458531-57-2Relevant academic research and scientific papers
Synthesis and characterization of some atypical sphingoid bases
Saied, Essa M.,Le, Thuy Linh-Stella,Hornemann,Arenz, Christoph
, p. 4047 - 4057 (2018/06/30)
Sphingolipids are ubiquitous and abundant components of all eukaryotic and some prokaryotic organisms. Sphingolipids show a large structural variety not only between the different species, but also within an individual cell. This variety is not limited to alterations in the polar headgroups of e.g. glycosphingolipids, but also affects the lipophilic anchors comprised of different fatty acids on the one hand and different sphingoid bases on the other hand. The structural variations within different sphingoid bases e.g. in pathogens can be used to identify novel biomarkers and drug targets and the specific change in the profile of common and uncommon sphingolipids are associated with pathological conditions like diabetes or cancer. Therefore, the emerging field of sphingolipidomics is dedicated to collect data on the sphingolipidome of a cell and hence to assign changes therein to certain states of a cell or to pathological conditions. This powerful tool however is still limited by the availability of structural information about the individual lipid species as well as by the availability of appropriate internal standards for quantification. Herein we describe the synthesis of a variety of 1-deoxy-sphingoid bases. 1-DeoxySphingolipids have recently acquired significant attention due to its pathological role in the rare inherited neuropathy, HSAN1 but also as predictive biomarkers in diabetes type II. Some of the compounds synthesized and characterized herein, have been used and will be used to elucidate the correct structure of these disease-related lipids and their metabolites.
Exploring Leishmania major Inositol Phosphorylceramide Synthase (LmjIPCS): Insights into the ceramide binding domain
Mina, John G.,Mosely, Jackie A.,Ali, Hayder Z.,Denny, Paul W.,Steel, Patrick G.
supporting information; experimental part, p. 1823 - 1830 (2011/04/26)
The synthesis of set of ceramide analogues exploring hydrophobicity in the acyl chains and the degree and nature of hydroxylation is described. These have been assayed against the parasitic protozoan enzyme LmjIPCS. These studies showed that whilst the C-3 hydroxyl group was not essential for turnover it provided enhanced affinity. Reflecting the membrane bound nature of the enzyme a long (C13) hydrocarbon ceramide tail was necessary for both high affinity and turnover. Whilst the N-acyl chain also contributed to affinity, analogues lacking the amide linkage functioned as competitive inhibitors in both enzyme and cell-based assays. A model that accounts for this observation is proposed.
An enantioselective synthesis of the bicyclic core of the marine natural product awajanomycin
Pritchard, Deiniol R.,Wilden, Jonathan D.
supporting information; experimental part, p. 1819 - 1821 (2010/09/07)
A concise stereoselective synthesis of the N-benzylated bicyclic core of the marine natural product awajanomycin is described starting with naturally occurring l-alanine. Key steps in the synthesis include a ring-closing metathesis to establish a δ-lactam ring followed by a stereoselective hydroxylation to instal the quaternary centre.
Design and synthesis of sulfur based inhibitors of matrix metalloproteinase-1.
Fujisawa, Tetsunori,Odake, Shinjiro,Ogawa, Yuji,Yasuda, Junko,Morita, Yasuo,Morikawa, Tadanori
, p. 239 - 252 (2007/10/03)
Fibroblast collagenase (MMP-1), a member of the matrix metalloproteinases family, is believed to be a pathogenesis of arthritis, by cleaving triple-helical type II collagen in cartilage. From the similarity of the active site zinc binding mode with hydroxamate, we designed and synthesized alpha-mercaptocarbonyl possessing compounds (3-5), which incorporated various peptide sequences as enzyme recognition sites. The P4-P1 peptide incorporating compound (3) exhibited as potent inhibition as the hydroxamate (1) and the carboxylate (2) type inhibitors, with an IC50 of 10(-6) M order against MMP-1. But the inhibitor (3) related compounds (6-8) displayed decreased or no inhibitory potencies. These results suggest that the existence of both the carbonyl and thiol groups might be critical for the inhibition, and the distance between the two functional groups is important for inhibitory potency. For Pn' peptide incorporating compounds (4a-k), except for 4h and 4k, all compounds showed IC50 values under sub-nanomolar. Among them, for potent inhibition, Leu was better than Phe and Val as the P1' amino acid, and the P2' position amino acid was necessary, and preferentially Phe. Insertion of the Pn peptide into 4d or 4k, giving compounds 5a-c, did not increase the activities of 4d and 4k. Substitution of the mercapto group with other functional groups lost the activity of compound 4a. The stereochemical preference at the thiol-attached position was also determined by preparation of both isomers of 4a. It was found that the S configuration compound (36b) is approximately 100 times more potent than the corresponding R-isomer (36a).
