Synthesis Of Peptidomimetics Research Articles

Synthesis and antitumor activity of new flavonoid hybrid peptidomimetics

To discover new antitumor drugs based on the structure of natural products, two series of d-2-Phenylglycine/D-Leucine hybridized isoflavone derivatives were synthesized, and their anti-proliferation activities against human cancer cells were evaluated in vitro. Most target compounds exhibit potent anti-proliferative activity against HeLa cells, among which the inhibitory ability of compound 8 s is close to the positive control. Compound 8 s showed significant broad-spectrum inhibitory activity against cancer cells (HeLa, MCF-7, MDA-MB231, and H460 cells) with IC50 values of 1.94±0.26 µM, 4.75±0.38 µM, 8.56±0.19 µM, and 4.36±0.11 µM, respectively. Furthermore, compound 8 s was discovered to have certain inhibitory effects on HeLa cell proliferation, apoptosis, invasion, and migration. Molecular docking experiments and in vitro enzyme inhibition assays revealed that 8 s binds to APN and inhibits its enzyme activity, which is likely a key factor contributing to its antitumor effects. Altogether, this study proposes compound 8 s as a new lead with great promise for further antitumor research.

Atom-economical synthesis, antimicrobial assessment, and molecular dynamics of indole-derived peptidomimetics for improved therapeutic insights

The emergence of multi-drug resistant strains spanning bacteria, fungi, viruses, and parasites poses a severe threat to public health and the economy. Tackling antimicrobial resistance requires swiftly identifying new agents with unique mechanisms. Multicomponent reactions offer a vital method to produce diverse analogs in various heterocyclic compounds, with broad medicinal applications. This study synthesized a range of peptidomimetics using isocyanide-based multicomponent Ugi reactions. These analogs were screened for antimicrobial efficacy against both Gram-negative (Escherichia coli, Pseudomonas aeruginosa) and Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, Staphylococcus aureus IGMS-01), with ampicillin as a reference antibiotic, and for antifungal activity against Candida albicans, using fluconazole as a reference. The compounds showed moderate but significant efficacy across all tests. Docking analysis with microbial proteins revealed notable binding affinities for peptidomimetics 5h (N-(2-(1H-indol-3-yl)ethyl)-N-(1-(4-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)stearamide) and 5i (N-(2-(1H-indol-3-yl)ethyl)-N-(1-(4-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)oleamide). Molecular dynamics simulations confirmed stable interactions between the ligands and proteins. Furthermore, the long alkyl chain analogs demonstrated the ability to form organo/hydrogels, facilitating the incorporation of silver sulfadiazine for controlled antimicrobial release. This innovative approach enhances drug dispersion within the gel structure, effectively inhibiting microbial growth. These findings highlight the potential of these adaptable materials to advance drug development efforts in the foreseeable future.

Isocyanide-Based Multicomponent Reactions Coupled One-Pot Process: Efficient Tools to Diversity-Oriented Synthesis of Structural Peptidomimetics.

Multicomponent diversity-oriented synthesis (DOS) of conformationally anchored structural peptidomimetics like 2,5-diketopiperazines (2,5-DKP) containing heterocyclic bioisosteres of the amide bond, such as 1,2,3-triazoles and 1,5-disubstituted tetrazoles (1,5-DS-T) is described. Structural peptidomimetics are synthesized from similar available starting materials, via a strategy based on isocyanide-based multicomponent reactions (IMCRs): Ugi-4CR and Ugi-Azide (UA), followed by a one-pot process: SN2/intramolecular alkyne-azide cycloaddition (IAAC). The sequential aligning of two powerful synthetic tools (IMCR and IAAC) has parallelly contributed to generate anchored conformation and complexity in target molecules, which are considered structural peptidomimetics of 2,5-DKP. Herein, the 1,2,3-triazole ring plays a key role in the preference for the boat conformation. Furthermore, the use of UA reaction generates scaffold diversity at the N-1 α-carbon of the pyrazinone ring, replacing a linear amide bond with a heterocyclic bioisostere such as 1,5-DS-T leading to the synthesis of novel tricyclic peptidomimetics. The DFT calculations confirmed the boat conformation of the synthesized molecules.

