Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Syntheses and biological activities of KRN7000 analogues having aromatic residues in the acyl and backbone chains with varying stereochemistry.

ABSTRACT: KRN7000 is an important ligand identified for CD1d protein of APC, and KRN7000/CD1d complex can stimulate NKT cells to release a broad range of bioactive cytokines. In an effort to understand the structure-activity relationships, we have carried out syntheses of 26 new KRN7000 analogues incorporating aromatic residues in either or both side chains. Structural variations of the phytosphingosine moiety also include varying stereochemistry at C3 and C4, and 4-deoxy and 3,4-dideoxy versions. Their biological activities are described.

SUBMITTER: Park JJ

PROVIDER: S-EPMC5584937 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Syntheses and biological activities of KRN7000 analogues having aromatic residues in the acyl and backbone chains with varying stereochemistry.

Park Jeong-Ju JJ Lee Ji Hyung JH Seo Kyung-Chang KC Bricard Gabriel G Venkataswamy Manjunatha M MM Porcelli Steven A SA Chung Sung-Kee SK

Bioorganic & medicinal chemistry letters 20100104 3

KRN7000 is an important ligand identified for CD1d protein of APC, and KRN7000/CD1d complex can stimulate NKT cells to release a broad range of bioactive cytokines. In an effort to understand the structure-activity relationships, we have carried out syntheses of 26 new KRN7000 analogues incorporating aromatic residues in either or both side chains. Structural variations of the phytosphingosine moiety also include varying stereochemistry at C3 and C4, and 4-deoxy and 3,4-dideoxy versions. Their b ...[more]

PMID: 20061147

Similar Datasets

Thermoresponsive Molecular Brushes with a Rigid-Chain Aromatic Polyester Backbone and Poly-2-alkyl-2-oxazoline Side Chains.

Project description:A new polycondensation aromatic rigid-chain polyester macroinitiator was synthesized and used to graft linear poly-2-ethyl-2-oxazoline as well as poly-2-isopropyl-2-oxazoline by cationic polymerization. The prepared copolymers and the macroinitiator were characterized by NMR, GPC, AFM, turbidimetry, static, and dynamic light scattering. The molar masses of the polyester main chain and the grafted copolymers with poly-2-ethyl-2-oxazoline and poly-2-isopropyl-2-oxazoline side chains were 26,500, 208,000, and 67,900, respectively. The molar masses of the side chains of poly-2-ethyl-2-oxazoline and poly-2-isopropyl-2-oxazoline and their grafting densities were 7400 and 3400 and 0.53 and 0.27, respectively. In chloroform, the copolymers conformation can be considered as a cylinder wormlike chain, the diameter of which depends on the side chain length. In water at low temperatures, the macromolecules of the poly-2-ethyl-2-oxazoline copolymer assume a wormlike conformation because their backbones are well shielded by side chains, whereas the copolymer with short side chains and low grafting density strongly aggregates, which was visualized by AFM. The phase separation temperatures of the copolymers were lower than those of linear analogs of the side chains and decreased with the concentration for both samples. The LCST were estimated to be around 45 °C for the poly-2-ethyl-2-oxazoline graft copolymer, and below 20 °C for the poly-2-isopropyl-2-oxazoline graft copolymer.

| S-EPMC8622345 | biostudies-literature

Convergent syntheses of Le analogues.

Project description:The synthesis of three Le(x) derivatives from one common protected trisaccharide is reported. These analogues will be used respectively for competitive binding experiments, conjugation to carrier proteins and immobilization on gold. An N-acetylglucosamine monosaccharide acceptor was first glycosylated at O-4 with a galactosyl imidate. This coupling was performed at 40° C under excess of BF₃.OEt₂ activation and proceeded best if the acceptor carried a 6-chlorohexyl rather than a 6-azidohexyl aglycon. The 6-chlorohexyl disaccharide was then converted to an acceptor and submitted to fucosylation yielding the corresponding protected 6-chlorohexyl Le(x) trisaccharide. This protected trisaccharide was used as a precursor to the 6-azidohexyl, 6-acetylthiohexyl and 6-benzylthiohexyl trisaccharide analogues which were obtained in excellent yields (70-95%). In turn, we describe the deprotection of these intermediates in one single step using dissolving metal conditions. Under these conditions, the 6-chlorohexyl and 6-azidohexyl intermediates led respectively to the n-hexyl and 6-aminohexyl trisaccharide targets. Unexpectedly, the 6-acetylthiohexyl analogue underwent desulfurization and gave the n-hexyl glycoside product, whereas the 6-benzylthiohexyl analogue gave the desired disulfide trisaccharide dimer. This study constitutes a particularly efficient and convergent preparation of these three Le(x) analogues.

