128609-40-5

Upstream product

• 24424-99-5 di-tert-butyl dicarbonate 
• 186826-30-2 (2S,3S)-2-Amino-3-benzyloxy-butyric acid 
• 188660-15-3 N-acetyl-O-benzyl-D-threonine benzyl ester 
• 188660-18-6 4-((S)-1-Benzyloxy-ethyl)-2-methyl-4H-oxazol-5-one 
• 186832-71-3 N-acetyl-O-benzyl-D-threonine 
• 2592-18-9 N-tert-butoxycarbonyl-L-allo-threonine 
• 100-39-0 benzyl bromide 
• 2592-18-9 (2R,3R)-allo-2-tert-butoxycarbonylamino-3-hydroxybutyric acid 

Downstream Products

• 452956-84-2 (S)-3-Benzyloxy-2-((2S,3S)-3-benzyloxy-2-tert-butoxycarbonylamino-butyrylamino)-propionic acid allyl ester 
• 60856-51-1 O-benzyl-L-allothreonine hydrochloride 
• 60856-51-1 O-benzyl-L-allothreonine hydrochloride 
• 1369586-42-4 C₁₈H₂₀N₄O₂ 
• 1369586-14-0 (2S,3S)-2-Boc-amino-1-(2-aminoimidazo[1,2-a]pyridin-3-yl)-3-(benzyloxy)butan-1-one 

Relevant academic research and scientific papers

Optimization of globomycin analogs as novel gram-negative antibiotics

Discovery of novel classes of Gram-negative antibiotics with activity against multi-drug resistant infections is a critical unmet need. As an essential member of the lipoprotein biosynthetic pathway, lipoprotein signal peptidase II (LspA) is an attractive target for antibacterial drug discovery, with the natural product inhibitor globomycin offering a modestly-active starting point. Informed by structure-based design, the globomycin depsipeptide was optimized to improve activity against E. coli. Backbone modifications, together with adjustment of physicochemical properties, afforded potent compounds with good in vivo pharmacokinetic profiles. Optimized compounds such as 51 (E. coli MIC 3.1 μM) and 61 (E. coli MIC 0.78 μM) demonstrate broad spectrum activity against gram-negative pathogens and may provide opportunities for future antibiotic discovery.

CYCLIC PEPTIDE ANTIBIOTICS

Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of lipoprotein signal peptidase II (LspA), a key protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.

CYCLIC PEPTIDE ANTIBIOTICS

Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of lipoprotein signal peptidase II (LspA), a key protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.

Inversion of the Side-Chain Stereochemistry of Indvidual Thr or Ile Residues in a Protein Molecule: Impact on the Folding, Stability, and Structure of the ShK Toxin

ShK toxin is a cysteine-rich 35-residue protein ion-channel ligand isolated from the sea anemone Stichodactyla helianthus. In this work, we studied the effect of inverting the side chain stereochemistry of individual Thr or Ile residues on the properties of the ShK protein. Molecular dynamics simulations were used to calculate the free energy cost of inverting the side-chain stereochemistry of individual Thr or Ile residues. Guided by the computational results, we used chemical protein synthesis to prepare three ShK polypeptide chain analogues, each containing either an allo-Thr or an allo-Ile residue. The three allo-Thr or allo-Ile-containing ShK polypeptides were able to fold into defined protein products, but with different folding propensities. Their relative thermal stabilities were measured and were consistent with the MD simulation data. Structures of the three ShK analogue proteins were determined by quasi-racemic X-ray crystallography and were similar to wild-type ShK. All three ShK analogues retained ion-channel blocking activity.

Simple methods for the preparation of protected derivatives of D-allo- and L-allo-threonine

Practical syntheses of protected derivatives of the non-proteinogenic allo-threonines are described. The key step is enzymatic resolution of threonine diastereomers, produced on controlled epimerization of the α-carbon atom. The protected allo-threonines are obtained in good overall yield and can be used in standard peptide synthesis protocols.

Synthetic studies on threonines. The preparation of protected derivatives of D-allo- and L-allo-threonine for peptide synthesis

N-Acetylated threonine derivatives, having tert-butyl or benzyl-based side-chain protection, form isolable 5(4H)-oxazalones on treatment with N-ethyl-N'-3-dimethylaminopropyl carbodiimide. N-chloroacetylated threonine derivatives, on the other hand, do not form oxazolones so readily. The N-acetylated oxazolones an easily epimerized and lead to diastereoisomeric mixtures of threonine derivatives on hydrolysis with dilute aqueous acid. The components of these mixtures can be separated chromatogaphically, but a useful alternative for the O-benzylated mixture is selective enzymatic hydrolysis using hog kidney acylase. These chemical transformations provide the basis for practical syntheses of protected derivatives of the non-proteinogenic allo-threonines, suitable for use in peptide synthesis.