Recent Advances in the Synthesis of Peptidomimetics via Ugi Reactions.

Peptidomimetics have been extensively explored in many area due to their ability to improve pharmacological qualities and interesting biological activities. Cycles could be incorporated in peptides to reduce their flexibility, often enhancing the affinity for a certain receptor. Many efforts have been made to synthesize various peptidomimetics. Among them, the Ugi reaction is a popular way for the synthesis of peptidomimetics because it provides peptide-like products. The Ugi reaction consists of the condensation of an aldehyde or ketone, a carboxylic acid, an amine, and an isocyanide usually giving a linear peptidomimetic. In order to obtain other linear, cyclic or polycyclic peptidomimetics, the acyclic products have to undergo additional transformations or cyclizations. This review covers the years from 2018-2023, regarding the synthesis of linear, cyclic and polycyclic peptidomimetics, employing Ugi reactions eventually followed by post-Ugi transformations. Organo-catalyzed reactions, base-promoted reactions, and metal-free reactions toward peptidomimetics are highlighted.

Synthesis And Conformational Behaviors of Unnatural Peptides Alternating Chiral And Achiral α,α-Disubstituted α-Amino Acid Units.

The development of peptidomimetics to modulate the conformational profile of peptides has been extensively studied in the fields of biological and medicinal chemistry. However, large-scale synthesis of peptidomimetics with both an ordered sequence and a controlled secondary structure is highly challenging. In this paper, the framework of peptidomimetics has been designed to be alternating an achiral α,α-disubstituted α-amino acid unit and a chiral α-methylphenylalanine unit. The polymers were synthesized via our invented Ugi reaction-based polycondensation technique. The chiral higher-order structures of the alternating peptides were evaluated mainly through CD spectroscopy. The UV-vis and CD spectra of the polymers in three solvents were systematically measured at various temperatures. The anisotropic factors of CD (gCD ) values were calculated to know the chiroptical response. The results indicate the characteristic conformational behaviors. In a polar solvent, the hydrogen bonds between the N-H group of MePhe unit and the C = O of α,α-diphenylglycine unit outweigh the intraresidue hydrogen bonds in α,α-diphenylglycine unit, leading to the formation of a prevailing preferred-handed 310 -helical conformation. On the other hand, in a less polar solvent, the intrachain hydrogen bonds switch to intraresidue hydrogen bonds in α,α-diphenylglycine unit, which make the polymer adopting a prevailing extended planar C5 -conformation. This article is protected by copyright. All rights reserved.

Synthesis of peptidomimetics as antibiotic adjuvants for combination with aztreonam to combat MDR Pseudomonas aeruginosa

Pseudomonas aeruginosa is one of the multipledrug-resistant (MDR) Gram-negative pathogens with few drugs available for treatment. Antibiotic adjuvant approach provides an alternative and complementary strategy. In this study, the stereo-structure-activity relationship of monobactams against MDR Gram-negative organisms was extended. Meanwhile, a series of novel peptidemimetic derivatives as antibiotic adjuvants was synthesized and evaluated for their synergistic effects with aztreonam (AZT) against P. aeruginosa, using dipeptide PAβN as the lead. Among the analogues, compound 22j showed a significant synergistic effect against MDR P. aeruginosa in vitro and in vivo, presumably through the mechanism of affecting the permeability of outer membrane. Thus, we identified 22j as a novel peptidemimetic lead compound to potentiate the activity of AZT against MDR P. aeruginosa, which is worthy of further development as antibiotic adjuvant candidates.