| S-EPMC2870943 | biostudies-literature

Structure-Activity Relationships of Rationally Designed Ritonavir Analogues: Impact of Side-Group Stereochemistry, Headgroup Spacing, and Backbone Composition on the Interaction with CYP3A4.

Project description:In a continuing effort to identify structural attributes required for strong binding and potent inhibition of human drug-metabolizing CYP3A4, we designed ten ritonavir-like analogues differing in the side-group stereochemistry, backbone atomic composition, and headgroup spacing. All analogues had pyridine and tert-butyloxycarbonyl (Boc) as the heme-ligating head and tail groups, respectively, phenyl side groups, and either a methyl- or ethyl-pyridyl linker. Each linker subseries had S/ R, R/ S, R/ R, and S/S side-group conformers (4a-d and 4e-h, respectively), and one S/S stereoisomer with the backbone S-to-N-heteroatom substitution (6a and 6b). To elucidate structure-activity relationships, ligand-dependent changes in optical spectra, dissociation constant ( Ks), inhibitory potency (IC50), thermostability, and heme ligation and reduction kinetics were analyzed. Comparison of the subseries and individual compounds showed that CYP3A4 only weakly discriminates between side-group configurations, associates more tightly with the pyridyl-ethyl-linker analogues, and strongly disfavors the N-containing backbone. Ks and IC50 for the pyridyl-ethyl R/ R conformer, 4g, were the lowest and close to those for ritonavir: 0.04 and 0.31 μM versus 0.02 and 0.13 μM, respectively. Determination of the X-ray structures of the inhibitory complexes was critical for experimental data interpretation, especially for the uniquely oriented 4a and 4e. Based on structural analysis, we conclude that, for this series of analogues, the ligand-mediated interactions near the heme are dominant and define the binding mode and that fine-tuning of these interactions as well as the backbone spacing could further improve the affinity and inhibitory strength.

| S-EPMC6467766 | biostudies-literature

Synthesis, Structure, Hydrodynamics and Thermoresponsiveness of Graft Copolymer with Aromatic Polyester Backbone at Poly(2-isopropyl-2-oxazoline) Side Chains.

Project description:New thermoresponsive graft copolymers with an aromatic polyester backbone and poly(2-isopropyl-2-oxazoline) (PiPrOx) side chains are synthesized and characterized by NMR and GPC. The grafting density of side chains is 0.49. The molar masses of the graft-copolymer, its backbone, side chains, and the modeling poly-2-isopropyl-2-oxaziline are 74,000, 19,000, 4300, and 16,600 g·mol-1, respectively. Their conformational properties in nitropropane as well as thermoresponsiveness in aqueous solutions are studied and compared with that of free side chains, i.e., linear PiPrOx with a hydrophobic terminal group. In nitropropane, the graft-copolymer adopts conformation of a 13-arm star with a core of a collapsed main chain and a PiPrOx corona. Similarly, a linear PiPrOx chain protects its bulky terminal group by wrapping around it in a selective solvent. In aqueous solutions at low temperatures, graft copolymers form aggregates due to interaction of hydrophobic backbones, which contrasts to molecular solutions of the model linear PiPrOx. The lower critical solution temperature (LCST) for the graft copolymer is around 20 °C. The phase separation temperatures of the copolymer solution were lower than that of the linear chain counterpart, decreasing with concentration for both polymers.

| S-EPMC7698206 | biostudies-literature

Palmitoylated acyl protein thioesterase APT2 deforms membranes to extract substrate acyl chains.

