Pyroglutamic Acid Derivatives: Building Blocks for Drug Discovery

Mollica, Adriano; Stefanucci, Azzurra; Costante, Roberto; Novellino, Ettore

doi:10.3987/rev-14-800

Cited by 22 publications

(3 citation statements)

References 86 publications

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“…All other amino acids are secondary ones, because they are formed as a result of the transamination of the amino acids listed above with the corresponding keto acids that arise during the metabolism, as well as by the conversion of some acids to others [58]. The dehydration of glutamic acid leads to the formation of its lactam-pyroglutamic acid, which is the key precursor in the biosynthesis of biologically active compounds of primary and secondary metabolites [59].…”

Section: Discussionmentioning

confidence: 99%

Comparative Investigation of Amino Acids Content in the Dry Extracts of Juno bucharica, Gladiolus Hybrid Zefir, Iris Hungarica, Iris Variegata and Crocus Sativus Raw Materials of Ukrainian Flora

et al. 2020

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The aim of this research was the comparative study of the amino acids content in the dry extracts of Iridaceae plants of Ukrainian flora: Juno bucharica leaves and corms, Gladiolus hybrid Zefir leaves, Iris hungarica and Iris variegata rhizomes, and Crocus sativus stigmas, flowers, leaves and corms. A gas chromatography–mass spectrometry (GC–MS) method has been used. Separation of amino acids in the samples was carried out using a Shimadzu GC-MS-QP2010 equipped with an Rxi-5ms (Restek Corporation capillary column (30 m long, 0.25 mm outer diameter and 0.25 µm) with a liquid stationary phase (5% diphenyl and 95% polysiloxane) after derivatization with N-(t-butyldimethylsilyl)-N109 methyltrifluoroacetamide (MTBSTFA) reagent. The results obtained have shown that extracts from the aerial parts of plants investigated have a higher amino acid content and more diverse composition than the underground organs. Experimental data showed that Crocus leaves and Juno leaves extracts contain the highest general content of amino acids—31.99 mg/g and 14.65 mg/g respectively. All samples showed a high content of L-pyroglutamic acid (0.33–12.35 mg/g). Moreover, Crocus leaves and Juno leaves extracts had the most suitable amino acids composition and are prospective for further pharmacological studies.

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Section: Discussionmentioning

confidence: 99%

Comparative Investigation of Amino Acids Content in the Dry Extracts of Juno bucharica, Gladiolus Hybrid Zefir, Iris Hungarica, Iris Variegata and Crocus Sativus Raw Materials of Ukrainian Flora

et al. 2020

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“…[1,2,24] In particular, 2,6-dimethyl-L-tyrosine (Dmt) and cis-4-amino-L-proline (cAmp) has become one of the most popular nonnatural amino acids for replacing tyrosine, and proline, respectively, in synthetic opioid peptides. [14,25] The structural limitation provided by the two additional methyl groups in Dmt and the additional amino group in proline in cAmp may influence receptor affinity, selectivity, and bioactivity of peptides containing such amino acids. The presence of Dmt in opioid peptides can lead to the design of unique peptidomimetic molecules.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, characterization, and biological study of new synthetic opioid hemorphin‐4 peptides containing sterically restricted nonnatural amino acids

Todorov,

Georgieva,

Trapella

et al. 2024

Archiv der Pharmazie

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Some new hemorphin‐4 analogs with structures of Xxx‐Pro‐Trp‐Thr‐NH2 and Tyr‐Yyy‐Trp‐Thr‐NH2, where Xxx is 2‐amino‐3‐(4−hydroxy‐2,6‐dimethylphenyl)propanoic acid or 2‐amino‐3‐(4‐dibenzylamino‐2,6‐dimethylphenyl)propanoic acid, and Yyy is (2S,4S)‐4‐amino‐pyrrolidine‐2‐carboxylic acid, were synthesized and characterized by electrochemical and spectral analyses. In vivo anticonvulsant and antinociceptive activities of peptide derivatives were studied after intracerebroventricular injection in mice. The therapeutic effects of the modified peptides on seizures and pain in mice were evaluated to provide valuable insights into the potential applications of the novel compounds. Electrochemical characterization showed that the compounds behave as weak protolytes and that they are in a soluble, stable molecular form at physiological pH values. The antioxidant activity of the peptides was evaluated with voltammetric analyses, which were confirmed by applying the 2,2‐Diphenyl‐1‐picrylhydrazyl method. The compounds showed satisfactory results regarding their structural stability, reaching the desired centers for the manifestation of biological activity without hydrolysis processes at 37°C and physiological pH. Dm‐H4 and H4‐P1 exhibited 100% and 83% potency to suppress the psychomotor seizures in the 6‐Hz test compared to 67% activity of H4. Notably, only the H4‐P1 had efficacy in blocking the tonic component in the maximal electroshock test with a potency comparable to H4. All investigated peptides containing unnatural conformationally restricted amino acids showed antinociceptive effects. The analogs Db‐H4 and H4‐P1 showed the most pronounced and long‐lasting effect in both experimental models of pain induced by thermal and chemical stimuli. Dm‐H4 produced a dose‐dependent thermal antinociception and H4‐P2 inhibited only formalin‐induced pain behavior.

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“…Pyroglutamates are of interest particularly for their role as starting materials and in drug discovery; , we have been interested in the application of pyroglutamic acids as a chiral starting material and have shown that, in a suitably protected form, it may be selectively alkylated, hydroxylated, and aminated, , as well as used for conjugate additions by carbon, oxygen, and nitrogen nucleophiles . While this does provide access to highly functionalized heterocyclic derivatives, it can require sequential activation of different positions around the heterocyclic ring and such a multistep sequence lacks convenience; an approach involving C–H activation for direct ring functionalization has, however, been recently reported .…”

Section: Introductionmentioning

confidence: 99%

Synthetic Access to 3-Substituted Pyroglutamic Acids from Tetramate Derivatives of Serine, Threonine, allo-Threonine, and Cysteine

et al. 2019

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A general route which provides direct access to pyroglutamates from tetramates, making use of Suzuki coupling on an enol mesylate, followed by reduction, is reported. This work permits direct scaffold hopping from tetramate to substituted pyroglutamates. Some compounds in the library showed modest antibacterial activity against Gram-positive bacteria. _______________________________________________________________________________4a 1.4:1 86 80 75 4b 1.0:1 88 67 73 4c 2.5:1 71 66 75 4d 1.5:1

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Pyroglutamic Acid Derivatives: Building Blocks for Drug Discovery

Cited by 22 publications

References 86 publications

Comparative Investigation of Amino Acids Content in the Dry Extracts of Juno bucharica, Gladiolus Hybrid Zefir, Iris Hungarica, Iris Variegata and Crocus Sativus Raw Materials of Ukrainian Flora

Comparative Investigation of Amino Acids Content in the Dry Extracts of Juno bucharica, Gladiolus Hybrid Zefir, Iris Hungarica, Iris Variegata and Crocus Sativus Raw Materials of Ukrainian Flora

Synthesis, characterization, and biological study of new synthetic opioid hemorphin‐4 peptides containing sterically restricted nonnatural amino acids

Synthetic Access to 3-Substituted Pyroglutamic Acids from Tetramate Derivatives of Serine, Threonine, allo-Threonine, and Cysteine

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