Preparation of Constrained Unnatural Aromatic Amino Acids<i>via</i> Unsaturated Diketopiperazine Intermediate

Mollica, Adriano; Costante, Roberto; Mirzaie, Sako; Carradori, Simone; Macedonio, Giorgia; Stefanucci, Azzurra; Novellino, Ettore

doi:10.1002/jhet.2489

Cited by 9 publications

(4 citation statements)

References 17 publications

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“…Derivatives 1 – 6 were commercially available. Conversely, a synthetic strategy to prepare derivatives ( 7 – 9 ) has been developed in our laboratory [ 37 ] involving Boc-solution chemistry ( Scheme 1 ). The starting common dipeptide precursor was obtained by coupling Boc-(L)HisOH with L-PheOCH 3 , l -MetOCH 3 and l -ProOCH 3 in N , N -dimethylformamide (DMF).…”

Section: Chemistrymentioning

confidence: 99%

Five- and Six-Membered Nitrogen-Containing Compounds as Selective Carbonic Anhydrase Activators

et al. 2017

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It has been proven that specific isoforms of human carbonic anhydrase (hCA) are able to fine-tune physiological pathways connected to signal processing, and that decreased CAs expression negatively influences cognition, leading to mental retardation, Alzheimer’s disease, and aging-related cognitive dysfunctions. For this reason, a small library of natural and synthetic nitrogen containing cyclic derivatives was assayed as activators of four human isoforms of carbonic anhydrase (hCA I, II, IV and VII). Most of the compounds activated hCA I, IV and VII in the micromolar range, with KAs ranging between 3.46 and 80.5 μM, whereas they were not active towards hCA II (KAs > 100 μM). Two natural compounds, namely l-(+)-ergothioneine (1) and melatonin (2), displayed KAs towards hCA VII in the nanomolar range after evaluation by a CO2 hydration method in vitro, showing a rather efficient and selective activation profile with respect to histamine, used as a reference compound. Corroborated with the above in vitro findings, a molecular modelling in silico approach has been performed to correlate these biological data, and to elucidate the binding interaction of these activators within the enzyme active site.

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Section: Chemistrymentioning

confidence: 99%

Five- and Six-Membered Nitrogen-Containing Compounds as Selective Carbonic Anhydrase Activators

et al. 2017

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“…Scheme 1. Examples of Synthetic Approaches to the Synthesis of 2,5-Diketopiperazines: (A) Condensation/ Cyclization between N-Protected C-Activated Amino Acid and C-Protected Amino Acid; 7,12,13 (B−D) Intramolecular Cyclization of Ugi Adducts: (B) Use of Convertible Isocyanides, 9 (C) Intramolecular N-Alkylation Using Alkyl Amines and Alkyl Isocyanides, 15,16 Compound detection was performed by chromatographic peak dissection with subsequent formula determination according to the exact mass and isotope pattern (MS1). Chemical Synthesis Procedures.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…A classical methodology for the construction of the 2,5-DKP ring consists of the amidation reaction between an activated carboxyl group of an N -Boc-protected amino acid with the amine group of a C -protected amino acid (amino acid ester). Following this, N -Boc deprotection is carried out by treatment with trifluoroacetic acid, and cyclization takes place through an intramolecular nucleophilic acyl substitution reaction involving the free amino group and the ester carbonyl (Scheme A). ,, In addition, among the most used synthetic methods are those based on the versatile Ugi four-component reaction (Ugi-4CR), which consists of a one-pot condensation of an aldehyde, an amine, an acid, and an isocyanide to provide an α- N -acylamino amide that can undergo further cyclization to produce the 2,5-DKP core. By varying the structures of any of the four reactants, the Ugi reaction makes it possible to generate a large range of structural diverse 2,5-DKP.…”

Section: Introductionmentioning

confidence: 99%

2,5-Diketopiperazines via Intramolecular N-Alkylation of Ugi Adducts: A Contribution to the Synthesis, Density Functional Theory Study, X-ray Characterization, and Potential Herbicide Application

Mendes

Varejão

Souza

et al. 2022

J. Agric. Food Chem.

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To investigate the herbicidal potential of 2,5-diketopiperazines (2,5-DKPs), we applied a known protocol to produce a series of 2,5-DKPs through intramolecular N-alkylation of Ugi adducts. However, the method was not successful for the cyclization of adducts presenting aromatic rings with some substituents at the ortho position. Results from DFT calculations showed that the presence of voluminous groups at the ortho position of a benzene ring results in destabilization of the transition structure. Lower activation enthalpies for the SN2-type cyclization of Ugi adducts were obtained when bromine, instead of a chlorine anion, is the leaving group, indicating that the activation enthalpy for the cyclization step controls the formation of the 2,5-DKP. Some Ugi adducts and 2,5-DKPs formed crystals with suitable qualities for single-crystal X-ray diffraction data collection. Phytotoxic damage of some 2,5-DKPs on leaves of the weed Euphorbia heterophylla did not differ from those caused by the commercial herbicide diquat.

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“…At the current state, while a series of synthetic pathways have been developed for the synthesis of Dmt [1,[19][20][21][22][23][24][25], there are only few methods for the obtainment of Mmt [26][27][28].…”

Section: Introductionmentioning

confidence: 99%

(L)-Monomethyl Tyrosine (Mmt): New Synthetic Strategy via Bulky ‘Forced-Traceless’ Regioselective Pd-Catalyzed C(sp2)–H Activation

Illuminati,

Trapella,

Zanirato

et al. 2023

Pharmaceuticals

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The enormous influence in terms of bioactivity, affinity, and selectivity represented by the replacement of (L)-2,6-dimethyl tyrosine (Dmt) instead of Phenylalanine (Phe) into Nociceptin/orphanin (N/OFQ) neuropeptide analogues has been well documented in the literature. More recently, the non-natural amino acid (L)-2-methyl tyrosine (Mmt), with steric hindrance included between Tyr and Dmt, has been studied because of the modulation of steric effects in opioid peptide chains. Here, we report a new synthetic strategy to obtain Mmt based on the well-known Pd-catalyzed ortho-C(sp2)–H activation approach, because there is a paucity of other synthetic routes in the literature to achieve it. The aim of this work was to force only the mono-ortho-methylation process over the double ortho-methylation one. In this regard, we are pleased to report that the introduction of the dibenzylamine moiety on a Tyr aromatic nucleus is a convenient and traceless solution to achieve such a goal. Interestingly, our method provided the aimed Mmt either as N-Boc or N-Fmoc derivatives ready to be inserted into peptide chains through solid-phase peptide synthesis (SPPS). Importantly, the introduction of Mmt in place of Phe1 in the sequence of N/OFQ(1-13)-NH2 was very well tolerated in terms of pharmacological profile and bioactivity.

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Preparation of Constrained Unnatural Aromatic Amino Acidsvia Unsaturated Diketopiperazine Intermediate

Cited by 9 publications

References 17 publications

Five- and Six-Membered Nitrogen-Containing Compounds as Selective Carbonic Anhydrase Activators

Five- and Six-Membered Nitrogen-Containing Compounds as Selective Carbonic Anhydrase Activators

2,5-Diketopiperazines via Intramolecular N-Alkylation of Ugi Adducts: A Contribution to the Synthesis, Density Functional Theory Study, X-ray Characterization, and Potential Herbicide Application

(L)-Monomethyl Tyrosine (Mmt): New Synthetic Strategy via Bulky ‘Forced-Traceless’ Regioselective Pd-Catalyzed C(sp2)–H Activation

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