Transition state isosteres of the γ‐glutamyl peptide bond hydrolysis: synthesis and characterization of the ψ[CH<sub>2</sub>NH] pseudopeptide analogue of glutathione

Cacciatore, Ivana; Stefano, Antonio Di; Luisi, Grazia; Pinnen, Francesco; Sozio, Piera

doi:10.1002/psc.501

Cited by 6 publications

(6 citation statements)

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“…Efficient synthesis of the fully protected forms and the first chemical characterization of the free forms of [CH 2 NH] glutathione (GSH) and [CH 2 NH] GSSG (oxidized dimer of GSH) were reported by Cacciatore et al [60]. The aminomethylene group was of interest, to mimic the tetrahedral intermediate of -Glu-Cys peptide bond hydrolysis as well as to introduce unique properties into the peptide sequence other than the expected enzyme resistance and increased flexibility, i.e.…”

Section: Miscellaneousmentioning

confidence: 98%

Recent Advances in the Synthesis and Applications of Reduced Amide Pseudopeptides

Živec¹,

Gobec

2009

CMC

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Being one of the simplest and widely used isosteric replacements for the peptide bond, reduced amide has been successfully applied in the synthesis of many bioactive compounds. The introduction of reduced amide not only confers the pseudopeptide a higher enzymatic resistance and a linear and more flexible structure, but also increases its hydrophylicity due to the introduction of a protonable group. It has also proved adequate as a transition state mimetic for the tetrahedral intermediate formed during the hydrolysis of the peptide bond. Recent advances in the solution and solid-phase synthesis of reduced amides that emerged during the past ten years are presented. Most of them include the use of microwave irradiation to shorten the reaction times and improve the yields. The bioorganic chemistry of reduced-peptide-containing compounds represents an area of growing interest and it has recently been expanded to include analogues of endogenous peptides/ hormones that are resistant to hydrolysis by serum peptidases and enzyme inhibitors. Under certain conditions, synthetic peptides are highly immunogenic in animals, and might constitute chemically defined, safe and cheap vaccines. Linear pseudooligolysines, containing multiple adjacent CH2NH amide bond are potential candidates for future use as DNA carriers in gene delivery. Reduced amides have also seen use in the preparation of peptide nucleic acids and antibacterial peptides.

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Section: Miscellaneousmentioning

confidence: 98%

Recent Advances in the Synthesis and Applications of Reduced Amide Pseudopeptides

Živec¹,

Gobec

2009

CMC

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“…While each of these strategies may be equally promising to increase GSH levels, this paper will mainly focus on codrugs approach since the other medicinal-chemistry-based strategies have been previously discussed [56, 60–62]. The codrug approach consists in linking, via a covalent chemical linkage, two different pharmacophores with similar or different pharmacological activities in order to improve physiochemical, biopharmaceutical, and drug delivery properties of therapeutic agents.…”

Section: Medicinal-chemistry-based Strategies To Increase Gsh Levelsmentioning

confidence: 99%

Recent Advances in the Treatment of Neurodegenerative Diseases Based on GSH Delivery Systems

Cacciatore

Baldassarre

Fornasari

et al. 2012

Oxidative Medicine and Cellular Longevity

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Neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease(AD), are a group of pathologies characterized by a progressive and specific loss of certain brain cell populations. Oxidative stress, mitochondrial dysfunction, and apoptosis play interrelated roles in these disorders. It is well documented that free radical oxidative damage, particularly on neuronal lipids, proteins, DNA, and RNA, is extensive in PD and AD brains. Moreover, alterations of glutathione (GSH) metabolism in brain have been implicated in oxidative stress and neurodegenerative diseases. As a consequence, the reduced GSH levels observed in these pathologies have stimulated a number of researchers to find new potential approaches for maintaining or restoring GSH levels. Unfortunately, GSH delivery to the central nervous system (CNS) is limited due to a poor stability and low bioavailability. Medicinal-chemistry- and technology-based approaches are commonly used to improve physicochemical, biopharmaceutical, and drug delivery properties of therapeutic agents. This paper will focus primarily on these approaches used in order to replenish intracellular GSH levels, which are reduced in neurodegenerative diseases. Here, we discuss the beneficial properties of these approaches and their potential implications for the future treatment of patients suffering from neurodegenerative diseases, and more specifically from PD and AD.

