62914-53-8Relevant academic research and scientific papers
Bromofatty aldehyde derived from bromine exposure and myeloperoxidase and eosinophil peroxidase modify GSH and protein
Duerr, Mark A.,Palladino, Elisa N. D.,Hartman, Celine L.,Lambert, James A.,Franke, Jacob D.,Albert, Carolyn J.,Matalon, Sadis,Patel, Rakesh P.,Slungaard, Arne,Ford, David A.
, p. 696 - 705 (2018)
α-Chlorofatty aldehydes (α-ClFALDs) and α-bromofatty aldehydes (α-BrFALDs) are produced in activated neutrophils and eosinophils. This study investigated the ability of α-BrFALD and α-ClFALD to react with the thiols of GSH and protein cysteinyl residues. Initial studies showed that 2-bromohexadecanal (2-BrHDA) and 2-chlorohexadecanal (2-ClHDA) react with GSH producing the same fatty aldehyde-GSH adduct (FALD-GSH). In both synthetic and cellular reactions, FALD-GSH production was more robust with 2-BrHDA compared with 2-ClHDA as precursor. NaBr-supplemented phorbol myristate acetate (PMA)-activated neutrophils formed more -BrFALD and FALD-GSH compared with non-NaBr-supplemented neutrophils. Primary human eosinophils, which preferentially produce hypobromous acid and α-BrFALD, accumulated FALD-GSH following PMA stimulation. Mice exposed to Br2 gas had increased levels of both α-BrFALD and FALD-GSH in the lungs, as well as elevated systemic plasma levels of FALD-GSH in comparison to mice exposed to air. Similar relative reactivity of α-ClFALD and α-BrFALD with protein thiols was shown using click analogs of these aldehydes. Collectively, these data demonstrate that GSH and protein adduct formation are much greater as a result of nucleophilic attack of cysteinyl residues on α-BrFALD compared with α-ClFALD, which was observed in both primary leukocytes and in mice exposed to bromine gas.
2-Chlorofatty Aldehyde Elicits Endothelial Cell Activation
Ford, David A.,McHowat, Jane,Shakya, Shubha
, (2020)
Endothelial activation and dysfunction are hallmarks of inflammation. Neutrophil-vascular endothelium interactions have significant effects on vascular wall physiology and pathology. Myeloperoxidase (MPO)-derived products released from activated neutrophils can mediate the inflammatory response and contribute to endothelial dysfunction. 2-Chlorofatty aldehyde (2-ClFALD) is the direct oxidation product of MPO-derived hypochlorous acid (HOCl) targeting plasmalogen phospholipids. The role of 2-ClFALD in endothelial dysfunction is poorly understood and may be dependent on the vascular bed. This study compared the role of 2-ClFALD in eliciting endothelial dysfunction in human coronary artery endothelial cells (HCAEC), human lung microvascular endothelial cells (HLMVEC), and human kidney endothelial cells (HKEC). Profound increases in selectin surface expression as well as ICAM-1 and VCAM-1 surface expression were observed in HCAEC and HLMVEC. The surface expression of these adherence molecules resulted in robust adherence of neutrophils and platelets to 2-ClFALD treated endothelial cells. In contrast to HCAEC and HLMVEC, 2-ClFALD-treated HKEC had substantially reduced adherence molecule surface expression with no resulting increase in platelet adherence. 2-ClFALD-treated HKEC did have an increase in neutrophil adherence. All three endothelial cell lines treated with 2-ClFALD displayed a time-dependent loss of barrier function. Further studies revealed 2-ClHDyA localizes to ER and Golgi when using a synthetic alkyne analog of 2-ClFALD in HCAEC and HLMVEC. These findings indicate 2-ClFALDs promote endothelial cell dysfunction with disparate degrees of responsiveness depending on the vascular bed of origin.