Synthesis and Applications of Peptides and Peptidomimetics in Drug Discovery

AbstractPeptides are described as naturally occurring short chains of amino acids and offer great potential as therapeutic agents because of their target selectivity, safe, and well tolerable. Hence, there is an increased interest in peptides in pharmaceutical research and development and approximately more than 170 peptide therapeutics are currently being evaluated in clinical trials and many are being used as therapeutic drugs for various diseases including COVID‐19. The present Review article focuses on recent progress in peptide drug discovery and advancements in synthetic methodologies to enhance their stability and physiological activity of peptides and as well peptidomimetics.

Rational design, synthesis and structural characterization of peptides and peptidomimetics to target Hsp90/Cdc37 interaction for treating hepatocellular carcinoma

Heat shock protein 90 (Hsp90) and cell division cycle 37 (Cdc37) work together as a molecular chaperone complex to regulate the activity of a multitude of client protein kinases. These kinases belong to a wide array of intracellular signaling networks that mediate multiple cellular processes including proliferation. As a result, Hsp90 and Cdc37 represent innovative therapeutic targets in various cancers (such as leukemia, multiple myeloma, and hepatocellular carcinoma (HCC)) in which their expression levels are elevated. Conventional small molecule Hsp90 inhibitors act by blocking the conserved adenosine triphosphate (ATP) binding site. However, by targeting less conserved sites in a more specific manner, peptides and peptidomimetics (modified peptides) hold potential as more efficacious and less toxic alternatives to the conventional small molecule inhibitors. Using a rational approach, we herein developed bioactive peptides targeting Hsp90/Cdc37 interaction. A six amino acid linear peptide derived from Cdc37, KTGDEK, was designed to target Hsp90. We used in silico computational docking to first define its mode of interaction, and binding orientation, and then conjugated the peptide with a cell penetrating peptide, TAT, and a fluorescent dye to confirm its ability to colocalize with Hsp90 in HCC cells. Based on the parent linear sequence, we developed a peptidomimetics library of pre-cyclic and cyclic derivatives. These peptidomimetics were evaluated for their binding affinity to Hsp90, and bioactivity in HCC cell lines. Among them, a pre-cyclic peptidomimetic demonstrates high binding affinity and bioactivity in HCC cells, causing reduced cell proliferation that is associated with induction of cell apoptosis, and down-regulation of phosphorylated MEK1/2. Overall, this generalized approach of rational design, structural optimization, and cellular validation of ‘drug-like’ peptidomimetics against Hsp90/Cdc37 offers a feasible and promising way to design novel therapeutic agents for malignancies and other diseases that are dependent on this molecular chaperone complex.

Synthesis of amphiphilic hydantoin-based universal peptidomimetics as antibiotic agents.

Three model hydantoin-based universal peptidomimetics were designed and synthetized. Their preferred amphiphilic β-turn conformation was assessed using molecular modeling and NMR experiments, and their antibacterial activity was tested against Gram-positive and Gram-negative bacteria strains, which demonstrated that these compounds could be a captivating class of antibiotics to fight emergent drug resistance.

Potent pan-group quorum sensing inhibitors in Staphylococcus aureus revealed by N-terminal tailoring of peptidomimetics.

Staphylococcus aureus uses small peptides to assess its population densisty (i.e., quorum sensing) and regulate virulence at high cell number. Here, we report the design and synthesis of peptidomimetics based on these native signals that strongly block this communication pathway in all four specificity groups of S. aureus.

Antheraea peptide and its analog: Their influence on the maturation of the reproductive system, embryogenesis, and early larval development in Tenebrio molitor L. beetle.

