Gino Lucente

γ-Turn conformation induced by α,α-disubstituted amino acids with a cyclic six-membered side chain

Abstract 4-Aminotetrahydrothiopyran-4-carboxylic acid (Thp) is an unusual achiral cyclic α,α-disubstituted amino acid mimicking the natural Met residue. The conformational energy map computed for Ac-Thp-NHMe shows that the γ-turn is the lowest minimum. 1 H-NMR and IR studies performed on For-Thp-Leu-OMe ( 2a ), a short peptide unable to give a 4…>1 H-bond, indicate that the γ-turn is adopted in CDCl 3 solution, whereas is not retained in (CD 3 ) 2 SO. An analogous conformational behaviour in solution has been observed for the strictly related For-Ac 6 c-Leu-OMe ( 2b ), containing 1-aminocyclohexane carboxylic acid (Ac 6 c).

Synthesis and evaluation of new endomorphin analogues modified at the Pro2 residue

Six new endomorphin analogues, incorporating constrained amino acids in place of native proline have been synthesized. Residues of (S)-azetidine-2-carboxylic acid (Aze), 3,4-dehydro-(S)-proline (Delta(3)Pro), azetidine-3-carboxylic acid (3Aze) and dehydro-alanine (DeltaAla) have been used to prepare [Delta(3)Pro(2)]EM-2 (1), [Aze(2)]EM-1 (2), [Aze(2)]EM-2 (3), [3Aze(2)]EM-1 (4), [3Aze(2)]EM-2 (5) and [DeltaAla(2)]EM-2 (6). Binding assays and functional bioactivities for mu- and delta-receptors are reported. The highest affinity, bioactivity and selectivity are shown by peptides 2 and 3 containing the Aze residue.

Design and synthesis of glutathione analogues

This review reports recent structural modifications (since 1989) performed on the glutathione molecular both in the oxidized and reduced form. Relevant chemical aspects, biochemical consequences and therapeutical implications are illustrated. Natural thiols related to glutathione are also considered.

Synthesis and evaluation of new endomorphin-2 analogues containing (Z)-α,β-didehydrophenylalanine (δZPhe) residues

New endomorphin-2 (EM-2) analogues incorporating (Z)-alpha,beta-didehydrophenylalanine (Delta(Z)Phe) in place of the native phenylalanine in EM-2 are reported. Tyr-Pro-Delta(Z)Phe-Phe-NH(2) {[Delta(Z)Phe(3)]EM-2} (1), Tyr-Pro-Phe-Delta(Z)Phe-NH(2) {[Delta(Z)Phe(4)]EM-2} (2), and Tyr-Pro-Delta(Z)Phe-Delta(Z)Phe-NH(2) {[Delta(Z)Phe(3,4)]EM-2}(3) have been synthesized, their opioid receptor binding affinities and tissue bioassay activities were determined, and their conformational properties were examined. Compound 2 shows high mu opioid receptor selectivity and mu agonist activity comparable to those of the native peptide. The conformation adopted in solution and in the crystal by N-Boc-Tyr-Pro-Delta(Z)Phe-Phe-NH(2) (8) is reported.

Synthesis and activity of endomorphin-2 and morphiceptin analogues with proline surrogates in position 2.

The opioid agonists endomorphins (Tyr-Pro-Trp-Phe-NH(2); EM1 and Tyr-Pro-Phe-Phe-NH(2); EM2) and morphiceptin (Tyr-Pro-Phe-Pro-NH(2)) exhibit an extremely high selectivity for mu-opioid receptor. Here a series of novel EM2 and morphiceptin analogues containing in place of the proline at position 2 the S and R residues of beta-homologues of proline (HPro), of 2-pyrrolidinemethanesulphonic acid (HPrs) and of 3-pyrrolidinesulphonic acid (betaPrs) have been synthesized and their binding affinity and functional activity have been investigated. The highest micro-receptor affinity is shown by [(S)betaPrs(2)]EM2 analogue (6e) which represents the first example of a beta-sulphonamido analogue in the field of opioid peptides.

