DL-2-Acetylamino-6-N-Boc-amino-4-hexynoic acid DCHA
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DL-2-Acetylamino-6-N-Boc-amino-4-hexynoic acid DCHA

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Category
BOC-Amino Acids
Catalog number
BAT-007222
CAS number
90102-79-7
Molecular Formula
C13H20N2O5·C12H23N
Molecular Weight
465.63
DL-2-Acetylamino-6-N-Boc-amino-4-hexynoic acid DCHA
IUPAC Name
2-acetamido-6-[(2-methylpropan-2-yl)oxycarbonylamino]hex-4-ynoic acid;N-cyclohexylcyclohexanamine
Synonyms
DL-2-Acetamido-6-(Boc-amino)-4-hexynoic acid . DCHA; DL-2-Acetylamino-6-N-Boc-amino-4-hexynoic acid.DCHA; Boc-Thr-OtBu
Appearance
Off-white powder
Purity
≥ 95% (TLC)
Storage
Store at 2-8 °C
InChI
InChI=1S/C13H20N2O5.C12H23N/c1-9(16)15-10(11(17)18)7-5-6-8-14-12(19)20-13(2,3)4;1-3-7-11(8-4-1)13-12-9-5-2-6-10-12/h10H,7-8H2,1-4H3,(H,14,19)(H,15,16)(H,17,18);11-13H,1-10H2
InChI Key
LPTMHHUXZJYCMC-UHFFFAOYSA-N
Canonical SMILES
CC(=O)NC(CC#CCNC(=O)OC(C)(C)C)C(=O)O.C1CCC(CC1)NC2CCCCC2
1. Identification of Slow-Binding Inhibitors of the BoNT/A Protease
Ealin N Patel, Lewis D Turner, Mark S Hixon, Kim D Janda ACS Med Chem Lett. 2022 Mar 8;13(4):742-747. doi: 10.1021/acsmedchemlett.2c00028. eCollection 2022 Apr 14.
Botulinum neurotoxin A (BoNT/A) is a lethal toxin, which causes botulism, and is categorized as a bioterrorism threat, which causes flaccid paralysis and death. Botulinum A neurotoxicity is governed through its light chain (LC), a zinc metalloprotease. Pharmacological investigations aimed at negating BoNT/A's LC have typically looked to inhibitors that have been shown to inhibit the light chain's activity by reversible zinc chelation within its active site. This report outlines the first examples of nonpeptidic inhibitors of the BoNT/A LC that possess slow-binding kinetics, a needed logic to counteract the longevity of BoNT/A. Cyclopropane, alkyl, and alkenyl derivatives of 2,4-dichlorocinamic hydroxamic acid (DCHA) were shown to possess both one-step and two-step slow-binding kinetics. Structure-kinetic relationships (SKRs) were observed and were rationalized with the aid of docking models that predicted improved interactions with residues within a hydrophobic cleft adjacent to the active site.
2. Diarylcyclopropane hydroxamic acid inhibitors of histone deacetylase 4 designed by combinatorial approach and QM/MM calculations
Jakub Kollar, Vladimir Frecer J Mol Graph Model. 2018 Oct;85:97-110. doi: 10.1016/j.jmgm.2018.08.008. Epub 2018 Aug 16.
Inhibitors of histone deacetylase superfamily (HDAC), which induce cell cycle arrest, trigger cell death and reduce angiogenesis appear as promising anti-cancer drugs targeting the epigenetic regulation of gene expression. Approved HDAC inhibitors were found effective against haematological and solid malignancies, other HDACIs are currently in clinical trials for the treatment of neurological diseases or immune disorders. Among those, diarylcyclopropane hydroxamic acids (DCHA) were found to be potent and selective inhibitors of the class IIa HDACs, specifically HDAC4, a pharmacological target for the treatment of Huntington's disease and muscular atrophy. Crystallographic analysis revealed that one of the aryl groups of the DCHA fills the lower specificity pocket of the HDAC4 catalytic site that is specific for the class IIa HDACs. We have used computer-assisted combinatorial chemistry, hybrid quantum mechanics/molecular mechanics (QM/MM) with implicit solvation and QSAR models to optimize DCHA inhibitors and propose more potent DCHA analogues. The QM/MM approach has been selected since the process of inhibitor binding to the catalytic zinc and polar amino acid residues of the deacetylase active site induces considerable rearrangement of electron density of the inhibitor. Virtual combinatorial library consisting of 12180 DCHA analogues was focused by means of structure-based evaluation to form a small combinatorial subset enriched in potentially interesting inhibitor candidates. Two validated QSAR models making use of computed relative binding affinities of the DCHA inhibitors to the HDAC4 (ΔΔGcomQM/MM) were utilized to estimate the inhibitory potencies of the new analogues. The predicted half-maximal inhibitory concentrations (IC50pre) of the designed analogues fall into the low nanomolar concentration range and their predicted ADME properties are also favourable. The best designed DCHA analogues contain indazole, phenylpiperidine, phenyloxazole or hydroxypyridine moieties and stabilize bound inhibitors by hydrogen bonds to the catalytic water molecule and backbone carbonyl groups of the deacetylase active site residues. This makes them more potent and more specific inhibitors towards the HDAC4 isoform than the known diarylcyclopropane hydroxamic acids. The analogues are recommended for synthesis and experimental verification of inhibitory potencies in medicinal chemistry laboratories.
3. Anti-inflammatory mechanisms of bioactive milk proteins in the intestine of newborns
Dereck E W Chatterton, Duc Ninh Nguyen, Stine Brandt Bering, Per Torp Sangild Int J Biochem Cell Biol. 2013 Aug;45(8):1730-47. doi: 10.1016/j.biocel.2013.04.028. Epub 2013 May 6.
The human newborn infant is susceptible to gut inflammatory disorders. In particular, growth-restricted infants or infants born prematurely may develop a severe form of intestinal inflammation known as necrotizing enterocolitis (NEC), which has a high mortality. Milk provides a multitude of proteins with anti-inflammatory properties and in this review we gather together some recent significant advances regarding the isolation and proteomic identification of these minor constituents of both human and bovine milk. We introduce the process of inflammation, with a focus on the immature gut, and describe how a multitude of milk proteins act against the inflammatory process according to both in vitro and in vivo studies. We highlight the effects of milk proteins such as caseins, and of whey proteins such as alpha-lactalbumin, beta-lactoglobulin, lactoferrin, osteopontin, immunoglobulins, trefoil factors, lactoperoxidase, superoxide dismutase, platelet-activating factor acetylhydrolase, alkaline phosphatase, and growth factors (TGF-β, IGF-I and IGF-II, EGF, HB-EGF). The effects of milk fat globule proteins, such as TLR-2, TLR-4, sCD14 and MFG-E8/lactadherin, are also discussed. Finally, we indicate how milk proteins could be useful for the prophylaxis and therapy of intestinal inflammation in infants and children.
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