The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites
Bogyo, Matthew,Boucher, Michael J.,Cieplak, Piotr,Fidock, David A.,Foe, Ian T.,Gn?dig, Nina F.,Kumpornsin, Krittikorn,Kurita, Kenji,Lee, Marcus C. S.,Linington, Roger G.,Long, Jonathan Z.,Mok, Sachel,Onguka, Ouma,Schulze, Christopher J.,Stokes, Barbara H.,Terrell, Stephanie M.,Uhlemann, Anne-Catrin,Weerapana, Eranthie,Yeo, Tomas,Yoo, Euna,Zhou, Yani
, p. 143 - 157 (2020)
Salinipostin A (Sal A) is a potent antiplasmodial marine natural product with an undefined mechanism of action. Using a Sal A-derived activity-based probe, we identify its targets in the Plasmodium falciparum parasite. All of the identified proteins contain α/β serine hydrolase domains and several are essential for parasite growth. One of the essential targets displays a high degree of homology to human monoacylglycerol lipase (MAGL) and is able to process lipid esters including a MAGL acylglyceride substrate. This Sal A target is inhibited by the anti-obesity drug Orlistat, which disrupts lipid metabolism. Resistance selections yielded parasites that showed only minor reductions in sensitivity and that acquired mutations in a PRELI domain-containing protein linked to drug resistance in Toxoplasma gondii. This inability to evolve efficient resistance mechanisms combined with the non-essentiality of human homologs makes the serine hydrolases identified here promising antimalarial targets. Using a probe analog of the antimalarial natural product Sal A, Yoo et al. identify its targets as multiple essential serine hydrolases, including a homolog of human monoacylglycerol lipase. Because parasites were unable to generate robust in vitro resistance to Sal A, these enzymes represent promising targets for antimalarial drugs.
2-Bromopalmitate analogues as activity-based probes to explore palmitoyl acyltransferases
Zheng, Baohui,Deran, Michael,Li, Xinyan,Liao, Xuebin,Fukata, Masaki,Wu, Xu
, p. 7082 - 7085 (2013)
Reversible S-palmitoylation is an important post-translational modification that regulates the trafficking, localization, and activity of proteins. Cysteine-rich Asp-His-His-Cys (DHHC) domain-containing enzymes are evolutionarily conserved protein palmitoyl acyltransferases (PATs). The human genome encodes 23 DHHC-PATs that regulate diverse cellular functions. Although chemical probes and proteomic methods to detect palmitoylated protein substrates have been reported, no probes for direct detection of the activity of PATs are available. Here we report the synthesis and characterization of 2-bromohexadec-15-ynoic acid and 2-bromooctadec-17-ynoic acid, which are analogues of 2-bromopalmitate (2-BP), as activity-based probes for PATs as well as other palmitoylating and 2-BP-binding enzymes. These probes will serve as new chemical tools for activity-based protein profiling to explore PATs, to dissect the functions of PATs in cell signaling and diseases, and to facilitate the identification of their inhibitors.
NUCLEOSIDE PRODRUGS AND USES RELATED THERETO
-
Page/Page column 144; 145, (2021/02/26)
Disclosed are acyclic nucleoside prodrugs with improved metabolic stability and oral bioavailability. In general, the prodrugs are derivatives of acyclic nucleoside phosphonates containing a lipid-like moiety that can increase oral absorption and subsequent stability in the liver and plasma. Preferably, the lipid-like moiety can resist enzyme-mediated ω-oxidation, such as ω -oxidation catalyzed by cytochrome P450 enzymes. Also disclosed are pharmaceutical formulations of the acyclic nucleoside prodrugs. The acyclic nucleoside prodrugs and pharmaceutical formulations thereof can be used to treat viral infections, such as HIV infections, and/or viral-associated cancer, such as HPV-associated cancers.
ω-Functionalized Lipid Prodrugs of HIV NtRTI Tenofovir with Enhanced Pharmacokinetic Properties
Bartsch, Perry W.,Basson, Adriaan E.,Burton, Samantha L.,Bushnev, Anatoliy,D'Erasmo, Michael,Dasari, Madhuri,Derdeyn, Cynthia A.,Giesler, Kyle E.,Hwang, Soyon S.,Iskandar, Sabrina,Liotta, Dennis C.,Miller, Eric J.,Pribut, Nicole,Raghuram, Akshay,Sharma, Savita K.
