title: 2,3-Dihydrowithaferin A-3beta-O-sulfate, a new potential prodrug of withaferin A from aeroponically grown Withania somnifera.
abstract: Preparations of the roots of the medicinal plant Withania somnifera (L.) Dunal commonly called ashwagandha have been used for millennia in the Ayurvedic medical tradition of India as a general tonic to relieve stress and enhance health, especially in the elderly. In modern times, ashwagandha has been shown to possess intriguing antiangiogenic and anticancer activity, largely attributable to the presence of the steroidal lactone withaferin A as the major constituent. When cultured using the aeroponic technique, however, this plant was found to produce a new natural product, 2,3-dihydrowithaferin A-3beta-O-sulfate (1), as the predominant constituent of methanolic extracts prepared from aerial tissues. The characteristic bioactivities exhibited by 1 including inhibition of cancer cell proliferation/survival, disruption of cytoskeletal organization and induction of the cellular heat-shock response paralleled those displayed by withaferin A (2). The delayed onset of action and reduced potency of 1 in cell culture along with previous observations demonstrating the requirement of the 2(3)-double bond in withanolides for bioactivity suggested that 1 might be converted to 2 in cell culture media and this was confirmed by HPLC analysis. The abundant yield of 1 from aeroponically cultivated plants, its good aqueous solubility and spontaneous conversion to 2 under cell culture conditions, suggest that 1 could prove useful as a readily formulated prodrug of withaferin A that merits further evaluation in animal models.
authors.affiliation: Southwest Center for Natural Products Research and Commercialization, Office of Arid Lands Studies, College of Agriculture and Life Sciences, The University of Arizona, 250 E. Valencia Road, Tucson, AZ 85706, USA.
authors.forename: Ya-ming
authors.initials: YM
authors.lastname: Xu
authors.forename: Marilyn T
authors.initials: MT
authors.lastname: Marron
authors.forename: Emily
authors.initials: E
authors.lastname: Seddon
authors.forename: Steven P
authors.initials: SP
authors.lastname: McLaughlin
authors.forename: Dennis T
authors.initials: DT
authors.lastname: Ray
authors.forename: Luke
authors.initials: L
authors.lastname: Whitesell
authors.forename: A A Leslie
authors.initials: AA
authors.lastname: Gunatilaka
mesh_terms: D045744:Cell Line, Tumor; D004875:Ergosterol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011355:Prodrugs / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D032341:Withania / Q000737:chemistry* / Q000254:growth & development; D054358:Withanolides
chemical_list: C541045:2,3-dihydrowithaferin A-3-O-sulfate; D011355:Prodrugs; D054358:Withanolides; C009684:withaferin A; D004875:Ergosterol