206191-48-2Relevant articles and documents
Synthesis, structure, and antibiotic activity of aryl-substituted LpxC inhibitors
Liang, Xiaofei,Lee, Chul-Jin,Zhao, Jinshi,Toone, Eric J.,Zhou, Pei
, p. 6954 - 6966 (2013/10/01)
The zinc-dependent deacetylase LpxC catalyzes the committed step of lipid A biosynthesis in Gram-negative bacteria and is a validated target for the development of novel antibiotics to combat multidrug-resistant Gram-negative infections. Many potent LpxC inhibitors contain an essential threonyl-hydroxamate headgroup for high-affinity interaction with LpxC. We report the synthesis, antibiotic activity, and structural and enzymatic characterization of novel LpxC inhibitors containing an additional aryl group in the threonyl-hydroxamate moiety, which expands the inhibitor-binding surface in LpxC. These compounds display enhanced potency against LpxC in enzymatic assays and superior antibiotic activity against Francisella novicida in cell culture. The comparison of the antibiotic activities of these compounds against a leaky Escherichia coli strain and the wild-type strain reveals the contribution of the formidable outer-membrane permeability barrier that reduces the compounds efficacy in cell culture and emphasizes the importance of maintaining a balanced hydrophobicity and hydrophilicity profile in developing effective LpxC-targeting antibiotics.
Stereoselective Synthesis of Threo and Erythro β-Hydroxy and β-Disubstituted-β-Hydroxy α-Amino Acids
Blaskovich, Mark A.,Evindar, Ghotas,Rose, Nicholas G. W.,Wilkinson, Scott,Luo, Yue,Lajoie, Gilles A.
, p. 3631 - 3646 (2007/10/03)
Optically pure N-protected serine aldehyde equivalents can be prepared by the protection of the carboxylic group of serine by a cyclic ortho ester. Alkylation of N-Cbz-, N-Fmoc- or N-Boc-protected serine with oxetane tosylate 1 or bromide 2 gives the corresponding oxetane esters 4a-c which can easily be converted to the cyclic ortho esters 5a-c. A variety of unusual threo β5-hydroxy amino acids have been synthesized by Grignard addition to these optically pure serine aldehyde equivalents. The erythro diastereomers can be obtained by oxidation of the initial threo adduct followed by reduction with LiBH4. Also described is a general approach for the diastereoselective synthesis of optically pure β,β-dialkyl-β-hydroxy α-amino acids. These highly substituted amino acids are prepared by a sequence of Grignard addition to the optically active serine aldehyde equivalent, followed by oxidation of the initial adduct, and a second Grignard addition to the resulting ketone. The hydroxy adduct is obtained with very high diastereoselectivity (84-96% de). All four diastereomers can be selectively synthesized by varying the order of the Grignard additions and the chirality of the initial synthon. Removal of the protecting groups can be effected in very mild conditions, giving excellent yields of highly substituted amino acids in high diastereomeric purity.
