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Journal of the American Chemical Society May 2021Terminal unactivated alkynes are nowadays considered the golden standard for cysteine-reactive warheads in activity-based probes (ABPs) targeting cysteine...
Terminal unactivated alkynes are nowadays considered the golden standard for cysteine-reactive warheads in activity-based probes (ABPs) targeting cysteine deubiquitinating enzymes (DUBs). In this work, we study the versatility of the thiol-alkyne addition reaction in more depth. Contrary to previous findings with UCHL3, we now show that covalent adduct formation can progress with substituents on the terminal or internal alkyne position. Strikingly, acceptance of alkyne substituents is strictly DUB-specific as this is not conserved among members of the same subfamily. Covalent adduct formation with the catalytic cysteine residue was validated by gel analysis and mass spectrometry of intact ABP-treated USP16CD and catalytically inactive mutant USP16CD. Bottom-up mass spectrometric analysis of the covalent adduct with a deuterated propargyl ABP provides mechanistic understanding of the thiol-alkyne reaction, identifying the alkyne rather than an allenic intermediate as the reactive species. Furthermore, kinetic analysis revealed that introduction of (bulky/electron-donating) methyl substituents on the propargyl moiety decreases the rate of covalent adduct formation, thus providing a rational explanation for the commonly lower level of observed covalent adduct compared to unmodified alkynes. Altogether, our work extends the scope of possible propargyl derivatives in cysteine targeting ABPs from unmodified terminal alkynes to internal and substituted alkynes, which we anticipate will have great value in the development of ABPs with improved selectivity profiles.
Topics: Alkynes; Cysteine Proteases; Deubiquitinating Enzymes; HEK293 Cells; Humans; Pargyline; Propylamines; Sulfhydryl Compounds; Ubiquitin Thiolesterase
PubMed: 33885283
DOI: 10.1021/jacs.0c10513 -
The Journal of Organic Chemistry Feb 2021The stereoselective synthesis of terminal bromo-substituted propargylamines via generation of lithium bromoacetylide from 1,2-dibromoethene and addition to Ellman...
The stereoselective synthesis of terminal bromo-substituted propargylamines via generation of lithium bromoacetylide from 1,2-dibromoethene and addition to Ellman chiral --butanesulfinyl aldimines is reported. Modest to good yields (43-85%) and diastereoselectivity (dr = 3:1 to >20:1) were achieved for a range of aryl, heteroaryl, alkyl, and α,β-unsaturated substrates. Terminal bromo-substituted propargylamines prepared via this method can be directly used in the frequently employed Cadiot-Chodkiewicz coupling to produce functionalized diynes. The method reported here increases the structural diversity of chiral terminal bromo-substituted propargylamines that can be readily synthesized as previous methods for the stereoselective synthesis of these compounds rely on amino acid precursors from the chiral pool.
Topics: Imines; Lithium; Pargyline; Propylamines; Stereoisomerism
PubMed: 33448846
DOI: 10.1021/acs.joc.0c02697 -
Journal of the American Chemical Society Sep 2020An efficient catalytic method to convert an α-C-H bond of -alkylamines into an α-C-alkynyl bond was developed. In the past, such transformations were carried out under...
Direct Conversion of -Alkylamines to -Propargylamines through C-H Activation Promoted by Lewis Acid/Organocopper Catalysis: Application to Late-Stage Functionalization of Bioactive Molecules.
An efficient catalytic method to convert an α-C-H bond of -alkylamines into an α-C-alkynyl bond was developed. In the past, such transformations were carried out under oxidative conditions, and the enantioselective variants were confined to tetrahydroisoquinoline derivatives. Here, we disclose a method for the union of -alkylamines and trimethylsilyl alkynes, without the presence of an external oxidant and promoted through cooperative actions of two Lewis acids, B(CF) and a Cu-based complex. A variety of propargylamines can be synthesized in high diastereo- and enantioselectivity. The utility of the approach is demonstrated by the late-stage site-selective modification of bioactive amines. Kinetic investigations that shed light on various mechanistic nuances of the catalytic process are presented.
Topics: Amines; Catalysis; Copper; Lewis Acids; Molecular Structure; Organometallic Compounds; Pargyline; Propylamines; Stereoisomerism
PubMed: 32830966
DOI: 10.1021/jacs.0c08599 -
International Journal of Biological... Dec 2020The magnetically isolable nanobiocomposites have significant impact as the modified new generation catalysts in recent days. This has persuaded us to design and...
