Nesfatin-1 in human and murine cardiomyocytes: synthesis, secretion, and mobilization of GLUT-4

Nesfatin-1, a satiety-inducing peptide identified in hypothalamic regions that regulate energy balance, is an integral regulator of energy homeostasis and a putative glucose-dependent insulin coadjuvant. We investigated its production by human cardiomyocytes and its effects on glucose uptake, in the main cardiac glucose transporter GLUT-4 and in intracellular signaling. Quantitative RT-PCR, Western blots, confocal immunofluorescence microscopy, and ELISA of human and murine cardiomyocytes and/or cardiac tissue showed that cardiomyocytes can synthesize and secrete nesfatin-1. Confocal microscopy of cultured cardiomyocytes after GLUT-4 labeling showed that nesfatin-1 mobilizes this glucose transporter to cell peripherals. The rate of 2-deoxy-D-[(3)H]glucose incorporation demonstrated that nesfatin-1 induces glucose uptake by HL-1 cells and cultured cardiomyocytes. Nesfatin-1 induced dose- and time-dependent increases in the phosphorylation of ERK1/2, AKT, and AS160. In murine and human cardiac tissue, nesfatin-1 levels varied with diet and coronary health. In conclusion, human and murine cardiomyocytes can synthesize and secrete nesfatin-1, which is able to induce glucose uptake and the mobilization of the glucose transporter GLUT-4 in these cells. Nesfatin-1 cardiac levels are regulated by diet and coronary health

Synthesis of α-aminoboronic acids

This review describes available methods for the preparation of α-aminoboronic acids in their racemic or in their enantiopure form. Both, highly stereoselective syntheses and asymmetric procedures leading to the stereocontrolled generation of α-aminoboronic acid derivatives are included. The preparation of acyclic, carbocyclic and azacyclic α-aminoboronic acid derivatives is covered. Within each section, the different synthetic approaches have been classified according to the key bond which is formed to complete the α-aminoboronic acid skeleton.Financial support from Ministerio de Economía y Competitividad (CTQ2010-17436, CTQ2013-40855-R; FPI fellowship to P. A.) and Gobierno de Aragón – Fondo Social Europeo (research group E40). is gratefully acknowledgedPeer Reviewe

Synthesis of enantiomerically pure δ-benzylproline derivatives

The (2S,5R) stereoisomer of 5-benzylproline, i.e. the l-proline analogue that bears a δ-benzyl substituent cis to the carbonyl function, has been prepared in enantiomerically pure form and excellent global yield. The procedure involves the construction of the pyrrolidine ring through intramolecular cyclization and uses as starting material the enantiopure β-amino acid obtained by homologation of l-phenylalanine. The generation of an intermediate vinyl triflate with full regiochemical control followed by a stereoselective hydrogenation reaction allowed the isolation of the target δ-substituted l-proline analogue in optically pure form and 43% overall yield from the initial β-amino acid. The trans stereoisomer of (2R,5R) configuration is obtained as a minor product through a less stereoselective hydrogenation reaction.The authors thank the Ministerio de Economía y Competitividad - FEDER (grants CTQ2010-17436, CTQ2013-40855-R, FPI fellowship to I.R.) and Gobierno de Aragón–FSE (research group E40). for financial support.Peer Reviewe

Synthesis of racemic δ,δ-dimethylproline derivatives

A versatile methodology for the preparation of racemic δ,δ- dimethylproline derivatives has been developed. Methyl N-Boc-δ,δ- dimethylprolinate was synthesized from a β-amino acid in six steps and 55 % overall yield. The route is amenable to the preparation of a broad range of δ,δ-disubstituted prolines by starting with the adequate β-amino acids. In addition, one of the intermediate compounds in the synthetic route has been used for the preparation of a δ,δ- dimethylproline derivative that is substituted at the β-position with a phenyl group. This has been achieved by coupling phenylboronic acid with a regioselectively generated vinyl triflate followed by a stereoselective hydrogenation. δ,δ-Dimethylproline derivatives have been efficiently synthesized by employing a β-amino acid as the starting material. The methodology is amenable to the preparation of other δ,δ- disubstituted prolines. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.Financial support from the Ministerio de Ciencia e Innovación – FEDER (grant CTQ2010-17436; FPI fellowship to I. R.), and the Gobierno de Aragón – FSE (research group E40) is gratefully acknowledged.Peer Reviewe

Access to the cis-fused stereoisomers of proline analogues containing an octahydroindole core

