Total Synthesis of the Potent Marine-Derived Elastase Inhibitor Lyngbyastatin 7 and in Vitro Biological Evaluation in Model Systems for Pulmonary Diseases.
J Org Chem
; 81(2): 532-44, 2016 Jan 15.
Article
em En
| MEDLINE
| ID: mdl-26709602
ABSTRACT
Lyngbyastatin 7 (1) is a marine cyanobacteria-derived lariat-type cyclic depsipeptide of which the macrocyclic core possesses modified amino acids, including a featured 3-amino-6-hydroxy-2-piperidone (Ahp) moiety and a (Z)-2-amino-2-butenoic acid (Abu) moiety. The first total synthesis of 1 was successfully established via 31 steps, and the conditions of several crucial steps were optimized to ensure smooth operations. The previously reported structural assignment and elastase inhibitory activity of the isolated natural product were confirmed. According to the extensive in vitro biological evaluation, compound 1 displayed low nanomolar IC50 in blocking elastase activity and strong ability in protecting bronchial epithelial cells against elastase-induced antiproliferation and abrogating the elastase-triggered induction of pro-inflammatory cytokine expression. Its overall performance was superior over sivelestat, the only approved small molecule drug targeting elastase, which indicated its potential in developing as a pharmacotherapeutic against elastase-mediated pathologies. The success in total synthesis, designed with a novel convergent strategy, not only overcame the supply issue for thorough preclinical studies but also paved the way for convenient synthesis of analogues with improved potency and druglike properties.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperidonas
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Elastase Pancreática
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Cianobactérias
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Depsipeptídeos
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Células Epiteliais
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Aminobutiratos
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Pneumopatias
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article