scholarly journals Modular synthesis of biologically active phosphatidic acid probes using click chemistry

2009 ◽  
Vol 5 (9) ◽  
pp. 962 ◽  
Author(s):  
Matthew D. Smith ◽  
Christopher G. Sudhahar ◽  
Denghuang Gong ◽  
Robert V. Stahelin ◽  
Michael D. Best
Keyword(s):  
Phosphatidic Acid ◽  
Click Chemistry ◽  
Biologically Active ◽  
Modular Synthesis

scholarly journals Modular synthesis of α-fluorinated arylmethanes via desulfonylative cross-coupling

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Masakazu Nambo ◽  
Jacky C.-H. Yim ◽  
Luiza B. O. Freitas ◽  
Yasuyo Tahara ◽  
Zachary T. Ariki ◽  
...  
Keyword(s):  
Biological Activity ◽  
Late Stage ◽  
Recent Progress ◽  
Cross Coupling ◽  
Biologically Active Compounds ◽  
Biologically Active ◽  
Active Compounds ◽  
Arylboronic Acids ◽  
Modular Synthesis ◽  
Synthetic Routes

Abstract α-Fluoromethylarenes are common substructures in pharmaceuticals and agrochemicals, with the introduction of fluorine often resulting in improved biological activity and stability. Despite recent progress, synthetic routes to α-fluorinated diarylmethanes are still rare. Herein we describe the Pd-catalyzed Suzuki-Miyaura cross-coupling of α-fluorinated benzylic triflones with arylboronic acids affording structurally diverse α-fluorinated diarylmethanes. The ease of synthesis of fluorinated triflones as the key starting materials enables powerful late-stage transformations of known biologically active compounds into fluorinated analogs.

scholarly journals From Wood to Tetrahydro-2-benzazepines in Three Waste-Free Steps: Modular Synthesis of Biologically Active Lignin-Derived Scaffolds

2019 ◽  
Vol 5 (10) ◽  
pp. 1707-1716 ◽  
Author(s):  
Saravanakumar Elangovan ◽  
Anastasiia Afanasenko ◽  
Jörg Haupenthal ◽  
Zhuohua Sun ◽  
Yongzhuang Liu ◽  
...  
Keyword(s):  
Biologically Active ◽  
Modular Synthesis

Modular synthesis of glycopolymers with well-defined sugar units in the side chain via Ugi reaction and click chemistry: hetero vs. homo

2016 ◽  
Vol 7 (25) ◽  
pp. 4263-4271 ◽  
Author(s):  
Lulu Xue ◽  
Xinhong Xiong ◽  
Kui Chen ◽  
Yafei Luan ◽  
Gaojian Chen ◽  
...  
Keyword(s):  
Click Chemistry ◽  
Ugi Reaction ◽  
Side Chain ◽  
Click Reactions ◽  
Modular Synthesis

Modularized glycopolymers were prepared via Ugi and click reactions, and used as models to investigate their binding abilities.

Lipid A activation of glomerular mesangial cells: mimicry of the bioactive lipid, phosphatidic acid

1992 ◽  
Vol 262 (2) ◽  
pp. C328-C338 ◽  
Author(s):  
S. L. Bursten ◽  
W. E. Harris ◽  
K. Resch ◽  
D. H. Lovett
Keyword(s):  
Phosphatidic Acid ◽  
Positive Feedback ◽  
Lipid A ◽  
Mesangial Cells ◽  
Biologically Active ◽  
Transferase Activity ◽  
Acyl Transferase ◽  
Glomerular Mesangial Cells ◽  
Cellular Activation ◽  
Acyl Transferase Activity

Lipid A, the active component of bacterial endotoxin, stimulates multiple cell types, including glomerular mesangial cells (MC), and yet the molecular mechanisms of cell activation remain unclear. Lipid A, in its monosaccharyl form, structurally resembles the biologically active lipid phosphatidic acid (PA). Given this, it was postulated that lipid A activates cells by acting as a structural and functional mimetic of PA. Lipid A was found to specifically stimulate an MC lyso-PA acyl transferase activity, leading to enhanced synthesis of sn-2-unsaturated forms of PA. Sn-2-unsaturated PA itself, in contrast to sn-2-saturated PA, also stimulated the lyso-PA acyl transferase activity, a positive feedback feature previously noted with lyso-lecithin acyl transferase. Structure-function correlations demonstrated that the phosphate moieties in both PA and lipid A were necessary to feedback stimulation of lyso-PA acyl transferase (AT), as dephosphorylated lipid A and 2-unsaturated 1,2-sn-diacylglycerol had no stimulatory effect on lyso-PA AT. The biologic relevance of the lipid A and PA-mediated increases in lyso-PA acyl transferase activity was shown, whereby limited exposure to these lipids rapidly induced identical MC morphologic and functional alterations characteristic of cellular activation. By mimicking the stimulatory action of PA, per se, on lyso-PA acyl transferase activity, lipid A may initiate a positive feedback cycle of acylation, yielding increased amounts of PA enriched in unsaturated fatty acids. This newly synthesized PA may subsequently act as the proximal mediator of cellular activation.

