“…The purification on a silica gel column or by semipreparative HPLC on a reverse-phase silica column allowed the separation of the isomers. The protected unnatural amino acids Sal (sulfoalanine), hSal (homo-sulfoalanine), and (3-COOH)Pro (3-carboxyproline) introduced in 36 − 43 were synthesized as described. , 7 Coupling of the Synthons II and Deprotections of the Inhibitors a a Reagents and conditions: (a) NaBH 4 , LiCl; (b) DMSO, (COCl) 2 ; (c) NaBH 4 , MeOH; (d) TFA, anisole; (e) HF, m -cresol; (f) BOP, DIEA, AA 1 R‘ or AA 1 -AA 2 R‘. * = R + S configuration. …”
Section: Resultsmentioning
confidence: 99%
“…The protected unnatural amino acids Sal (sulfoalanine), hSal (homo-sulfoalanine), and (3-COOH)-Pro (3-carboxyproline) introduced in 36-43 were synthesized as described. 33,34 Comparative Inhibition of APA and APN Activities. In a first step, a combinatorial library of pseudotripeptides 35 derived from the sulfonamide synthon IIa was studied to discriminate APA and APN active sites.…”
The study of the physiological roles of the membrane-bound zinc-aminopeptidase A (glutamyl aminopeptidase, EC 3.4.11.7) needs the design of efficient and selective inhibitors of this enzyme. An acute exploration of aminopeptidase A active site was performed by a combinatorial approach using (3-amino-2-mercapto-acyl)dipeptides able to fit its S(1), S(1)', and S(2)' subsites. This analysis confirmed that the S(1) subsite is optimally blocked by a glutamate or isosteric residues and demonstrated that the S(1)' subsite is hydrophobic whereas the S(2)' subsite recognizes preferentially negatively charged residues derived from aspartic acid. The optimization of these structural parameters led to the synthesis of nanomolar and subnanomolar inhibitors of aminopeptidase A such as H(3)N(+)CH(CH(2)CH(2)SO(3)(-))CH(SH)CO-Ile-(3-COOH)Pro that exhibits a K(i) of 0.87 nM. The best compounds were synthesized by a stereochemically controlled route. These first described highly potent inhibitors could allow studies about the role of physiological substrates of APA such as angiotensin II and cholecystokinin CCK(8) in the central nervous system.
“…The purification on a silica gel column or by semipreparative HPLC on a reverse-phase silica column allowed the separation of the isomers. The protected unnatural amino acids Sal (sulfoalanine), hSal (homo-sulfoalanine), and (3-COOH)Pro (3-carboxyproline) introduced in 36 − 43 were synthesized as described. , 7 Coupling of the Synthons II and Deprotections of the Inhibitors a a Reagents and conditions: (a) NaBH 4 , LiCl; (b) DMSO, (COCl) 2 ; (c) NaBH 4 , MeOH; (d) TFA, anisole; (e) HF, m -cresol; (f) BOP, DIEA, AA 1 R‘ or AA 1 -AA 2 R‘. * = R + S configuration. …”
Section: Resultsmentioning
confidence: 99%
“…The protected unnatural amino acids Sal (sulfoalanine), hSal (homo-sulfoalanine), and (3-COOH)-Pro (3-carboxyproline) introduced in 36-43 were synthesized as described. 33,34 Comparative Inhibition of APA and APN Activities. In a first step, a combinatorial library of pseudotripeptides 35 derived from the sulfonamide synthon IIa was studied to discriminate APA and APN active sites.…”
The study of the physiological roles of the membrane-bound zinc-aminopeptidase A (glutamyl aminopeptidase, EC 3.4.11.7) needs the design of efficient and selective inhibitors of this enzyme. An acute exploration of aminopeptidase A active site was performed by a combinatorial approach using (3-amino-2-mercapto-acyl)dipeptides able to fit its S(1), S(1)', and S(2)' subsites. This analysis confirmed that the S(1) subsite is optimally blocked by a glutamate or isosteric residues and demonstrated that the S(1)' subsite is hydrophobic whereas the S(2)' subsite recognizes preferentially negatively charged residues derived from aspartic acid. The optimization of these structural parameters led to the synthesis of nanomolar and subnanomolar inhibitors of aminopeptidase A such as H(3)N(+)CH(CH(2)CH(2)SO(3)(-))CH(SH)CO-Ile-(3-COOH)Pro that exhibits a K(i) of 0.87 nM. The best compounds were synthesized by a stereochemically controlled route. These first described highly potent inhibitors could allow studies about the role of physiological substrates of APA such as angiotensin II and cholecystokinin CCK(8) in the central nervous system.
“…Direct alkylation of aspartic acid derivatives was first reported by Seebach in 1981, 2 and later by Baldwin and other workers. [3][4][5][6][7][8][9][10][11][12] Except for reports of stereospecific allylation, 10,11 these reactions gave mixtures of diastereoisomers. A recent study has indicated how the structural and experimental features in such reactions affect the diastereoselectivity.…”
“…Starting from orthogonally protected aspartic acid, North and co-workers have reported the synthesis of cis- and trans- 3-carboxyproline derivatives ( Scheme 13 ) [ 34 ]:…”
Among the twenty natural proteinogenic amino acids, proline is unique as its secondary amine forms a tertiary amide when incorporated into biopolymers, thus preventing hydrogen bond formation. Despite the lack of hydrogen bonds and thanks to conformational restriction of flexibility linked to the pyrrolidine ring, proline is able to stabilize peptide secondary structures such as β-turns or polyproline helices. These unique conformational properties have aroused a great interest in the development of proline analogues. Among them, proline chimeras are tools combining the proline restriction of flexibility together with the information brought by natural amino acids side chains. This review will focus on the chemical syntheses of 3-substituted proline chimeras of potential use for peptide syntheses and as potential use as tools for SAR studies of biologically active peptides and the development of secondary structure mimetics. Their influence on peptide structure will be briefly described.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
