 toward NAMPT using the crystal structure of the FK866-NAMPT complex (PDB code: 2GVJ) with replacing the boron atom type by the C3 atom type of carboranes predicted that the NAMPT inhibitory activity of 2c was improved by the hydrogen bond formation between the carborane amide and H191 of NAMPT. Although dicarborane compounds 38, 50, 51, and 55 were synthesize aiming to two hydrophobic pockets present in the binding pocket of NAMPT, their inhibitory activity was moderate.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is an attractive therapeutic strategy for targeting cancer metabolism. So far, many potent NAMPT inhibitors have been developed and shown ...to bind to two unique tunnel-shaped cavities existing adjacent to each active site of a NAMPT homodimer. However, cytotoxicities and resistances to NAMPT inhibitors have become apparent. Therefore, there remains an urgent need to develop effective and safe NAMPT inhibitors. Thus, we designed and synthesized two close structural analogues of NAMPT inhibitors, azaindole-piperidine (
)- and azaindole-piperazine (
)-motif compounds, which were modified from the well-known NAMPT inhibitor FK866 (
). Notably,
displayed considerably stronger enzyme inhibitory activity and cellular potency than did
and
. The main reason for this phenomenon was revealed to be due to apparent electronic repulsion between the replaced nitrogen atom (N1) of piperazine in
and the Nδ atom of His191 in NAMPT by our in silico binding mode analyses. Indeed,
had a lower binding affinity score than did
and
, although these inhibitors took similar stable chair conformations in the tunnel region. Taken together, these observations indicate that the electrostatic enthalpy potential rather than entropy effects inside the tunnel cavity has a significant impact on the different binding affinity of
from that of
in the disparate enzymatic and cellular potencies. Thus, it is better to avoid or minimize interactions with His191 in designing further effective NAMPT inhibitors.
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Bis(carboranyl)amides 1,1′-μ-(CH2NH(O)C(CH2)n-1,2-C2B10H11)2 (n = 0, 1) were prepared by the reactions of the corresponding carboranyl acyl chlorides with ethylenediamine. Crystal molecular structure ...of 1,1′-μ-(CH2NH(O)C-1,2-C2B10H11)2 was determined by single crystal X-ray diffraction. Treatment of bis(carboranyl)amides 1,1′-μ-(CH2NH(O)C(CH2)n-1,2-C2B10H11)2 with ammonium or cesium fluoride results in partial deboronation of the ortho-carborane cages to the nido-carborane ones with formation of 7,7′(8′)-μ-(CH2NH(O)C(CH2)n-7,8-C2B9H11)22−. The attempted reaction of 7,7′(8′)-μ-(CH2NH(O)CCH2-7,8-C2B9H11)22− with GdCl3 in 1,2-dimethoxy- ethane did not give the expected metallacarborane. The stability of different conformations of Gd-containing metallacarboranes has been estimated by quantum-chemical calculations using 3,3-μ-DME-3,3′-Gd(1,2-C2B9H11)2− as a model. It was found that in the most stable conformation the CH groups of the dicarbollide ligands are in anti,anti-orientation with respect to the DME ligand, while any rotation of the dicarbollide ligand reduces the stability of the system. This makes it possible to rationalize the design of carborane ligands for the synthesis of gadolinium metallacarboranes on their base.
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•Trisubstituted carboranes efficiently increased the T-cell proliferation.•The carboranes specifically increased the binding of Grb2 SH2 to CD28.•The carboranes specifically decreased ...the binding of PI3K cSH2 to CD28.
Binding of adaptor molecules, such as growth factor receptor-bound protein 2 (Grb2) and phosphoinositide 3-kinase (PI3K), to the cytoplasmic region of CD28 is critical for T-cell activation. The Src homology 2 (SH2) domains of Grb2 and PI3K interact with the cytoplasmic region, including phosphorylated Tyr, of CD28. We found that trisubstituted carboranes efficiently increased the proliferation of T cells obtained from C57BL/6 mice. The carboranes specifically increased the binding of Grb2 Src homology 2 (SH2) to CD28-derived phosphopeptide but decreased the binding of PI3K C-terminal SH2 (cSH2). Based on the crystal structures of CD28-derived phosphopeptides complexed with Grb2 SH2 and PI3K cSH2, the bound structures of compound 4 (CRL266481) were modeled to determine the molecular mechanism of the regulation.
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Discoidin domain receptor 1 (DDR1) inhibitors with a desired pharmacophore were designed using deep generative models (DGMs). DDR1 is a receptor tyrosine kinase activated by matrix collagens and ...implicated in diseases such as cancer, fibrosis and hypoxia. Herein we describe the synthesis and inhibitory activity of compounds generated from DGMs. Three compounds were found to have sub‐micromolar inhibitory activity. The most potent of which, compound 3 (N‐(4‐chloro‐3‐((pyridin‐3‐yloxy)methyl)phenyl)‐3‐(trifluoromethyl)benzamide), had an IC50 value of 92.5 nM. Furthermore, these compounds were predicted to interact with DDR1, which have a desired pharmacophore derived from a known DDR1 inhibitor. The results of synthesis and experiments indicated that our de novo design strategy is practical for hit identification and scaffold hopping.
Helpful for scaffold hopping: DDR1 inhibitors were designed using a deep generative model that generates chemical structures with the desired pharmacophore. In structure sampling, about 10,000 generated structures from the agent network have pharmacophore scores greater than 0.8. After filtering the structures, nine compounds were synthesized and their inhibitory activities were evaluated against DDR1. The results of this study show that our de novo design strategy is practical for hit identification and scaffold hopping.
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