In recent years, many new immunologically active peptides from insects have been identified. Unfortunately, in most cases, their physiological functions are not fully known. One example is yamamarin, a pentapeptide isolated from the caterpillars of the Antheraea yamamai moth. This peptide has strong antiproliferative properties and is probably involved in the regulation of diapause. Additionally, antiviral activity was discovered. The results of the research presented in this paper are, to our knowledge, the first attempt to characterize the biological effects of yamamarin on the functioning of the reproductive processes and embryonic development of insects using a model species, the beetle Tenebrio molitor, a commonly known pest of grain storage. Simultaneously, we tested the possible activity of the molecule in an in vivo system. In this research, we present the multifaceted effects of yamamarin in this beetle. We show that yamamarin influences ovarian growth and development, maturation of terminal oocytes, level of vitellogenin gene transcript, the number of laid eggs, duration of embryonic development, and larval hatching. In experiments with palmitic acid-conjugated yamamarin (C16-yamamarin), we also showed that this peptide is a useful starting molecule for the synthesis of biopharmaceuticals or new peptidomimetics with gonadotropic activity and effects on embryonic development. The data obtained additionally provide new knowledge about the possible function of yamamarin in insect physiology, pointing to the important role of this pentapeptide as a regulator of reproductive processes and embryonic development in a heterologous bioassay with T. molitor.

Enantiopure β-isocyano-boronic esters: synthesis and exploitation in isocyanide-based multicomponent reactions

Various boron-containing isocyanides have been efficiently synthesized from the corresponding enantiopure β-substituted β-amino boronic acid pinacol esters, without need for protecting group interconversion, through a two-step, purification-free procedure. They were employed in a variety of isocyanide-based multicomponent reactions, proving to be reliable components for all of them and allowing the efficient synthesis of unprecedented, boron-containing peptidomimetics and heteroatom-rich small molecules, including biologically relevant cyclic boronates. Jointing together the β-amido boronic acid moiety, deriving from the isocyanide component, with prominent pharmacophoric rings emerging from the multicomponent process, a successful application of the molecular hybridization concept could be realized.Graphical abstract

Selective and quantitative functionalization of unprotected α-amino acids using a recyclable homogeneous catalyst

<h2>Summary</h2> A new Ir(III)-NHC catalyst is reported that shows remarkable activity in the <i>N</i>-alkylation of unprotected amino acids. The catalytic system gives excellent selectivity toward monoalkylated α-amino acids and a high degree of retention of stereochemistry. A wide range of unprotected nonnatural amino acids have been prepared. These compounds represent an array of building blocks that could be used for the direct synthesis of peptidomimetics. The synthesis of amino-acid-based surfactants is also reported. This catalytic method gives the amino acid products in quantitative yield; hence, tedious purifications by derivatization are therefore avoided. Furthermore, although the catalyst is a homogeneous metal complex, it can be recycled and reused for several runs. This also contributes to the efficiency and sustainability of the method.

Late-Stage Functionalisation of Peptides on the Solid Phase by an Iodination-Substitution Approach.

The functionalisation of peptides at a late synthesis stage holds great potential, for example, for the synthesis of peptide pharmaceuticals, fluorescent biosensors or peptidomimetics. Here we describe an on‐resin iodination‐substitution reaction sequence on homoserine that is also suitable for peptide modification in a combinatorial format. The reaction sequence is accessible to a wide range of sulfur nucleophiles with various functional groups including boronic acids, hydroxy groups or aromatic amines. In this way, methionine‐like thioethers or thioesters and thiosulfonates are accessible. Next to sulfur nucleophiles, selenols, pyridines and carboxylic acids were successfully used as nucleophiles, whereas phenols did not react. The late‐stage iodination‐substitution approach is not only applicable to short peptides but also to the more complex 34‐amino‐acid WW domains. We applied this strategy to introduce 7‐mercapto‐4‐methylcoumarin into a switchable ZnII responsive WW domain to design an iFRET‐based ZnII sensor.

Exploiting Enantiopure β‐Amino Boronic Acids in Isocyanide‐Based Multicomponent Reactions

AbstractVarious isocyanide‐based multicomponent reactions prove to be highly reliable when β‐substituted β‐amino boronic esters are employed as the amine component, allowing the efficient synthesis of unprecedented peptidomimetics and heteroatom‐rich boron‐containing small molecules. In particular, the scope of the Ugi reaction is widely exploited, to give a family of enantiopure β‐substituted β‐amido boronates. The Ugi‐azide and the van Leusen reactions allow to joint together prominent pharmacophoric moieties, such as β‐amino boronic acids on one side, and tetrazole or imidazole rings on the other side, realizing a successful application of the molecular hybridization concept.