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“…Of necessity we considered some structural modifications of the GSH peptide moiety to achieve stability toward g-GT and possibly ameliorate bioavailability. Over the years we designed a variety of GSH mimics and derivatives characterized by amino acid substitution and/or bioisosteric replacements of the g-glutamyl linkage, addressed to enhance both metabolic resistance and affinity to GST binding sites, through the attribution of specific chemical and conformational properties to the modified GSH backbone [27][28][29][30][31][32][33][34] . Among these, the g-oxa-glutamyl (Glo) analog of GSH, H-Glo[Cys-Gly-OH]-OH, deserves particular attention for more than one reason: (1) as expected, the replacement of the scissile g-glutamyl-cysteinyl peptide bond with the OCONH unit assures resistance to g-GTmediated hydrolysis 29,35 ; (2) the substitution does not sensibly alter the physico-chemical properties of the tripeptide; (3) groups crucial for binding to the G-site resemble those of the natural ligand, with the H-bond donor/acceptor potential of the GSH backbone fairly maintained and (4) more importantly, S-conjugates of this urethane mimic of glutathione have been shown to inhibit MRP1 36 .…”

Section: Introductionmentioning

confidence: 99%

Nitrobenzoxadiazole-based GSTP1-1 inhibitors containing the full peptidyl moiety of (pseudo)glutathione

Luisi

Mollica

Carradori

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Context: The inhibition of glutathione S-transferase P1-1 (GSTP1-1) is a sound strategy to overcome drug resistance in oncology practice. Objective: The nitrobenzoxadiazolyl (NBD) S-conjugate of glutathione and the corresponding g-oxa-glutamyl isostere (compounds 1 and 5, respectively) have been disclosed as GST inhibitors. The rationale of their design is discussed in juxtaposition to non-peptide NBD thioethers. Materials and methods: Synthesis of derivatives 1 and 5 and in vitro evaluation on human GSTP1-1 and M2-2 are reported. Results: Conjugates 1 and 5 were found to be low micromolar inhibitors of both isoforms. Furthermore, they display a threefold reduction in selectivity for GSTM2-2 over the P1-1 isozyme in comparison with the potent non-peptide inhibitor nitrobenzoxadiazolyl-thiohexanol (NBDHEX). Discussion and conclusions: Spectroscopic data are congruent with the formation of a stable sigma-complex between GSH and the inhibitors in the protein active site. Conjugate 5 is suitable for in vivo modulation of GST activity in cancer treatment.

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Transition state isosteres of the γ‐glutamyl peptide bond hydrolysis: synthesis and characterization of the ψ[CH₂NH] pseudopeptide analogue of glutathione

Abstract: The fully deprotected glutathione analogue containing the aminomethylene unit as transition state isostere of the gamma-Glu-Cys peptide bond was synthesized for the first time and characterized in both the reduced and oxidized forms.

Cited by 6 publications

References 32 publications

Recent Advances in the Synthesis and Applications of Reduced Amide Pseudopeptides

Recent Advances in the Synthesis and Applications of Reduced Amide Pseudopeptides

Recent Advances in the Treatment of Neurodegenerative Diseases Based on GSH Delivery Systems

Nitrobenzoxadiazole-based GSTP1-1 inhibitors containing the full peptidyl moiety of (pseudo)glutathione

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Transition state isosteres of the γ‐glutamyl peptide bond hydrolysis: synthesis and characterization of the ψ[CH2NH] pseudopeptide analogue of glutathione

Abstract: The fully deprotected glutathione analogue containing the aminomethylene unit as transition state isostere of the gamma-Glu-Cys peptide bond was synthesized for the first time and characterized in both the reduced and oxidized forms.

Cited by 6 publications

References 32 publications

Recent Advances in the Synthesis and Applications of Reduced Amide Pseudopeptides

Recent Advances in the Synthesis and Applications of Reduced Amide Pseudopeptides

Recent Advances in the Treatment of Neurodegenerative Diseases Based on GSH Delivery Systems

Nitrobenzoxadiazole-based GSTP1-1 inhibitors containing the full peptidyl moiety of (pseudo)glutathione

Contact Info

Product

Resources

About

Transition state isosteres of the γ‐glutamyl peptide bond hydrolysis: synthesis and characterization of the ψ[CH₂NH] pseudopeptide analogue of glutathione