Project description:Many biochemical reactions require controlled recruitment of proteins to membranes. This is largely regulated by posttranslational modifications. A frequent one is S-acylation, which consists of the addition of acyl chains and can be reversed by poorly understood acyl protein thioesterases (APTs). Using a panel of computational and experimental approaches, we dissect the mode of action of the major cellular thioesterase APT2 (LYPLA2). We show that soluble APT2 is vulnerable to proteasomal degradation, from which membrane binding protects it. Interaction with membranes requires three consecutive steps: electrostatic attraction, insertion of a hydrophobic loop and S-acylation by the palmitoyltransferases ZDHHC3 or ZDHHC7. Once bound, APT2 is predicted to deform the lipid bilayer to extract the acyl chain bound to its substrate and capture it in a hydrophobic pocket to allow hydrolysis. This molecular understanding of APT2 paves the way to understand the dynamics of APT2-mediated deacylation of substrates throughout the endomembrane system.

| S-EPMC7610442 | biostudies-literature

One-pot syntheses of irida-polycyclic aromatic hydrocarbons.

Project description:Metalla-analogues of polycyclic aromatic hydrocarbons (PAHs) have captivated chemists with their fascinating structures and unique electronic properties. To date, metallabenzene, metallanaphthalene and metallaanthracene have been reported. Metalla-analogues with more complicated fused rings have rarely been reported. Herein, we have successfully synthesized a series of new iridafluoranthenes and fused-ring iridafluoranthenes ranging from pentacyclic to heptacyclic metallaaromatic hydrocarbons in high yields under mild reaction conditions for the first time. Their photophysical and redox properties were also explored using UV-vis spectroscopy and electrochemistry combined with TD-DFT calculations. The present work may offer an important guideline for the design and construction of new polycyclic metallaaromatic hydrocarbons and metalla-nanographenes.

| S-EPMC7046080 | biostudies-literature

Efficient asymmetric synthesis of tryptophan analogues having useful photophysical properties.

Project description:Two new fluorescent probes of protein structure and dynamics have been prepared by concise asymmetric syntheses using the Schöllkopf chiral auxiliary. The site-specific incorporation of one probe into dihydrofolate reductase is reported. The utility of these tryptophan derivatives lies in their absorption and emission maxima which differ from those of tryptophan, as well as in their large Stokes shifts and high molar absorptivities.

| S-EPMC3955165 | biostudies-literature

CYP2C9 amino acid residues influencing phenytoin turnover and metabolite regio- and stereochemistry.

Project description:Phenytoin has been an effective anticonvulsant agent for over 60 years, although its clinical use is complicated by nonlinear pharmacokinetics, a narrow therapeutic index, and metabolically based drug-drug interactions. Although it is well established that CYP2C9 is the major cytochrome P450 enzyme controlling metabolic elimination of phenytoin through its oxidative conversion to (S)-5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), nothing is known about the amino acid binding determinants within the CYP2C9 active site that promote metabolism and maintain the tight stereocontrol of hydroxy metabolite formation. This knowledge gap was addressed here through the construction of nine active site mutants at amino acid positions Phe100, Arg108, Phe114, Leu208, and Phe476 and in vitro analysis of the steady-state kinetics and stereochemistry of p-HPPH formation. The F100L and F114W mutants exhibited 4- to 5-fold increases in catalytic efficiency, whereas the F100W, F114L, F476L, and F476W mutants lost >90% of their phenytoin hydroxylation capacity. This pattern of effects differs substantially from that found previously for (S)-warfarin and (S)-flurbiprofen metabolism, suggesting that these three ligands bind within discrete locations in the CYP2C9 active site. Only the F114L, F476L, and L208V mutants altered phenytoin's orientation during catalytic turnover. The L208V mutant also uniquely demonstrated enhanced 6-hydroxylation of (S)-warfarin. These latter data provide the first experimental evidence for a role of the F-G loop region in dictating the catalytic orientation of substrates within the CYP2C9 active site.

| S-EPMC2683772 | biostudies-literature

Syntheses of cyclotriveratrylene analogues and their long elusive triketone congeners.

Project description:Although interest in cyclotriveratrylene and its analogues has been significant, limitations in the ability to adjust its structure fully have hampered studies into their complete range of properties. A unique strategy to synthesize a previously unobtainable cyclotriveratrylene analogue and a procedure which adjusts the inner methylene bridges of that material to a triketone is reported. A second triketone synthesis and computational studies indicate the parameters needed for success.

| S-EPMC4334237 | biostudies-literature

Total syntheses of heimiol A, hopeahainol D, and constrained analogues.

Project description: Not available

| S-EPMC3263399 | biostudies-literature