The Properties, Formation, and Biological Activity of 2,5-Diketopiperazines

Milne, P. J.; Kilian, Gareth

doi:10.1016/b978-008045382-8.00716-4

Cited by 12 publications

(5 citation statements)

References 215 publications

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“…The peptide chemistry of 2,5-diketopiperazines and advances in the previous decade in general methods for their solid-phase synthesis were reviewed by Fischer in 2003, and their solid-phase synthesis has recently been brought up to date (mid-2007). More recently in 2007, a brief review covering the biology and synthesis was published, and most recently, a review solely based on properties, formation, and biological activity of the monocyclic 2,5-diketopiperazines was published.…”

Section: Introductionmentioning

confidence: 99%

2,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural Products

Borthwick¹

2012

Chem. Rev.

739

726

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amide with a bivalent electrophile. For example, the aminoamide adducts 118 of tryptamine and an L-amino acid were reacted with a range of pyruvic acids to give the ketoamides 119. These were cyclized with HCl in EtOAc to give the 2,5-DKP ring that underwent a Pictet−Spengler-type condensation to give the tetrahydro-β-carboline and tetrahydroisoquinoline 2,5-diketopiperazines 120a and 120b. 102 However, reacting 118 (R = 5,6-DiMeO, R 1 = Me) with pyruvic acid gave the hydroxylactam 121 as a mixture of diastereroisomers rather than the ketoamide, and they underwent cyclization in the presence of HCl to give the corresponding tetrahydroisoquinoline 2,5-diketopiperazine derivatives 120b (Scheme 30). The L-amino acids were promoters of 1,4-chirality transfer with up to 100% diastereomeric excess (de). The stereochemistry of the final 2,5-diketopiperazines strongly depended on the structure of the L-amino acids used: acyclic amino acids gave predominantly the (R)-configuration at the newly created stereogenic center, whereas L-proline afforded the opposite configuration 122.

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Section: Introductionmentioning

confidence: 99%

2,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural Products

Borthwick¹

2012

Chem. Rev.

739

726

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“…The nature of DKP substitution and the stereochemistry around the C α position can drastically vary the 3D structures and the bioactivities of these 2,5-DKPs. , Our previous study investigating N α -alkylated-2,5-diketopiperazines as antimicrobial candidates, which focused primarily on diastereomeric mixtures, showed that the evaluated DKPs exhibited similar or superior antimicrobial activities when compared to those of structurally related linear peptides . These compounds were designed around an antimicrobial pharmacophore, which dictated that the minimum requirement for potent antimicrobial activity was two regions of hydrophobicity and two regions of cationic charge. , For comparison, an enantiopure sample was also prepared and shown to display improved activity against all tested bacteria when compared to the diastereomeric mixture .…”

mentioning

confidence: 99%

Stereochemical Effects on the Antimicrobial Properties of Tetrasubstituted 2,5-Diketopiperazines

Grant

Rennison

Mros

et al. 2022

ACS Med. Chem. Lett.

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Antimicrobial drug resistance is a looming health crisis facing us in the modern era, and new drugs are urgently needed to combat this growing problem. Synthetic mimics of antimicrobial peptides have recently emerged as a promising class of compounds for the treatment of persistent microbial infections. In the current study, we investigate five cyclic N-alkylated amphiphilic 2,5-diketopiperazines against 15 different strains of bacteria and fungi, including drug-resistant clinical isolates. Several of the 2,5-diketopiperazines displayed activities similar or superior to antibiotics currently in clinical use, with activities coupled to both the cationic and hydrophobic substituents. All possible stereoisomers of the lead peptide were prepared, and the effects of stereochemistry and amphiphilicity were investigated via 1D and 2D NMR spectroscopy, solution dynamics, and membrane interaction modeling. Clear differences in solution structures and membrane interaction potentials explain the differences seen in the bioactivity and physicochemical properties of each stereoisomer.