, p. 12917 - 12937 (2021/09/13)
Tenofovir (TFV) is the cornerstone nucleotide reverse transcriptase inhibitor (NtRTI) in many combination antiretroviral therapies prescribed to patients living with HIV/AIDS. Due to poor cell permeability and oral bioavailability, TFV is administered as one of two FDA-approved prodrugs, both of which metabolize prematurely in the liver and/or plasma. This premature prodrug processing depletes significant fractions of each oral dose and causes toxicity in kidney, bone, and liver with chronic administration. Although TFV exalidex (TXL), a phospholipid-derived prodrug of TFV, was designed to address this issue, clinical pharmacokinetic studies indicated substantial hepatic extraction, redirecting clinical development of TXL toward HBV. To circumvent this metabolic liability, we synthesized and evaluated ω-functionalized TXL analogues with dramatically improved hepatic stability. This effort led to the identification of compounds 21 and 23, which exhibited substantially longer t1/2 values than TXL in human liver microsomes, potent anti-HIV activity in vitro, and enhanced pharmacokinetic properties in vivo.
3-O-SULFO-GALACTOSYLCERAMIDE ANALOGS AS ACTIVATORS OF TYPE II NKT CELLS AND USES THEREOF
-
Paragraph 0095; 0108, (2019/10/19)
Disclosed is a compound of the formula (I) or (II): wherein a f are as described herein. The compounds are useful in the activation of Type II NKT cells and in treating cancer.
Enantioselective Rhodium-Catalyzed Atom-Economical Macrolactonization
Ganss, Stephanie,Breit, Bernhard
supporting information, p. 9738 - 9742 (2016/08/10)
A highly attractive route toward macrolactones, which form the cyclic scaffold of a multitude of diverse natural compounds, is described. Although many chemical approaches to this structural motif have been explored, an asymmetric variant of the cyclization is unprecedented. Herein we present an enantioselective macrolactonization through an intramolecular atom-economical rhodium-catalyzed coupling of ω-allenyl-substituted carboxylic acids. The use of a modified diop ligand, chiral DTBM-diop, led to high enantioselectivity (up to 93 % ee). The reaction tolerated a large variety of functionalities, including α,β-unsaturated carboxylic acids and depsipeptides, and provided the desired macrocycles with very high enantio- and diastereoselectivity.
Total synthesis of the phenolic glycolipid mycoside B and the glycosylated p-hydroxybenzoic acid methyl ester HBAD-I, virulence markers of mycobacterium tuberculosis
Barroso, Santiago,Geerdink, Danny,Ter Horst, Bjorn,Casas-Arce, Eva,Minnaard, Adriaan J.
, p. 4642 - 4654 (2013/07/26)
The phenolic glycolipid mycoside B, present in Mycobacterium bovis and hypervirulent strains of Mycobacterium tuberculosis, has been synthesized for the first time. Multiple methyl groups were introduced by the extensive use of catalytic asymmetric 1,4-addition reactions, asymmetric hydrogenation of a β-keto ester afforded the basis for the central 1,3-diol moiety, and introduction of the 2-O-methyl-α-L-rhamnoside unit was achieved by stereoselective glycosylation with p-iodophenol and subsequent Sonogashira coupling, providing a basis for the generation of analogues. In addition, the related monosaccharide HBAD-I, present in the same species, has been efficiently synthesized for the first time by selective methylation of the hydroxy group at C-2 of a rhamnoside. The phenolic glycolipid mycoside B and the related phenolic glycoside HBAD-I from Mycobacterium tuberculosis have been synthesized for the first time. A highly convergent strategy was used featuring catalytic asymmetric 1,4-additions of MeMgBr and Me2Zn and a late-stage Sonogashira coupling as the key steps. Copyright
Patterned monolayer self-assembly programmed by side chain shape: Four-component gratings
Xue, Yi,Zimmt, Matthew B.
supporting information; experimental part, p. 4513 - 4516 (2012/04/23)
A molecular recognition strategy based on alkadiyne side chain shape is used to self-assemble a four-component, 1D-patterned monolayer at the solution-HOPG interface. The designed monolayer unit cell contains six molecules and spans 23 nm × 1 nm. The unit cell's internal structure and packing are driven by complementary shapes and lengths of six different alkadiyne side chains. A solution of the four compounds on HOPG self-assembles monolayers (i) comprised, almost entirely, of the intended unit cell, (ii) exhibiting patterned domains spanning 104 nm2, and (iii) which are sufficiently robust that patterned domains survive solvent rinsing and drying. The patterned monolayer affords 1D-feature spacings ranging from 3.3 to 23 nm. The results demonstrate the remarkable selectivity afforded by molecular recognition based on alkadiyne side chain shape and the ability to program highly complex 1D-patterns in self-assembled monolayers.
