147489-31-4Relevant academic research and scientific papers
Synthesis and evaluation of conformationally restricted inhibitors of aspartate semialdehyde dehydrogenase
Evitt, Andrew S.,Cox, Russell J.
experimental part, p. 1564 - 1575 (2012/03/27)
Inhibitors of the enzyme aspartate semialdehyde dehydrogenase, a key biological target for the generation of a new class of antibiotic compounds, have been developed. To investigate improvements to binding within an inhibitor series, the lowering of the entropic barrier to binding through conformational restriction was investigated. A library of linear and cyclic substrate analogues was generated and computational docking used to aid in structure selection. The cyclic phosphonate inhibitor 18 was thus identified as complimentary to the enzyme active-site. Synthesis and in vitro inhibition assay revealed a K i of 3.8 mM against natural substrate, where the linear analogue of 18, compound 15, had previously shown no inhibitory activity. Two further inhibitors, phosphate analogue diastereoisomers 17a and 17b, were synthesised and also found to have low millimolar Ki values. As a result of the computational docking investigations, a novel substrate binding interaction was discovered: hydrogen bonding between the substrate (phosphate hydroxy-group as the hydrogen bond donor) and the NADPH cofactor (2′-oxygen as the hydrogen bond acceptor). The Royal Society of Chemistry 2011.
Diastereoselective synthesis of (2S,5S)- and (2S,5R)-N-benzyloxycarbonyl-5-hydroxypipecolic acids from trans-4-hydroxy-l-proline
Jung, Jae-Chul,Avery, Mitchell A.
, p. 2479 - 2486 (2007/10/03)
An efficient diastereoselective synthesis of cis- and trans-5-hydroxy-(2S)-N-benzyloxycarbonyl pipecolic acids, starting from trans-4-hydroxy-l-proline is described. The key synthetic strategies involve the regioisomeric ring expansion of keto ester 8 and diastereoselective reduction of ketone 11 in high selectivity and yield.