El pdf del artículo es la versión post-print.An overview of the synthetic methods developed to build all the cis-fused stereoisomers of octahydroindole-2-carboxylic acid and its α-methylated derivative in enantiomerically pure form is presented. Both asymmetric synthetic strategies(auxiliary- or substrate-controlled processes) and procedures based on the resolution of racemic compounds (chemical, enzymatic, and chromatographic processes) are summarized. Special emphasis has been placed on those strategies able to provide multigram quantities of enantiopure compounds, a prerequisite to make downstream biological applications feasible.Financial support from the Ministerio de Ciencia e Innovación (projects CTQ2007-62245 and CTQ2010-17436; predoctoral fellowship for P. L.) and the Gobierno de Aragón (project PIP206/ 2005 and research group E40) is gratefully acknowledged.Peer Reviewe

Stereoselective multigram-scale synthesis of cis- and trans-β- phenylproline derivatives

Efficient routes for the gram-scale preparation of the proline analogues that bear a phenyl substituent attached to the pyrrolidine β carbon (cis- and trans-β-phenylproline) have been developed. The cis derivative was synthesized from N-Boc-β-alanine in six steps and 78% overall yield. The generation of a vinyl triflate with full regiochemical control together with a high-yielding cross-coupling reaction and a completely stereoselective hydrogenation are at the basis of the high efficiency of the procedure. Epimerization of the cis β-phenylproline derivative with lithium bis(trimethylsilyl)amide provided access to the trans isomer. © 2012 Elsevier Ltd. All rights reserved.The authors thank the Ministerio de Ciencia e Innovación-FEDER (grant CTQ2010-17436; FPI fellowship to I.R.) and Gobierno de Aragón-FSE (research group E40) for financial support.Peer Reviewe

Practical access to the proline analogs (S,S,S)- and (R,R,R)-2- methyloctahydroindole-2-carboxylic acids by HPLC enantioseparation

An efficient methodology for the preparation of the α- tetrasubstituted proline analog (S,S,S)-2-methyloctahydroindole-2-carboxylic acid, (S,S,S)-(αMe)Oic, and its enantiomer, (R,R,R)-(αMe)Oic, has been developed. Starting from easily available substrates and through simple transformations, a racemic precursor has been synthesized in excellent yield and further subjected to HPLC resolution using a cellulose-derived chiral stationary phase. Specifically, a semipreparative (250 mm × 20 mm ID) Chiralpak® IC column has allowed the efficient resolution of more than 4 g of racemate using a mixture of n-hexane/tert-butyl methyl ether/2-propanol as the eluent. Multigram quantities of the target amino acids have been isolated in enantiomerically pure form and suitably protected for incorporation into peptides. © 2011 Wiley-Liss, Inc.Contract grant sponsors: Ministerio de Ciencia e Innovación–FEDER, Gobierno de Aragón; Contract grant numbers: CTQ2007-62245, CTQ2010- 17436, PIP206/2005 and research group E40.Peer Reviewe

Synthesis of [c]-fused bicyclic proline analogues

An overview of synthetic methods developed to build [c]fused bicyclic proline analogues is presented. The focus is on the preparation of azabicycles that bear a carbocyclic ring fused to the [c] face of the pyrrolidine unit. Attention is paid both to procedures that afford the desired compounds in racemic form and to asymmetric strategies. Procedures are or-ganized according to the size of the carbocycle that is fused to the pyrrolidine moiety. Strategies able to provide multigram quantities of enantiopure compounds that have application in the synthesis of marketed drugs are highlighted.This study was supported by the Russian Foundation for Basic Research (RFBR), Russia (Projects No. 14-03-31685, 14-03-31709, 14-03-01114).Peer Reviewe

Effect of a β-phenyl substituent on the puckering modes of proline

Trabajo presentado a la Small Molecule NMR Conference celebrada en Santiago de Compostela (España) del 22 al 25 de septiembre de 2013.The high significance of proline in peptide conformation and biology stimulates the development of proline analogues with tailored properties. The attachment of substituents to the five-membered ring is particularly atractive in this regard. Such substituents may serve to incorporate additional functionality as well as to modulate the conformational properties of proline. In this context, we have explored the effect produced by a phenyl substituent attached to the β-carbon atom of proline on the puckering modes adopted by the pyrrolidine ring. Both the cis and trans configurations of the β-phenyl group relative to the carbonyl moiety have been considered. The puckering modes of such proline analogues, cis- and trans-β-phenylproline, have been examined by NMR when incorporated into model dipeptides. We observed that the pyrrolidine conformation is significantly affected by the presence of the β-phenyl group. Those conformations that alleviate most the steric hindrance introduced by the bulky phenyl substituent are preferred. The orientation adopted by the aromatic moiety is much more restricted in the cis isomer. Thus, cis-β-phenylproline shows a highly marked propensity to adopt a Cγ-endo arrangement. In contrast, the trans derivative exhibits a higher flexibility, with Cγ-endo and Cγ-exo pyrrolidine shapes being accessible, as for proline itself.Peer reviewe