title: UPLC-MS-ELSD-PDA as a powerful dereplication tool to facilitate compound identification from small-molecule natural product libraries.
abstract: The generation of natural product libraries containing column fractions, each with only a few small molecules, using a high-throughput, automated fractionation system, has made it possible to implement an improved dereplication strategy for selection and prioritization of leads in a natural product discovery program. Analysis of databased UPLC-MS-ELSD-PDA information of three leads from a biological screen employing the ependymoma cell line EphB2-EPD generated details on the possible structures of active compounds present. The procedure allows the rapid identification of known compounds and guides the isolation of unknown compounds of interest. Three previously known flavanone-type compounds, homoeriodictyol (1), hesperetin (2), and sterubin (3), were identified in a selected fraction derived from the leaves of Eriodictyon angustifolium. The lignan compound deoxypodophyllotoxin (8) was confirmed to be an active constituent in two lead fractions derived from the bark and leaves of Thuja occidentalis. In addition, two new but inactive labdane-type diterpenoids with an uncommon triol side chain were also identified as coexisting with deoxypodophyllotoxin in a lead fraction from the bark of T. occidentalis. Both diterpenoids were isolated in acetylated form, and their structures were determined as 14S,15-diacetoxy-13R-hydroxylabd-8(17)-en-19-oic acid (9) and 14R,15-diacetoxy-13S-hydroxylabd-8(17)-en-19-oic acid (10), respectively, by spectroscopic data interpretation and X-ray crystallography. This work demonstrates that a UPLC-MS-ELSD-PDA database produced during fractionation may be used as a powerful dereplication tool to facilitate compound identification from chromatographically tractable small-molecule natural product libraries.
authors.affiliation: National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, §Department of Medicinal Chemistry, ⊥Department of Pharmacognosy, and ∥Department of Pharmacology, School of Pharmacy, The University of Mississippi , University, Mississippi 38677, United States.
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.forename: Qian
authors.initials: Q
authors.lastname: Liang
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.forename: Cynthia
authors.initials: C
authors.lastname: Jeffries
authors.forename: David
authors.initials: D
authors.lastname: Smithson
authors.forename: Ying
authors.initials: Y
authors.lastname: Tu
authors.forename: Nidal
authors.initials: N
authors.lastname: Boulos
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Jacob
authors.forename: Anang A
authors.initials: AA
authors.lastname: Shelat
authors.forename: Yunshan
authors.initials: Y
authors.lastname: Wu
authors.forename: Ranga Rao
authors.initials: RR
authors.lastname: Ravu
authors.forename: Richard
authors.initials: R
authors.lastname: Gilbertson
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Avery
authors.forename: Ikhlas A
authors.initials: IA
authors.lastname: Khan
authors.forename: Larry A
authors.initials: LA
authors.lastname: Walker
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.forename: Xing-Cong
authors.initials: XC
authors.lastname: Li
mesh_terms: D001130:Arizona; D001688:Biological Products / Q000737:chemistry* / Q000302:isolation & purification*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification*; D047309:Flavones / Q000737:chemistry / Q000302:isolation & purification*; D006569:Hesperidin / Q000737:chemistry / Q000302:isolation & purification*; D013058:Mass Spectrometry / Q000379:methods*; D008968:Molecular Conformation; D015394:Molecular Structure; D018515:Plant Leaves / Q000737:chemistry; D054852:Small Molecule Libraries; D029783:Thuja / Q000737:chemistry*
chemical_list: D001688:Biological Products; D004224:Diterpenes; D047309:Flavones; D054852:Small Molecule Libraries; C433017:labdane; D006569:Hesperidin; C503231:homoeriodictyol; C013015:hesperetin