title: LC-MS- and (1)H NMR Spectroscopy-Guided Identification of Antifungal Diterpenoids from Sagittaria latifolia.
abstract: Antifungal screening of small-molecule natural product libraries showed that a column fraction (CF) derived from the plant extract of Sagittaria latifolia was active against the fungal pathogen Cryptococcus neoformans. Dereplication analysis by liquid chromatography-mass spectrometry (LC-MS) and proton nuclear magnetic resonance spectroscopy ((1)H NMR) indicated the presence of new compounds in this CF. Subsequent fractionation of the plant extract resulted in the identification of two new isopimaradiene-type diterpenoids, 1 and 2. The structures of 1 and 2 were determined by chemical methods and spectroscopic analysis as isopimara-7,15-dien-19-ol 19-O-α-l-arabinofuranoside and isopimara-7,15-dien-19-ol 19-O-α-l-(5'-acetoxy)arabinofuranoside, respectively. Compound 1 exhibited IC50 values of 3.7 and 1.8 μg/mL, respectively, against C. neoformans and C. gattii. Its aglycone, isopimara-7,15-dien-19-ol (3), resulting from acid hydrolysis of 1, was also active against the two fungal pathogens, with IC50 values of 9.2 and 6.8 μg/mL, respectively. This study demonstrates that utilization of the combined LC-MS and (1)H NMR analytical tools is an improved chemical screening approach for hit prioritization in natural product drug discovery.
authors.forename: Ranga Rao
authors.initials: RR
authors.lastname: Ravu
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Jacob
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital , Memphis, Tennessee 38105, United States.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Jeffries
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital , Memphis, Tennessee 38105, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tu
authors.forename: Shabana I
authors.initials: SI
authors.lastname: Khan
authors.forename: Ameeta K
authors.initials: AK
authors.lastname: Agarwal
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital , Memphis, Tennessee 38105, United States.
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.forename: Larry A
authors.initials: LA
authors.lastname: Walker
authors.forename: Alice M
authors.initials: AM
authors.lastname: Clark
authors.forename: Xing-Cong
authors.initials: XC
authors.lastname: Li
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D003454:Cryptococcus / Q000187:drug effects; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D055808:Drug Discovery; D006027:Glycosides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D011728:Pyridones; D034903:Sagittaria / Q000737:chemistry*; D054852:Small Molecule Libraries; D014922:Wisconsin
chemical_list: D000935:Antifungal Agents; D004224:Diterpenes; D006027:Glycosides; D011728:Pyridones; D054852:Small Molecule Libraries; C000603542:isopimara-7,15-dien-19-ol 19-O-alpha-L-(5'-acetoxy)arabinofuranoside; C000603541:isopimara-7,15-dien-19-ol 19-O-alpha-L-arabinofuranoside; C000603466:tolypyridone A