M. Teresa García-López

Azetidine-Derived Amino Acids versus Proline Derivatives. Alternative Trends in Reverse Turn Induction

The influence of 2-alkyl-2-carboxyazetidines (Aze) on the 3D structure of model tetrapeptides R2CO-2-R1Aze-l-Ala-NHMe has been analyzed by molecular modeling, 1H NMR, and FT-IR studies. The conformational constraints introduced by the four-membered ring resulted in an effective way to stabilize gamma-turn-like conformations in these short peptides. The conformational preferences of these Aze-containing peptides have been compared to those of the corresponding peptide analogues containing Pro or alpha-MePro in the place of 2-alkyl-Aze residue. In the model studied, both Pro and Aze derivatives are able to induce reverse turns, but the nature of the turn is different as a function of the ring size. While the five-membered ring of Pro tends to induce beta-turns, as previously suggested by different authors, the four-membered ring of Aze residues forces the peptide to preferentially adopt gamma-turn conformations. In both cases, the presence of an alkyl group at the alpha-position of Pro or the azetidine-2-carboxylate ring enhances significantly the turn-inducing ability. These results might open the opportunity of using 2-alkyl-Aze residues as versatile tools in defining the role of gamma-turn structures within the bioactive conformation of selected peptides, and represent an alternative to Pro derivatives as turn inducers.

Quaternary α,α-2-oxoazepane α-amino acids: synthesis from ornithine-derived β-lactams and incorporation into model dipeptides.

To explore further the chemistry of amino acid-derived β-lactams, their conversion to α,α-heterocyclic quaternary amino acid derivatives is investigated. The latter derivatives, containing 2-oxoazepane as the α,α-substituent, are synthesized by a simple Pd-C-catalyzed hydrogenolysis of Orn(Z)-derived 2-azetidinones. The rearrangement from four- to seven-membered lactam ring is driven by the key intramolecular opening of the 1-Boc-β-lactam, initiated by 7-exotrig ring closure from the NH(2) of the Orn side chain. The synthetic route is applied to the stereoselective preparation of enantiomerically pure 4-amino-3-methyl-2-oxoazepane-4-carboxylate derivatives, for which the structure and configuration is confirmed by X-ray diffraction. Molecular modeling and NMR experiments indicate that these quaternary amino acids are able to drive the adoption of β-turn secondary structures when incorporated in model dipeptide derivatives.

Strategies for Design of Non Peptide CCK1R Agonist/Antagonist Ligands

This review mainly covers last five year literature on CCK1R agonists and antagonists. These CCK1R ligands have been found following the two usual and complementary strategies for drug discovery: rational design based on structure activity relationships on the CCK-7 and CCK-4 peptide sequences of the endogenous ligands and random screening of diverse compounds, followed by hit optimization. The first group includes: chimeric bifunctional opioid/CCK peptides, designed as opioid agonists with balanced CCK1R/CCK2R antagonist activity for the treatment of neuropathic pain, antagonist and agonist dipeptoids, and 1,3-dioxoperhydropyrido[1,2-c]pyrimidine- and anthranilic acid-based antagonists. Among the ligands derived from random screening, a few new 1,4-benzodiazepine-, 1,5-benzodiazepine-, and five member ring heterocycle-based CCK1R ligands have been reported. Finally, taking into account the importance of receptor mapping studies for ligand optimization and future precise de novo receptor structure-based design of new selective and more effective ligands, the most significant conclusions of these studies have also been reviewed.

A simple and versatile route to ketomethylene dipeptide analogs

Abstract A facile and versatile procedure for the synthesis of ketomethylene dipeptides by using Nα-Z-amino acid halomethyl ketones and dimethyl malonate as starting materials is reported. By application of this method, alanyl and phenylalanyl derivatives containing C-terminal Gly, Ala, Asp, Phe and Trp residues have been prepared.

