TY - JOUR
T1 - 2,3-Dihydrowithaferin A-3β-O-sulfate, a new potential prodrug of withaferin A from aeroponically grown Withania somnifera
AU - Xu, Ya ming
AU - Marron, Marilyn T.
AU - Seddon, Emily
AU - McLaughlin, Steven P.
AU - Ray, Dennis T.
AU - Whitesell, Luke
AU - Leslie Gunatilaka, A. A.
N1 - Funding Information:
This work was supported by a grant from USDA-CSREES and this support is gratefully acknowledged. Ms. Betsy Lewis is thanked for her assistance with fabricating the aeroponic chambers.
PY - 2009/3/15
Y1 - 2009/3/15
N2 - 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-3β-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.
AB - 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-3β-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.
KW - 2,3-Dihydrowithaferin A-3β-O-sulfate
KW - Aeroponic culture
KW - Anticancer activity
KW - Cytoskeletal reorganization
KW - Heat-shock induction
KW - Prodrug
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U2 - 10.1016/j.bmc.2008.10.091
DO - 10.1016/j.bmc.2008.10.091
M3 - Article
C2 - 19056281
AN - SCOPUS:62149100375
SN - 0968-0896
VL - 17
SP - 2210
EP - 2214
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 6
ER -