title: Solving the supply of resveratrol tetramers from Papua New Guinean rainforest anisoptera species that inhibit bacterial type III secretion systems.
abstract: The supply of (-)-hopeaphenol (1) was achieved via enzymatic biotransformation in order to provide material for preclinical investigation. High-throughput screening of a prefractionated natural product library aimed to identify compounds that inhibit the bacterial virulence type III secretion system (T3SS) identified several fractions derived from two Papua New Guinean Anisoptera species, showing activity against Yersinia pseudotuberculosis outer proteins E and H (YopE and YopH). Bioassay-directed isolation from the leaves of A. thurifera, and similarly A. polyandra, resulted in three known resveratrol tetramers, (-)-hopeaphenol (1), vatalbinoside A (2), and vaticanol B (3). Compounds 1-3 displayed IC50 values of 8.8, 12.5, and 9.9 μM in a luminescent reporter-gene assay (YopE) and IC50 values of 2.9, 4.5, and 3.3 μM in an enzyme-based YopH assay, respectively, which suggested that they could potentially act against the T3SS in Yersinia. The structures of 1-3 were confirmed through a combination of spectrometric, chemical methods, and single-crystal X-ray structure determinations of the natural product 1 and the permethyl ether analogue of 3. The enzymatic hydrolysis of the β-glycoside 2 to the aglycone 1 was achieved through biotransformation using the endogenous leaf enzymes. This significantly enhanced the yield of the target bioactive natural product from 0.08% to 1.3% and facilitates ADMET studies of (-)-hopeaphenol (1).
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.
authors.forename: Rohan A
authors.initials: RA
authors.lastname: Davis
authors.forename: Karren D
authors.initials: KD
authors.lastname: Beattie
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Xinzhou
authors.initials: X
authors.lastname: Yang
authors.forename: Sheng
authors.initials: S
authors.lastname: Yin
authors.forename: Harish
authors.initials: H
authors.lastname: Holla
authors.forename: Peter C
authors.initials: PC
authors.lastname: Healy
authors.forename: Melissa
authors.initials: M
authors.lastname: Sykes
authors.forename: Todd
authors.initials: T
authors.lastname: Shelper
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.forename: Mikael
authors.initials: M
authors.lastname: Elofsson
authors.forename: Charlotta
authors.initials: C
authors.lastname: Sundin
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Quinn
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry; D001572:Benzofurans / Q000737:chemistry / Q000302:isolation & purification; D053958:Dipterocarpaceae; D006576:Heterocyclic Compounds, 4 or More Rings; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D063191:Odonata; D010219:Papua New Guinea; D010636:Phenols / Q000737:chemistry / Q000302:isolation & purification; D065947:Rainforest; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry* / Q000302:isolation & purification* / Q000494:pharmacology*; D015011:Yersinia pseudotuberculosis / Q000737:chemistry / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D001572:Benzofurans; D006576:Heterocyclic Compounds, 4 or More Rings; D010636:Phenols; D013267:Stilbenes; C522219:Vaticanol B; C518233:hopeaphenol; C000595531:vatalbinoside A; D000077185:Resveratrol