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Cytotoxic and non-cytotoxic cardiac glycosides isolated from the combined flowers, leaves, and twigs of Streblus asper
journal contributionposted on 06.05.2022, 16:59 by Yulin Ren, Qingwei Tan, Kimberly Heath, Sijin Wu, James R Wilson, Jinhong Ren, Pratik Shriwas, Chunhua Yuan, Tran Ngoc Ninh, Hee-Byung Chai, Xiaozhuo Chen, Djaja SoejartoDjaja Soejarto, Michael JohnsonMichael Johnson, Xiaolin Cheng, Joanna BurdetteJoanna Burdette, A Douglas Kinghorn
A new non-cytotoxic [(+)-17β-hydroxystrebloside (1)] and two known cytotoxic [(+)-3'-de-O-methylkamaloside (2) and (+)-strebloside (3)] cardiac glycosides were isolated and identified from the combined flowers, leaves, and twigs of Streblus asper collected in Vietnam, with the absolute configuration of 1 established from analysis of its ECD and NMR spectroscopic data and confirmed by computational ECD calculations. A new 14,21-epoxycardanolide (3a) was synthesized from 3 that was treated with base. A preliminary structure-activity relationship study indicated that the C-14 hydroxy group and the C-17 lactone unit and the established conformation are important for the mediation of the cytotoxicity of 3. Molecular docking profiles showed that the cytotoxic 3 and its non-cytotoxic analogue 1 bind differentially to Na+/K+-ATPase. Compound 3 docks deeply in the Na+/K+-ATPase pocket with a sole pose, and its C-10 formyl and C-5, C-14, and C-4' hydroxy groups may form hydrogen bonds with the side-chains of Glu111, Glu117, Thr797, and Arg880 of Na+/K+-ATPase, respectively. However, 1 fits the cation binding sites with at least three different poses, which all depotentiate the binding between 1 and Na+/K+-ATPase. Thus, 3 was found to inhibit Na+/K+-ATPase, but 1 did not. In addition, the cytotoxic and Na+/K+-ATPase inhibitory 3 did not affect glucose uptake in human lung cancer cells, against which it showed potent activity, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na+/K+-ATPase but not by interacting with glucose transporters.
Discovery of Anticancer Agents of Diverse Natural Origin | Funder: NIH / NCI | Grant ID: P01 5P01CA125066-08
CitationRen, Y., Tan, Q., Heath, K., Wu, S., Wilson, J. R., Ren, J., Shriwas, P., Yuan, C., Ngoc Ninh, T., Chai, H. -B., Chen, X., Soejarto, D. D., Johnson, M. E., Cheng, X., Burdette, J. E.Kinghorn, A. D. (2020). Cytotoxic and non-cytotoxic cardiac glycosides isolated from the combined flowers, leaves, and twigs of Streblus asper. Bioorganic & Medicinal Chemistry, 28(4), 115301-. https://doi.org/10.1016/j.bmc.2019.115301
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Streblus asperCardiac glycosidesCytotoxicityDocking profilesNa+/K+-ATPase inhibitionGlucose transport inhibitionNa(+)/K(+)-ATPase inhibitionAntineoplastic Agents, PhytogenicCardiac GlycosidesCell Line, TumorCell ProliferationDose-Response Relationship, DrugDrug Screening Assays, AntitumorEnzyme InhibitorsFlowersHumansMolecular ConformationMolecular Docking SimulationMoraceaePlant LeavesPlant StemsSodium-Potassium-Exchanging ATPaseStructure-Activity RelationshipMedicinal & Biomolecular ChemistryMedicinal and Biomolecular ChemistryOrganic ChemistryPharmacology and Pharmaceutical Sciences