Synthesis and characterization of peptidomimetics containing oxazolidin-2-one and oxazolidine scaffolds

Synthesis and characterization of peptidomimetics containing oxazolidin-2-one and oxazolidine scaffolds

Identification of a Common Pharmacophore for Binding to MMP2 and RGD Integrin: Towards a Multitarget Approach to Inhibit Cancer Angiogenesis and Metastasis.

During tumor angiogenesis different growth factors, cytokines and other molecules interact closely with each other to facilitate tumor cell invasion and metastatic diffusion. The most intensively studied as molecular targets in anti-angiogenic therapies are vascular endothelial growth factor (VEGF) and related receptors, integrin receptors and matrix metalloproteinases (MMPs). Considering the poor efficacy of cancer angiogenesis monotherapies, we reasoned combining the inhibition of αvβ3 and MMP2 as a multitarget approach to deliver a synergistic blockade of tumor cell migration, invasion and metastasis. Accordingly, we identified a common pharmacophore in the binding cavity of MMP2 and αvβ3, demonstrating such approach with the design, synthesis and bioassays of tyrosine-derived peptidomimetics carrying the necessary functional groups to bind to key pharmacophoric elements of MMP2 and αvβ3 RGD integrin.

Integration of C-Acylation in the Solid-Phase Synthesis of Peptides and Peptidomimetics Employing Meldrum’s Acid, Phosphorus, and Sulfur Ylides

AbstractThe modification of native peptides to peptidomimetics is an important goal in medicinal chemistry and requires, in many cases, the integration of C-acylation steps involving amino acids with classical peptide synthesis. Many classical C-acylation protocols involving Claisen condensations and the use of ylides are not compatible with peptide synthesis, mostly due to the requirements for strong bases leading to epimerization or deprotection of peptides. Meldrum’s acid as well as several specific phosphorus and sulfur ylides, however, are acidic enough to provide reactive C-nucleophiles under mildly basic conditions tolerated during peptide synthesis. This review provides an overview of peptide-compatible C-acylations using Meldrum’s acid and phosphorus and sulfur ylides, and their application in the medicinal chemistry of peptides.1 Introduction2 C-Acylation of Meldrum’s Acid2.1 C-Acylation of Meldrum’s Acid on Solid Phase3 Ylides as Substrates for C-Acylation3.1 C-Acylation of Phosphorus Ylides in Solution Phase3.2 C-Acylation of Solid-Supported Phosphorus Ylides3.3 C-Acylation of Sulfur Ylides3.4 C-Acylation of Solid-Supported Sulfur Ylides4 Miscellaneous Ylides as Acyl Anion Equivalents5 Summary

Mechanochemical IMCR and IMCR-post transformation domino strategies: towards the sustainable DOS of dipeptide-like and heterocyclic peptidomimetics

A facile, rapid, sustainable one-pot Diversity Oriented Synthesis of peptidomimeticsviamechanochemical IMCR-based domino strategies.

Coupling Interrupted Fischer and Multicomponent Joullié-Ugi to Chase Chemical Diversity: from Batch to Sustainable Flow Synthesis of Peptidomimetics.

The generation of peptidomimetic substructures for medicinal chemistry purposes requires effective and divergent synthetic methods. We present in this work an efficient flow process that allows quick modulation of reagents for Joullié‐Ugi multicomponent reaction, using spiroindolenines as core motifs. This sterically hindered imine equivalent could successfully be diversified using various isocyanides and amino acids in generally good space‐time yields. A telescoped flow process combining interrupted Fischer reaction for spiroindolenine synthesis and subsequent Joullié‐Ugi‐type modification resulted in product formation in very good overall yield in less than 2 hours compared to 48 hours required in batch mode. The developed protocol can be seen as a general tool for rapid and facile generation of peptidomimetic compounds. We also showcase preliminary biological assessments for the prepared compounds.