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Total synthesis of [¹⁵N]-labelled C6-substituted purines from [¹⁵N]-formamide-easy preparation of isotopically labelled cytokinins and derivatives.

ABSTRACT: Cytokinins (CKs) and their metabolites and derivatives are essential for cell division, plant growth regulation and development. They are typically found at minute concentrations in plant tissues containing very complicated biological matrices. Therefore, defined standards labelled with stable isotopes are required for precise metabolic profiling and quantification of CKs, as well as in vivo elucidation of CK biosynthesis in various plant species. In this work, 11 [¹⁵N]-labelled C6-purine derivatives were prepared, among them 5 aromatic (4, 5, 6, 7, 8) and 3 isoprenoid (9, 10, 11) CKs. Compared to current methods, optimized syntheses of 6-amino-9H-[¹⁵N₅]-purine (adenine) and 6-chloro-9H-[¹⁵N₄]-purine (6-chloropurine) were performed to achieve more effective, selective and generally easier approaches. The chemical identity and purity of prepared compounds were confirmed by physico-chemical analyses (TLC; HRMS; HPLC-MS; ¹H, ¹³C, ¹⁵N NMR). The presented approach is applicable for the synthesis of any other desired [¹⁵N₄]-labelled C6-substituted purine derivatives.

SUBMITTER: Bucek J

PROVIDER: S-EPMC6281904 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Total synthesis of [15N]-labelled C6-substituted purines from [15N]-formamide-easy preparation of isotopically labelled cytokinins and derivatives.

Buček Jan J Zatloukal Marek M Havlíček Libor L Plíhalová Lucie L Pospíšil Tomáš T Novák Ondřej O Doležal Karel K Strnad Miroslav M

Royal Society open science 20181114 11

Cytokinins (CKs) and their metabolites and derivatives are essential for cell division, plant growth regulation and development. They are typically found at minute concentrations in plant tissues containing very complicated biological matrices. Therefore, defined standards labelled with stable isotopes are required for precise metabolic profiling and quantification of CKs, as well as in vivo elucidation of CK biosynthesis in various plant species. In this work, 11 [15N]-labelle ...[more]

PMID: 30564417

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Project description:IntroductionCeliac disease is a common autoimmune-like enteropathy caused by an aberrant response to incompletely digested dietary gluten. Gluten immunogenic peptides including the immunodominant 33-mer are thought to be resistant to proteolytic digestion by human gastrointestinal peptidases. We developed a novel enzyme therapy approach to support gluten peptide digestion using a combination of two tandem-acting exopeptidases, AMYNOPEP, that complement the intrinsic enzymatic activity of intestinal brush border enterocytes.MethodsWe evaluated the effects of AMYNOPEP supplementation on 33-mer degradation in vitro and in vivo. In a cross-over clinical study, healthy volunteers with no gastrointestinal disorders were given stable isotope (SI) labelled 33-mer peptides in the presence of varying peptide substrates and caloric loads, with and without AMYNOPEP. 33-mer degradation products (SI-labelled single amino acids) were measured in the blood plasma using LC-MS/MS.ResultsAMYNOPEP achieved rapid, complete amino-to-carboxyl terminal degradation of the 33-mer in vitro, generating single amino acids and dipeptides. In healthy volunteers, AMYNOPEP supplementation significantly increased 33-mer degradation and absorption of SI-labelled amino acids even in the presence of competing substrates. Specifically, we observed a 2.8-fold increase in the Cmax of stable isotope-labelled amino acids in the presence of wheat gluten. The absorption kinetics of labelled amino acids derived from 33-mer digestion with AMYNOPEP closely resembled that of SI-labelled X-Proline dipeptides administered without enzyme supplementation, highlighting the rapid hydrolytic activity of AMYNOPEP on polypeptides.ConclusionsAMYNOPEP achieved complete degradation of the 33-mer into single amino acids and dipeptides in vitro and significantly improved 33-mer degradation kinetics in healthy volunteers, as measured by labelled amino acid detection, warranting further investigation into the potential therapeutic benefits of exopeptidase combinations for patients with gluten-related health disorders including celiac disease.

Dataset Information

Total synthesis of [¹⁵N]-labelled C6-substituted purines from [¹⁵N]-formamide-easy preparation of isotopically labelled cytokinins and derivatives.

Publications

Total synthesis of [<sup>15</sup>N]-labelled C6-substituted purines from [<sup>15</sup>N]-formamide-easy preparation of isotopically labelled cytokinins and derivatives.

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