ABSTRACT
A metal-free C-H allylation strategy is described to access diverse functionalized ortho-allyl-iodoarenes. The method employs hypervalent (diacetoxy)iodoarenes and proceeds through the iodane-guided "iodonio-Claisen" allyl transfer. The use of allylsilanes bearing electron-withdrawing functional groups unlocks the functionalization of a broad range of substrates, including electron-neutral and electron-poor rings. The resulting ortho-allylated iodoarenes are versatile building blocks, with examples of downstream transformation including a concise synthesis of the experimental antimitotic core of Dosabulin. DFT calculations shed additional light on the reaction mechanism, with notable aspects including the aromatic character of the transition-state structure for the [3,3] sigmatropic rearrangement, as well as the highly stereoconvergent nature of the trans-product formation.
ABSTRACT
A novel series of CD1d ligand α-galactosylceramides (α-GalCers) were synthesized by incorporation of the heavy atoms Br and Se in the acyl chain backbone of α-galactosyl-N-cerotoylphytosphingosine. The synthetic analogues are potent CD1d ligands and stimulate mouse invariant natural killer T (iNKT) cells to selectively enhance Th1 cytokine production. These synthetic analogues would be efficient X-ray crystallographic probes to disclose precise atomic positions of alkyl carbons and lipid-protein interactions in KRN7000/CD1d complexes.
Subject(s)
Galactosylceramides/pharmacology , Halogens/chemistry , Natural Killer T-Cells/drug effects , Selenium/chemistry , Animals , Carbon-13 Magnetic Resonance Spectroscopy , Crystallography, X-Ray , Cytokines/biosynthesis , Female , Galactosylceramides/chemistry , Mass Spectrometry , Mice , Mice, Inbred C57BL , Natural Killer T-Cells/immunology , Proton Magnetic Resonance Spectroscopy , Spleen/cytology , Spleen/drug effects , Spleen/immunologyABSTRACT
Correction for 'Stereoselective synthesis of the head group of archaeal phospholipid PGP-Me to investigate bacteriorhodopsin-lipid interactions' by Jin Cui, et al., Org. Biomol. Chem., 2015, DOI: 10.1039/c5ob01252j.
ABSTRACT
Phosphatidylglycerophosphate methyl ester (PGP-Me), a major constituent of the archaeal purple membrane, is essential for the proper proton-pump activity of bacteriorhodopsin (bR). We carried out the first synthesis of the bisphosphate head group of PGP-Me using H-phosphonate chemistry that led to the production of a simplified PGP-Me analogue with straight alkyl chains. To investigate the role of this head group in the structural and functional integrity of bR, the analogue was used to reconstitute bR into liposomes, in which bR retained the original trimeric structure and light-induced photocycle activity. Enhanced ordering of an alkyl chain of the (2)H-labelled analogue was observed in (2)H NMR spectra upon interaction with bR. These results together suggest that the bisphosphate moiety plays a role in the proper functioning of bR through the lipid-protein interaction.
Subject(s)
Bacteriorhodopsins/chemistry , Phospholipids/chemistry , Phospholipids/chemical synthesis , Molecular Conformation , StereoisomerismABSTRACT
Lipid organization has been at the center of research on lipid rafts. Dioleoylphosphatidylcholine (DOPC) is a typical unsaturated lipid. Very few studies have reported its thermodynamics in raft-like membranes. Herein, we have developed a highly efficient synthetic method for [C6-(2)H2] oleic acid, and newly synthesized [C6-(2)H2] DOPC. In raft-like oriented bilayers, [C6-(2)H2] DOPC shows clear phase separation and characteristic phase behavior at various temperature. It has been successfully utilized for the comparison of membrane properties between sphingomyelin (SM) and dihydrosphingomyelin (DHSM) membranes.
Subject(s)
Magnetic Resonance Spectroscopy/methods , Membrane Microdomains/chemistry , Oleic Acid/chemistry , Phosphatidylcholines/chemistry , Oleic Acid/analysis , Phosphatidylcholines/analysisABSTRACT
Long-chain fatty acids (FAs) with low water solubility require fatty-acid-binding proteins (FABPs) to transport them from cytoplasm to the mitochondria for energy production. However, the precise mechanism by which these proteins recognize the various lengths of simple alkyl chains of FAs with similar high affinity remains unknown. To address this question, we employed a newly developed calorimetric method for comprehensively evaluating the affinity of FAs, sub-Angstrom X-ray crystallography to accurately determine their 3D structure, and energy calculations of the coexisting water molecules using the computer program WaterMap. Our results clearly showed that the heart-type FABP (FABP3) preferentially incorporates a U-shaped FA of C10-C18 using a lipid-compatible water cluster, and excludes longer FAs using a chain-length-limiting water cluster. These mechanisms could help us gain a general understanding of how proteins recognize diverse lipids with different chain lengths.
Subject(s)
Fatty Acid-Binding Proteins/metabolism , Myocardium/metabolism , Water/metabolism , Binding Sites , Calorimetry , Crystallography, X-Ray , Fatty Acid Binding Protein 3 , Fatty Acid-Binding Proteins/chemistry , Fatty Acids/chemistry , Fatty Acids/metabolism , Humans , Molecular Dynamics Simulation , Protein Structure, Tertiary , Thermodynamics , Water/chemistryABSTRACT
An efficient synthesis involving two copper-catalyzed alkyl-alkyl coupling reactions has been designed to easily access doubly isotope-labeled fatty acids. Such NMR- and IR-active compounds were obtained in excellent overall yields and will be further used for determining the conformation of an alkyl chain of lipidic biomolecules upon interaction with proteins.
ABSTRACT
A new synthetic pathway was devised to reach tetrasubstituted 3-arylthiophene 2-carboxylic acids in a three-step solid-phase synthesis. This very efficient methodology provided more than 20 new compounds that were evaluated for their ability to inhibit protein farnesyltransferase from different species as well as Trypanosoma brucei and Plasmodium falciparum proliferation.
Subject(s)
Carboxylic Acids/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase/antagonists & inhibitors , Solid-Phase Synthesis Techniques/methods , Base Sequence , Enzyme Inhibitors/chemistry , Farnesyltranstransferase/genetics , Humans , Molecular Sequence Data , Plasmodium falciparum/drug effects , Plasmodium falciparum/growth & development , Structure-Activity Relationship , Thiophenes/chemistry , Trypanosoma brucei brucei/drug effects , Trypanosoma brucei brucei/enzymology , Trypanosoma brucei brucei/growth & developmentABSTRACT
Screening of the ICSN chemical library led to the discovery of 3-(4-chlorophenyl)-4-cyano-5-thioalkylthiophene 2-carboxylic acids as potent farnesyltransferase inhibitors. Enzymatic kinetic studies showed that this original FTI series belongs to the CaaX competitive inhibitor class. Preliminary SAR studies allowed us to improve the IC50 from 110 to 7.5 nM.