The magnetically isolable nanobiocomposites have significant impact as the modified new generation catalysts in recent days. This has persuaded us to design and synthesis of a novel Ag NPs decorated biguanidine-chitosan (Bigua-CS) dual biomolecular functionalized core-shell type magnetic nanocomposite (Ag/Bigua-CS@FeO). Bigua-CS could be introducing polysaccharide materials as potential coating agent to immobilizing and stabilizing metal nanoparticles. The material was characterized using several advanced techniques like fourier transformed infrared spectroscopy (FT-IR), inductively coupled plasma (ICP), field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDX), atomic mapping, high resolution transmission electron microscopy (HR-TEM), vibrating sample magnetometer (VSM) and X-ray diffraction (XRD). Towards the chemical applications of the material, we headed the multicomponent synthesis of diverse propargylamines by A coupling in water, which ended up with excellent yields. Due to strong paramagnetism, the catalyst was easily isolable and reused in 9cycles without any leaching and considerable change in reactivity. In addition, the catalyst was engaged in biological assays like study of anti-oxidant properties by DPPH mediated free radical scavenging test using BHT as a reference molecule. Thereafter, on having a significant IC value in radical scavenging assay, we extended the bio-application of the catalyst in anticancer study of adenocarcinoma cells of human lungs. The three different cancer cell lines, PC-14, LC-2/ad and HLC-1 were used in this regard. The best result was achieved in the case of PC-14 cell line with strong IC values.
Topics: Antineoplastic Agents; Cell Line, Tumor; Chitosan; Coated Materials, Biocompatible; Guanidines; Humans; Lung Neoplasms; Magnetite Nanoparticles; Metal Nanoparticles; Pargyline; Propylamines; Silver
PubMed: 32991899
DOI: 10.1016/j.ijbiomac.2020.09.193 -
Neurotoxicity Research Mar 2020Serotoninergic nerves are known to modulate sensitization of dopamine receptors (DA-R) in a rodent model of Parkinson's disease (PD). However, serotoninergic nerves are...
Serotoninergic nerves are known to modulate sensitization of dopamine receptors (DA-R) in a rodent model of Parkinson's disease (PD). However, serotoninergic nerves are not known to have a prominent role on DA exocytosis in intact rats. The current study was undertaken to explore the possible influence of serotoninergic nerves on DA exocytosis in Parkinsonian rats. Rat pups were treated at 3 days after birth with the neurotoxin 6-hydroxydopamine (6-OHDA; 134 μg icv, half into each lateral ventricle; desipramine, 1 h pretreatment), in order to produce marked long-lasting destruction of neostriatal dopaminergic innervation, as evidenced by the 90-95% depletion of DA (p < 0.001) [HPLC/ED] into adulthood. Controls received vehicle/desipramine in place of 6-OHDA. Other groups received the serotoninergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 25 μg base, icv, half in each lateral ventricle; desipramine, 1 h; 75 mg/kg pargyline HCl, 30 min) at 3 days post-birth; or both 6-OHDA+5,7-DHT treatments. In adulthood, an in vivo microdialysis study was undertaken to ascertain that p-chloroamphetamine (PCA, 1 mM in the microdialysate)-evoked DA release in the neostriatum was reduced approximately 50% in the 6-OHDA group, while PCA-evoked DA release in the 6-OHDA+5,7-DHT group was substantially increased, to a level equivalent to that of the vehicle control. The baseline neostriatal microdialysate level of 3,4-dihydroxyphenylacetic acid (DOPAC) was also higher in the 6-OHDA+5,7-DHT group vs 6-OHDA group; also, during the 2nd hour of PCA infusion. PCA-enhanced DA exocytosis occurred in the absence of changes in hydroxyl radical (HO·) in the microdialysate (i.e., assay of 2,3- and 2,5-dihydroxybenzoic acid, 2,3-DHBA; 2,5-DHBA). The overall findings demonstrate that an adulthood serotoninergic nerve lesion enhanced PCA-evoked DA exocytosis in a rodent model of severe PD, while susceptibility to oxidative stress was unchanged. The implication is that serotoninergic nerves may normally suppress the release of DA and/or act as an uptake site and storage sink for accumulated DA in parkinsonian-like neostriatum. Potentially, serotoninergic agonists or antagonists, targeting subtype-selective serotonin receptors, may be viable therapeutic adjuncts in PD.
Topics: 3,4-Dihydroxyphenylacetic Acid; 5,7-Dihydroxytryptamine; Animals; Animals, Newborn; Dopamine; Exocytosis; Female; Male; Microdialysis; Neostriatum; Oxidopamine; Parkinson Disease; Rats; Serotonin; p-Chloroamphetamine
PubMed: 31939043
DOI: 10.1007/s12640-019-00145-4 -
Computational Biology and Chemistry Dec 2019We have recently explored novel class of potentially anti-breast cancer active enamidines in which four molecules 4a-c and 4h showed higher anticancer activity compared...
