title: Total Synthesis of the Potent Marine-Derived Elastase Inhibitor Lyngbyastatin 7 and in Vitro Biological Evaluation in Model Systems for Pulmonary Diseases.
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.
authors.affiliation: Department of Medicinal Chemistry, University of Florida , Gainesville, Florida 32610, United States.|Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610, United States.
authors.forename: Danmeng
authors.initials: D
authors.lastname: Luo
authors.affiliation: Department of Medicinal Chemistry, University of Florida , Gainesville, Florida 32610, United States.|Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610, United States.
authors.forename: Qi-Yin
authors.initials: QY
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, University of Florida , Gainesville, Florida 32610, United States.|Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610, United States.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Luesch
mesh_terms: D000613:Aminobutyrates / Q000737:chemistry*; D005075:Biological Evolution; D000458:Cyanobacteria / Q000737:chemistry*; D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004847:Epithelial Cells / Q000737:chemistry / Q000187:drug effects*; D008171:Lung Diseases / Q000188:drug therapy* / Q000378:metabolism; D015394:Molecular Structure; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D010881:Piperidones / Q000737:chemistry*
chemical_list: C000608474:2-amino-2-butenoic acid; C555955:3-amino-6-hydroxy-2-piperidone; D000613:Aminobutyrates; D047630:Depsipeptides; D010881:Piperidones; C524907:lyngbyastatin 7; D010196:Pancreatic Elastase