105181-72-4Relevant articles and documents
Synthesis of di- and tripeptide analogues containing α-ketoamide as a new core structure for inhibition of HIV-1 protease
Sheha, Mahmoud M.,Mahfouz, Nadia M.,Hassan, Hoda Y.,Youssef, Adel F.,Mimoto, Tsutomu,Kiso, Yoshiaki
, p. 887 - 894 (2000)
Di- and tripeptide analogues containing α-ketoamide as a new core structure and incorporating allophenylnorstatine (Apns) as a transition state mimic, were designed and synthesized in the hope of obtaining a novel structural type of HIV-1 protease inhibitors. The immediate precursor, Apns-Thz-NHBu(t) was prepared by coupling of Boc-Apns with N-tert·butyl Thz-4-carboxamide hydrochloride. Removal of Boc group followed by coupling with the respective α-ketoacid residue (P2) gave the desired dipeptides (8-12) in almost quantitative yields. The α-keto tripeptides (18-21) were obtained by oxidation of the hydroxyl group of Apns (PI) in the appropriate tripeptide, iQOA-Val-Apns-(un)substituted Thz(Oxa)-NHBu1 with DMSO/DCC. Preliminary evaluation of the activity of the synthesized derivatives was determined as percentage of enzyme inhibition at 5 μM and 50 nM levels of the di- and tripeptides respectively. The α-ketoamides displayed a significant enhanced potency relative to their parent isosteres as inhibitors of HIV-1 protease and are shown to be a promising new core structure for the development of enzyme inhibitors. A quantitative approach was attempted, using an LFE model, correlating the effect of structural modification and HIV-1 protease inhibition activity of the prepared dipeptides. The result indicates the contribution of the torsion angle by 84% to the activity of the inhibitors. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
A practical and convenient synthesis of the protease inhibitor epibestatin
Richter, Anja,Hedberg, Christian
experimental part, p. 2039 - 2042 (2010/08/13)
A convenient synthesis of the protease inhibitor epibestatin, a useful component in protease inhibition cocktails for use in proteomics research, is described. The synthesis sequence consists of seven steps, starting from phenylacetaldehyde, yielding enantiopure epibestatin in 8% overall yield. A regioselective Mitsunobu transformation of a diol is the key step in the sequence. Georg Thieme Verlag Stuttgart.
Application of the lewis acid-lewis base bifunctional asymmetric catalysts to pharmaceutical syntheses: Stereoselective chiral building block syntheses of human immunodeficiency virus (HIV) protease inhibitor and β3- adenergic receptor agonist
Nogami, Hiroyuki,Kanai, Motomu,Shibasaki, Masakatsu
, p. 702 - 709 (2007/10/03)
Chiral building block syntheses of promising drugs were achieved using two types of catalytic stereoselective cyanosilylations of aldehydes promoted by Lewis acid-Lewis base bifunctional catalysts 1 and 2 as the key steps (diastereoselective cyanosilylation of amino aldehyde and enantioselective cyanosilylation). In the first part of this article, syntheses of chiral building blocks (6) of Atazanavir (3: human immunodeficiency virus (HIV) protease inhibitor) using the bifunctional catalyst 2 are discussed. The reaction of Boc-protected phenylalaninal 21 in the presence of 1 mol% catalyst 2 selectively afforded the anti isomer 22 as the major product (diastereomeric ratio=97:3), which was successively converted to the corresponding epoxide 6 in six steps. In the second part, we describe a chiral building block synthesis of β3-adrenergic receptor agonists. The enantioselective cyanosilylation of 3-chlorobenzaldehyde (38) with 9 mol% catalyst 1 gave the chiral cyanohydrin 39, which was converted to β-hydroxyethylamine 40 by reduction. Moreover, the chiral ligand of catalyst 1 could be recovered without column chromatography and reused without decreasing its activity.