We have recently explored novel class of potentially anti-breast cancer active enamidines in which four molecules 4a-c and 4h showed higher anticancer activity compared to standard drug doxorubicin. As a part of extension of this work, we have further evaluated in silico cheminformatic studies on bioactivity prediction of synthesized series of enamidines using mole information. The normal cell line study of four lead compounds 4a-c and 4h against African green monkey kidney vero strain further revealed that the compounds complemented good selectivity in inhibition of cancer cells. The in silico bioactivity and molecular docking studies also revealed that the compounds have significant interactions with the drug targets. The results reveal that enamidine moieties are vital for anti-breast cancer activity as they possess excellent drug-like characteristics, being potentially good inhibitors of cyclin dependent kinases7 (CDK7).
Topics: Amines; Animals; Antineoplastic Agents; Azides; Binding Sites; Breast Neoplasms; Cell Proliferation; Cell Survival; Chlorocebus aethiops; Computer Simulation; Cyclin-Dependent Kinases; Drug Screening Assays, Antitumor; Female; Humans; Hydrogen Bonding; MCF-7 Cells; Molecular Docking Simulation; Molecular Structure; Pargyline; Protein Kinase Inhibitors; Vero Cells; Cyclin-Dependent Kinase-Activating Kinase
PubMed: 31563021
DOI: 10.1016/j.compbiolchem.2019.107124 -
Molecular Diversity Aug 2020Magnetic mesoporous polymelamine formaldehyde nanocomposite-incorporating ZnO nanoparticles were successfully synthesized using solvothermal and sol-gel methods....
One-pot synthesis of propargylamines using magnetic mesoporous polymelamine formaldehyde/zinc oxide nanocomposite as highly efficient, eco-friendly and durable nanocatalyst: optimization by DOE approach.
Magnetic mesoporous polymelamine formaldehyde nanocomposite-incorporating ZnO nanoparticles were successfully synthesized using solvothermal and sol-gel methods. Fourier-transform infrared spectrometry (FT-IR), X-ray diffraction, Brunauer-Emmett-Teller, vibrating sample magnetometer, thermogravimetric analysis, elemental analysis, transmission electron microscopy and field emission scanning electron microscopy techniques were then utilized for evaluation of nanocomposites. The as-prepared nanocomposite can be used as heterogeneous nanocatalyst with remarkable performance for A coupling reaction toward one-pot synthesis of propargylamine and its derivatives under solvent-less condition. In order to maximize the product yield, the variables, i.e., reaction time, temperature and catalyst amount, were optimized by using a statistical approach. The synthesized nanocomposite can be easily separated from the reaction medium and reused over and over, without significant changes in its catalytic activity.
Topics: Catalysis; Chemistry Techniques, Synthetic; Formaldehyde; Green Chemistry Technology; Magnets; Nanocomposites; Nanostructures; Pargyline; Porosity; Propylamines; Zinc Oxide
PubMed: 31359369
DOI: 10.1007/s11030-019-09977-w -
Carbohydrate Research Aug 2020An efficient three component coupling of aromatic aldehyde, deoxy sugar based alkyne (α-2-deoxy propargyl glycoside) and heterocyclic amine have been refluxed to...
An efficient three component coupling of aromatic aldehyde, deoxy sugar based alkyne (α-2-deoxy propargyl glycoside) and heterocyclic amine have been refluxed to synthesize stereoselective chiral propargylamines with good to excellent yield using only CuI catalyst along with bifunctional ligand l-proline. This method has proved to be applicable in wide range of substrates and found highly enantioselective with respect to earlier reported methods. In addition, l-proline was found as a chiral source which demonstrated that it could be developed as a highly enantioselective method for the construction of deoxy sugar based chiral propargylamines. The ligand l-proline was used for the first time in enantioselective A-coupling reaction of α-2-deoxy propargyl glycosides involving substituted aromatic aldehyde and heterocyclic amines. Herein, we have synthesized 15 novel compounds based on A-coupling reaction and structures of all the enantioselective compounds were characterised by TLC and NMR spectroscopy.
Topics: Copper; Deoxy Sugars; Ligands; Molecular Structure; Pargyline; Proline; Propylamines; Stereoisomerism
PubMed: 32559510
DOI: 10.1016/j.carres.2020.108053