Yahya E. Jad

Synthesis and Biological Evaluation of a Teixobactin Analogue

The first synthesis and biological activity of a teixobactin analogue is reported. Substitution of the unusual L-allo-enduracididine residue by the naturally occurring L-arginine was achieved, and the analogue gave an activity trend similar to that of teixobactin (against Gram-postive bacteria) and meropenem, which was approved by the FDA in 1996. The synthetic route used allows for the synthesis of the natural product as well as the development of a program of medicinal chemistry.

Re-evaluation of the N-terminal substitution and the D-residues of teixobactin

Teixobactin is a head to side-chain cyclic depsipeptide with a guanidino based residue within the cycle, three D-amino acids in the tail, and a N-methylated terminal residue. The synthesis of the first analogue, containing Arg, was recently described by our group. Herein, we demonstrated that analogues of Arg. Teixobactin bearing either (a) three L-amino acids in the tail and keeping the N-methyl at the N-terminal or (b) with three D-amino acids, but with acetylation of the N-terminal, are inactive against Gram(+) and Gram(−) bacteria. These results complement those published by the groups of Madder, Taylor, and Singh that have shown that both modifications: L-amino acids and N-acetylation also led to loss of biological activity.

Lysine Scanning of Arg10–Teixobactin: Deciphering the Role of Hydrophobic and Hydrophilic Residues

Teixobactin is a recently discovered antimicrobial cyclodepsipeptide with good activity against Gram positive bacteria. Taking Arg10–teixobactin as a reference, where the nonproteinogenic residue l-allo-enduracididine was substituted by arginine, a lysine scan was performed to identify the importance of keeping the balance between hydrophilic and hydrophobic amino acids for the antimicrobial activities of this peptide family. Thus, the substitution of four isoleucine residues present in the natural sequence by lysine led to a total loss of activity. On the other hand, the substitution of the polar noncharged residues and alanine by lysine allowed us to keep and in some cases to improve the antimicrobial activity.

2-Methyltetrahydrofuran and cyclopentyl methyl ether for green solid-phase peptide synthesis

Abstract2-MeTHF and CPME were evaluated as greener alternatives for the most employed solvents in peptide synthesis. The ability of these solvents to dissolve amino acid derivatives and a range of coupling reagents were evaluated as well as the swelling of polystyrene and polyethylene glycol resins. In addition, racemization and coupling efficiencies were also determined. We concluded that the use of 2-MeTHF with combination of DIC/OxymaPure gave the lowest racemization level during stepwise synthesis of Z-Phg-Pro-NH2 and the highest purity during SPPS of Aib-enkephalin pentapeptide (H-Tyr-Aib-Aib-Phe-Leu-NH2).

TOMBU and COMBU as Novel Uronium-type peptide coupling reagents derived from Oxyma-B.

Here we describe two novel uronium salts, TOMBU and COMBU, derived from the recently described Oxyma-B for use in peptide bond synthesis. These coupling reagents are more stable than COMU in DMF. Furthermore, using various peptide synthetic models in solution and solid-phase synthesis, we reveal that they show better performance than HBTU in terms of preserving chiral integrity and coupling yields, but slightly worse performance than COMU.

Synthesis, Characterization, and Tautomerism of 1,3-Dimethyl Pyrimidine-2,4,6-Trione s-Triazinyl Hydrazine/Hydrazone Derivatives

1,3,5-Triazines and pyrimidine-2,4,6-triones belong to that class of compounds which are well known in literature for possessing wide range of biological activities. Here, we report a new family of compounds that encompasses these two structures. The union of both heterocycles was carried out through a hydrazone moiety incorporated into an acetyl group at the position 5 of 1,3-dimethyl pyrimidine derivative. The synthetic strategy adopted allowed the preparation of the target compounds with excellent yields and good purities. The synthesized compounds were well characterized by NMR (1H and 13C), HRMS, and elemental analysis. Furthermore, the tautomerism of enhydrazine versus hydrazone has also been studied.

Chapter 15:Cyclic Peptides as Privileged Structures

There is increasing interest in the use of peptide drugs as therapeutics. In comparison to small molecules, peptides can be more specific, less toxic and do not accumulate in organs. Cyclic peptides are often more beneficial than their linear counterparts due to conformational rigidity. They are also often more stable to exopeptidases and even endopeptidases because of flexible cyclic backbone. Literature encompasses several cyclic peptides that show diverse biological activities. Out of these, we have selected the so-called “privileged structures” among cyclic peptides, viz. diketopiperazines, benzodiazepines and cyclotides, for our discussion in this chapter, with a summary of their structure, function and therapeutic activities.

Oxime-Based Carbonates as Useful Reagents for Both N-Protection and Peptide Coupling

We have demonstrated that oxime-based mixed carbonates are very effective reagents for both N-protection and peptide coupling.

N-methylation in amino acids and peptides: Scope and limitations

Active pharmaceutical ingredients (APIs) can be divided into two types, namely chemical and biological entities. Traditionally, the former has been associated with the so‐called small molecules. The revival of peptides in pharmaceutical industry results from their importance in many biological roles. However, low metabolic stability and the lack of oral availability of most peptides is the main drawback for peptide to fulfill that paradigmatic situation. In this regard, efforts are being channeled into addressing this issue by introducing restrictions into the flexible peptide backbone, mainly through N‐methyl amino acids (NMAAs) or development of small cyclic peptides. In many cases, both the above restrictions are combined with the aim to enhance oral availability. The synthesis of NMAAs is complex and their introduction into the peptide chain brings additional synthetic challenges and also sometimes leads to side‐reactions. Here we discuss the most efficient methods for the synthesis of NMAAs (either in solution or in solid phase) and also their introduction into peptide sequences. Special attention is also given to the detection of side reactions and the most efficient way to prevent them.

Solid-Phase Synthesis of Pyrrole Derivatives through a Multicomponent Reaction Involving Lys-Containing Peptides

The synthesis of pyrroles has received considerable attention because of their biological and pharmaceutical activities. Herein we describe a solid-phase multicomponent reaction that utilizes Lys as a N donor, β-nitrostyrenes, 1,3-dicarbonyl compounds, and FeCl3 as an easily accessible catalyst under microwave irradiation to afford the subsequent pyrrole derivatives in high conversions. The strategy combines three of the most powerful tools in modern synthetic chemistry: the solid-phase mode, microwave activation, and a multicomponent reaction. The excellent results in terms of rapidity, versatility, and purity obtained herein support once again that this combined strategy is efficient for gaining chemical diversity.