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“…These DKPs could activate biosensors on TLC assays, underscoring and suggesting the importance of chemical characterization of molecules identified in the bioassay (62,63). DKPs naturally show a wide range of antimicrobial, antiviral, antitumor, and immunosuppressive activities (55,63). In a previous study, 64 reported insecticidal activity of DPKs in Diptera, specifically in Ceratitis capitata (64).…”

Section: Discussionmentioning

confidence: 86%

“…Molecular characterization by UHPLC-MRM-MS/MS facilitated the identification of DKPs cyclo(L-Pro-L-Tyr) and cyclo(DAla-L-Val) in the extract of free supernatant obtained from P. ananatis. These DKPs could activate biosensors on TLC assays, underscoring and suggesting the importance of chemical characterization of molecules identified in the bioassay (62,63). DKPs naturally show a wide range of antimicrobial, antiviral, antitumor, and immunosuppressive activities (55,63).…”

Section: Discussionmentioning

confidence: 91%

Detection of Quorum Sensing Signal Molecules, Particularly N-Acyl Homoserine Lactones, 2-Alky-4-Quinolones, and Diketopiperazines, in Gram-Negative Bacteria Isolated From Insect Vector of Leishmaniasis

Mesa¹,

Higuita-Castro²,

Robledo³

et al. 2021

Front. Trop. Dis

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Gram-negative bacteria are known to use a quorum sensing system to facilitate and stimulate cell to cell communication, mediated via regulation of specific genes. This system is further involved in the modulation of cell density and metabolic and physiological processes that putatively either affect the survival of insect vectors or the establishment of pathogens transmitted by them. The process of quorum sensing generally involves N-acyl homoserine lactones and 2-alkyl-4-quinolones signaling molecules. The present study aimed to detect and identify quorum sensing signaling molecules of AHLs and AHQs type that are secreted by intestinal bacteria, and link their production to their extracellular milieu and intracellular content. Isolates for assessment were obtained from the intestinal tract of Pintomyia evansi (Leishmania insect vector). AHLs and AHQs molecules were detected using chromatography (TLC) assays, with the aid of specific and sensitive biosensors. For identity confirmation, ultra-high-performance liquid chromatography coupled with mass spectrometry was used. TLC assays detected quorum sensing molecules (QSM) in the supernatant of the bacterial isolates and intracellular content. Interestingly, Pseudomonas otitidis, Enterobacter aerogenes, Enterobacter cloacae, and Pantoea ananatis isolates showed a migration pattern similar to the synthetic molecule 3-oxo-C6-HSL (OHHL), which was used as a control. Enterobacter cancerogenus secreted C6-HSL, a related molecules to N-hexanoyl homoserine lactone (HHL), while Acinetobacter gyllenbergii exhibited a migration pattern similar to 2-heptyl-4-quinolone (HHQ) molecules. In comparison to this, 3-oxo-C12-HSL (OdDHL) type molecules were produced by Lysobacter soli, Pseudomonas putida, A. gyllenbergii, Acinetobacter calcoaceticus, and Pseudomonas aeruginosa, while Enterobacter cloacae produced molecules similar to 2-heptyl-3-hydroxy-4-quinolone (PQS). For Pseudomonas putida, Enterobacter aerogenes, P. ananatis, and Pseudomonas otitidis extracts, peak chromatograms with distinct retention times and areas, consistent with the molecules described in case of TLC, were obtained using HPLC. Importantly, P. ananatis produced a greater variety of high QSM concentration, and thus served as a reference for confirmation and identification by UHPLC-MRM-MS/MS. The molecules that were identified included N-hexanoyl-L-homoserine lactone [HHL, C10H18NO3, (M + H)], N-(3-oxohexanoyl)-L-homoserine lactone [OHHL, C10H16NO4, (M + H)], N-(3-oxododecanoyl)-L-homoserine lactone [OdDHL, C16H28NO4, (M + H)], and 2-heptyl-3-hydroxy-4(1H)-quinolone [PQS, C16H22NO2, (M + H)]. Besides this, the detection of diketopiperazines, namely L-Pro-L-Tyr and ΔAla-L-Val cyclopeptides was reported for P. ananatis. These molecules might be potentially associated with the regulation of QSM system, and might represent another small molecule-mediated bacterial sensing system. This study presents the first report regarding the detection and identification of QSM and diketopiperazines in the gut sand fly bacteria. The possible effect of QSM on the establishment of Leishmania must be explored to determine its role in the modulation of intestinal microbiome and the life cycle of Pi. evansi.

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The Properties, Formation, and Biological Activity of 2,5-Diketopiperazines

Cited by 12 publications

References 215 publications

2,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural Products

2,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural Products

Stereochemical Effects on the Antimicrobial Properties of Tetrasubstituted 2,5-Diketopiperazines

Detection of Quorum Sensing Signal Molecules, Particularly N-Acyl Homoserine Lactones, 2-Alky-4-Quinolones, and Diketopiperazines, in Gram-Negative Bacteria Isolated From Insect Vector of Leishmaniasis

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