Exploring the interest of 1,2-dithiolane ring system in peptide chemistry. Synthesis of a chemotactic tripeptide and X-ray crystal structure of a 4-amino-1,2-dithiolane-4-carboxylic acid derivative

Due to their relevant biological functions and specific chemical reactivity 1,2-dithiolanes (five-membered cyclic disulfides) represent an emerging class of heterocyclic compounds. However, despite the extensive research centered on lipoic acid and its analogues, only very few data are at the present available on peptides containing this ring system. We report here synthesis, conformation and bioactivity of a fMLF-OMe analogue, namely For-Met-Adt-Phe-OMe (7), in which the residue of the 4-amino-1,2-dithiolane-4-carboxylic acid (Adt) (4) replaces the central L-leucine. The crystal conformation of the synthetic intermediate Boc-Adt-OMe (5) is also described and compared to that of lipoic acid (R-1,2-dithiolane-3-pentanoic acid) (3) and asparagusic acid (1,2-dithiolane-4-carboxylic acid) (2).

The cis-4-Amino-l-proline Residue as a Scaffold for the Synthesis of Cyclic and Linear Endomorphin-2 Analogues

Endomorphin-2 (EM-2: Tyr-Pro-Phe-Phe-NH(2)) is an endogenous tetrapeptide that combines potency and efficacy with high affinity and selectivity toward the μ opioid receptor, the most responsible for analgesic effects in the central nervous system. The presence of the Pro(2) represents a crucial factor for the ligand structural and conformational properties. Proline is in fact an efficient stereochemical spacer, capable of inducing favorable spatial orientation of aromatic rings, a key factor for ligand recognition and interaction with receptors. Here the Pro(2) has been replaced by 4(S)-NH(2)-2(S)-proline (cAmp), a proline/GABA cis-chimera residue. This bivalent amino acid maintains the capacity to influenc the tetrapeptide conformation and offers the opportunity to generate new linear models and unusually constrained cyclic analogues characterized by an N-terminal Tyr bearing a free α-amino group. The results indicate that the new analogues do not show affinity for both δ and κ opioid receptors and bind only poorly to the μ receptors (for cyclopeptide 9: K(i)(μ) = 660 nM; GPI (IC(50)) = 1.4% at 1 μM; for linear tetrapeptide acid 13: K(i)(μ) = 2000 nM; GPI (IC(50)) = 0% at 1 μM; for linear tetrapeptide amide 15: K(i)(μ) = 310 nM; GPI (IC(50)) = 894 nM).

Retrosulfonamido peptide analogues. Synthesis and crystal conformation of Boc-Pro-Leu-Ψ(NH-SO2)-Gly-NH2

Abstract Boc-Pro-Leu-Ψ(NH-SO 2 )-Gly-NH 2 ( 3 ) has been synthesized as the first example of a pseudopeptide incorporating the NH-SO 2 junction. The crystal structure of 3 indicates that the Ψ(NH-SO 2 ) induces a cisoidal (gauche − ) conformation which induces a backbone folding and prevents the H-bonded β-turn found in the parent peptide.

Synthesis and activity of fibrillogenesis peptide inhibitors related to the 17–21 β-amyloid sequence

Peptide derivatives 1-5, incorporating synthetic non-proteinogenic amino acids, related to the beta-amyloid 17-21 fragment of the amyloidogenic Abeta(1-40), and the N-protected decapeptide 6, corresponding to a dimeric sequence of the same fragment, have been synthesized. These compounds were designed by using Sotos pentapeptide Ac-LPFFD-NH(2) (iAbeta5p) as lead compound. Their activity as inhibitors of fibrillogenesis and stability against enzymatic degradation have been determined. Compounds 1, 5 and 6 are potent inhibitors in comparison to the lead compound. Exposure to chymotrypsin of peptide derivatives 1-5, all containing unnatural amino acids, shows increased stability as compared with iAbeta5p and 6. Conformational properties of the new compounds have been determined by CD and FT-IR spectroscopies.

Biochemical properties of new synthetic carnosine analogues containing the residue of 2,3-diaminopropionic acid: the effect of N-acetylation

Summary.Three novel carnosine analogues 7–9 containing the residue of L(+)2,3-diaminopropionic acid with different degree of N-acetylation instead of β-alanine have been synthesized and characterized. Comparative analysis of hydrolysis by carnosinase revealed that the mono- and bis-acetylated compounds 8 and 9 are resistant to enzymatic hydrolysis and act as competitive inhibitors of this enzyme. The hydroxyl radical scavenging potential of the three analogues was evaluated by their ability to inhibit iron/H2O2-induced degradation of deoxyribose. The second-order rate constants of the reaction of compounds 7–9 with hydroxyl radical were almost identical to that of carnosine. These compounds were also found to act as protective agents against peroxynitrite-dependent damage as assessed by their ability to prevent nitration of free tyrosine induced by this species.