New routes for the synthesis of pyrrolo-[3,2-d]- and -[2,3-d]-pyrimidine systems starting from a common pyrrole derivative

New routes for the synthesis of pyrrolo-[3,2-d]- and -[2,3-d]-pyrimidines from a common 2,3-dicarboxypyrrole derivative are described. The common starting material, 3-ethoxycarbonyl-2-carboxy-4-methylpyrrole (1) is conveniently functionalized to give 2- or 3-azidocarbonylpyrroles (4), (17), and (22) which on Curtius rearrangement followed by treatment with ammonia or amines give the pyrrolylurea (6a) or its derivatives (6b–d), or (23). These, in basic medium cyclise to 7-methylpyrrolo[3,2-d]pyrimidine-2,4-diones (7a), its 3-substituted derivatives (7b–d), or to 5-methylpyrrolo[2,3-d]pyrimidine-2,4-diones (19).

Further Evidence for 2-Alkyl-2-carboxyazetidines as γ-Turn Inducers

Reverse turns, a common motif in proteins and peptides, have attracted attention due to their relevance in a wide variety of biological processes. In an attempt to artificially imitate and stabilize these turns in short peptides, we have developed versatile synthetic methodologies for the preparation of 2-alkyl-2-carboxyazetidines and incorporated them into the i + 1 position of model tetrapeptides, where they have shown a tendency to induce gamma-turns. However, to ascertain the general utility of these restricted amino acids as gamma-type reverse turn inducers, it was then required to study the conformational preferences when located at other positions. To this end, model tetrapeptides R-CO-Ala-Xaa-NHMe, containing differently substituted azetidine moieties (Xaa = Aze, 2-MeAze, 2-BnAze) at the i + 2 position, were synthesized and subjected to a thorough conformational analysis. The theoretical and experimental results obtained, including the X-ray diffraction structure of a dipeptide derivative containing this skeleton, provide evidence that the 2-alkyl-2-carboxyazetidine scaffold is able to efficiently induce gamma-turns when incorporated into these short peptides, irrespective of their localization in the peptide chain.

Synthesis of Ψ[CH(CN)NH] pseudopeptides. A new peptide bond surrogate

Abstract An easy and versatile general method for the preparation of the new peptide bond surrogate Ψ[CH(CN)NH], by the Lewis acid catalyzed reaction of N-protected α-amino aldehydes with a C-protected amino acid or peptide in the presence of TMSCN, is described.

Synthesis and SAR studies on azetidine-containing dipeptides as HCMV inhibitors

Abstract SAR studies on an azetidine-containing dipeptide prototype inhibitor of HCMV are described. Three series of structurally modified analogues, involving substitutions at the N- and C-terminus, and at the C-terminal side-chain were synthesized and evaluated for antiviral activity. Aliphatic or no substituents at the C-carboxamide group, an aliphatic C-terminal side-chain, as well as a benzyloxycarbonyl moiety at the N-terminus were absolute requirements for anti-HCMV activity. The conformational restriction induced by the 2-azetidine residue into the dipeptide derivatives, identified by 1H NMR as a γ-type reverse turn, seems to have influence on the activity of these molecules.

Design, synthesis and biological evaluation of new peptide-based ureas and thioureas as potential antagonists of the thrombin receptor PAR1.

By applying a diversity oriented synthesis strategy for the search of new antagonists of the thrombin receptor PAR1, a series of peptide-based ureas and thioureas, including analogues of the PAR1 reference antagonist RWJ-58259, has been designed and synthesized. The general synthetic scheme involves reduction of basic amino acid-derived amino nitriles by hydrogen transfer from hydrazine monohydrate in the presence of Raney Ni, followed by reaction with diverse isocyanates and isothiocyanates, and protecting group removal. All new compounds have been evaluated as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN. Some protected peptide-based ureas displayed significant antagonist activity.

Pseudopeptide CCK-4 analogues incorporating the Ψ[CH(CN)NH] peptide bond surrogate

Abstract The synthesis, binding to CCK receptors, and in vitro functional activity of pseudopeptide CCK-4 analogues incorporating the ( R ) or ( S ) Ψ[CH(CN)NH] peptide bond surrogate at the NIe 31 -Asp 32 or or Trp 30 -NIe 13 bonds are described. Z-TrpΨ[( S )CH(CN)NH]NIe-Asp-Phe-NH 2 retained the high CCK-B receptor binding affinity of Boc-[NIe 31 ]-CCK-4, and was a potent and selective CCK-B antagonist in the isolated guinea pig ileum.