SuFEx-Enabled High-Throughput Medicinal Chemistry

2019 ◽  
Author(s):  
Seiya Kitamura ◽  
Qinheng Zheng ◽  
Jordan L. Woehl ◽  
angelo solan ◽  
Emily Chen ◽  
...  
Keyword(s):  
Click Chemistry ◽  
Small Molecule ◽  
High Throughput ◽  
Cysteine Protease ◽  
High Throughput Screening ◽  
Medicinal Chemistry ◽  
Biologically Active ◽  
Drug Candidates ◽  
Biological Probes ◽  
Small Molecule Probes

<p>Optimization of small-molecule probes or drugs is a lengthy, challenging and resource-intensive process. Lack of automation and reliance on skilled medicinal chemists is cumbersome in both academic and industrial settings. Here, we demonstrate a high-throughput hit-to-lead process based on the biocompatible SuFEx click chemistry. A modest high-throughput screening hit against a bacterial cysteine protease SpeB was modified with a SuFExable iminosulfur oxydifluoride [RN=S(O)F2] motif, rapidly diversified into 460 analogs in overnight reactions, and the products directly screened to yield drug-like inhibitors with 300-fold higher potency. We showed that the improved molecule is drug-like and biologically active in a bacteria-host coculture. Since these reactions can be performed on a picomole scale to conserve reagents, we anticipate our methodology can accelerate the development of robust biological probes and drug candidates.</p>

scholarly journals Sequential Actions of Phospholipase D and Phosphatidic Acid Phosphohydrolase 2b Generate Diglyceride in Mammalian Cells

1999 ◽  
Vol 10 (11) ◽  
pp. 3863-3876 ◽  
Author(s):  
Vicki A. Sciorra ◽  
Andrew J. Morris
Keyword(s):  
Phosphatidic Acid ◽  
Phospholipase D ◽  
Mammalian Cells ◽  
Biologically Active ◽  
Membrane Microdomains ◽  
Caveolin 1 ◽  
Messenger Molecules ◽  
Biochemical Fractionation ◽  
Membrane Compartment ◽  
In Series

Phosphatidylcholine (PC) is a major source of lipid-derived second messenger molecules that function as both intracellular and extracellular signals. PC-specific phospholipase D (PLD) and phosphatidic acid phosphohydrolase (PAP) are two pivotal enzymes in this signaling system, and they act in series to generate the biologically active lipids phosphatidic acid (PA) and diglyceride. The identity of the PAP enzyme involved in PLD-mediated signal transduction is unclear. We provide the first evidence for a functional role of a type 2 PAP, PAP2b, in the metabolism of PLD-generated PA. Our data indicate that PAP2b localizes to regions of the cell in which PC hydrolysis by PLD is taking place. Using a newly developed PAP2b-specific antibody, we have characterized the expression, posttranslational modification, and localization of endogenous PAP2b. Glycosylation and localization of PAP2b appear to be cell type and tissue specific. Biochemical fractionation and immunoprecipitation analyses revealed that PAP2b and PLD2 activities are present in caveolin-1–enriched detergent-resistant membrane microdomains. We found that PLD2 and PAP2b act sequentially to generate diglyceride within this specialized membrane compartment. The unique lipid composition of these membranes may provide a selective environment for the regulation and actions of enzymes involved in signaling through PC hydrolysis.

scholarly journals PPARγNetworks in Cell Signaling: Update and Impact of Cyclic Phosphatidic Acid

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Tamotsu Tsukahara
Keyword(s):  
Phosphatidic Acid ◽  
Biologically Active ◽  
Peroxisome Proliferator ◽  
Glycerol Phosphate ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pharmacological Interest ◽  
Sphingosine 1 Phosphate ◽  
Cyclic Phosphatidic Acid ◽  
G Protein Coupled ◽  
Therapeutic Compound

Lysophospholipid (LPL) has long been recognized as a membrane phospholipid metabolite. Recently, however, the LPL has emerged as a candidate for diagnostic and pharmacological interest. LPLs include lysophosphatidic acid (LPA), alkyl glycerol phosphate (AGP), cyclic phosphatidic acid (cPA), and sphingosine-1-phosphate (S1P). These biologically active lipid mediators serve to promote a variety of responses that include cell proliferation, migration, and survival. These LPL-related responses are mediated by cell surface G-protein-coupled receptors and also intracellular receptor peroxisome proliferator-activated receptor gamma (PPARγ). In this paper, we focus mainly on the most recent findings regarding the biological function of nuclear receptor-mediated lysophospholipid signaling in mammalian systems, specifically as they relate to health and diseases. Also, we will briefly review the biology of PPARγand then provide an update of lysophospholipids PPARγligands that are under investigation as a therapeutic compound and which are targets of PPARγrelevant to diseases.

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