10.1016/j.bmcl.2009.07.065
The research focuses on the design, synthesis, and biological evaluation of new Ras CAAX mimetics. These compounds were designed by replacing cysteine in the Ras protein's C-terminal CAAX tetrapeptide with 2-hydroxymethylbenzodioxane or 2-aminomethylbenzodioxane, and using pluri-substituted biphenyl systems as internal spacers and AA dipeptide bioisosteres. The resultant compounds were linked to the methyl ester of L-methionine, glycine, or L-leucine by an amide bond. The synthesized compounds were tested for their antiproliferative effects on human aortic smooth muscle cells (SMCs) and their ability to inhibit Ras prenylation. The most potent compound was found to be the methionine derivative with a methyleneoxy linker between benzodioxane and 2-methylbiphenyl, which demonstrated significant antiproliferative activity and direct interference with Ras prenylation. The study highlights the importance of the linker between the dioxane and biphenyl core and the o-substitution on the biphenyl core for the observed biological activities.
10.1021/jo980821a
The research aims to develop an efficient chemoenzymatic synthesis of enantiopure 4-amino-2-hydroxy acids, which are valuable as ?-turn mimics for studying the secondary structure of peptides. The study employs a single-pot process in an aqueous medium, using carbobenzyloxy (CBZ)-protected 4-amino-2-keto esters derived from L-amino acids (alanine, leucine, phenylalanine, and valine) as substrates. Lipase from Candida rugosa is used to hydrolyze the keto esters to keto acids. The study compares the performance of wild-type lactate dehydrogenases (LDHs) from Bacillus stearothermophilus (BS-LDH) and Staphylococcus epidermidis (SE-LDH) with the genetically engineered H205Q mutant of D-hydroxyisocaproate dehydrogenase (LB-hicDH) in reducing the keto acids to the corresponding 2-hydroxy acids. The wild-type LDHs effectively reduced the alanine-derived keto acid but were inefficient with more bulky substrates. In contrast, the H205Q mutant demonstrated broad substrate specificity and high catalytic activity, successfully reducing all tested keto acids to yield the desired 4-amino-2-hydroxy acids as single diastereomers with excellent yields. The study concludes that the H205Q mutant has significant potential for the large-scale production of these compounds due to its enhanced performance and versatility.
10.1021/jm00104a004
This research investigates the development and evaluation of N-substituted peptides containing α,α-difluorostatone residues as potent inhibitors of human leukocyte elastase (HLE), a serine protease implicated in various diseases such as emphysema and arthritis. The study aims to design inhibitors that can effectively bind to HLE and inhibit its activity, potentially serving as therapeutic agents. Key chemicals used include α,α-difluorostatone derivatives of amino acids like L-valine, L-leucine, and L-phenylalanine, with the α,α-difluoromethylene ketone derivative of L-valine proving to be the most effective at the P1 position. The peptides also incorporate a nonproteinogenic residue, N-(2,3-dihydro-lH-inden-2-yl)glycine, at the P2 position, which acts as a bioisosteric replacement for L-proline. The most potent in vitro compound, 17b, has an IC50 of 0.635 μM. Extended inhibitors like 23b and 24b were designed to interact with additional binding subsites of HLE, enhancing their potency. The study concludes that these α,α-difluoromethylene ketone inhibitors effectively inhibit HLE through transition-state analog mechanisms, forming reversible hemiketals with the active site Ser195 of HLE. The inhibitors were also tested in an elastase-induced pulmonary hemorrhage model in hamsters, with 22c showing significant inhibition of hemorrhage in a dose-dependent manner. The research highlights the potential of these peptides as therapeutic agents for HLE-related diseases.
10.1021/acschembio.7b00949
The research investigates the role of amide bond formation during the biosynthesis of Dehydrophos, a phosphonate antibiotic produced by Streptomyces luridus. The study focuses on the enzyme DhpH-C, a peptidyltransferase that utilizes Leu-tRNALeu for the first amide bond formation in the biosynthetic pathway. Experiments involved site-directed mutagenesis of DhpH-C and tRNALeu to probe enzyme mechanism and substrate specificity, respectively. The substrate scope was analyzed for the production of a set of dipeptides, examining DhpH-C's recognition of the amino acyl group on tRNA and the tRNA acceptor stem, as well as its acceptance of other hydrophobic residues besides leucine. The analyses included 31P NMR spectroscopy to monitor product formation over time in a coupled enzyme assay, which involved E. coli leucyl-tRNA synthetase (LeuRS) to generate aa-tRNA in situ from E. coli total tRNA, L-Leu, and ATP. The study provides insights into enzyme-aa-tRNA interactions and the broader use of aa-tRNA in natural product biosynthesis beyond canonical translation activities.
10.1080/00397910903051259
The research explores the synthesis of N-phenyl methyl esters of various amino acids using diphenyliodonium bromide as a key reagent. The study focuses on the efficient and selective N-phenylation of α-amino acids, including glycine, alanine, valine, leucine, isoleucine, phenylalanine, methionine, proline, serine, threonine, tyrosine, aspartic acid, and glutamic acid. The process involves converting the amino acids into their methyl ester hydrochloride salts, followed by neutralization to obtain free amines. These amines are then subjected to N-phenylation in the presence of diphenyliodonium bromide, silver nitrate, and a catalytic amount of copper bromide. The chiral integrity of the amino acids is maintained throughout the reactions, as confirmed by the synthesis of dipeptides for each N-phenyl amino acid. The structures of the new compounds are characterized using IR, 1H, and 13C NMR spectroscopy, as well as CHN microanalysis or high-resolution mass spectrometry. The study highlights the utility of diphenyliodonium bromide in the synthesis of N-phenylated amino acids, demonstrating good to excellent yields and maintaining the chirality of the starting amino acids.
