Cytotoxic and non-cytotoxic cardiac glycosides isolated from the combined flowers, leaves, and twigs of Streblus asper

• Published in: Bioorganic & medicinal chemistry 2020-02, Vol.28 (4), p.115301-115301, Article 115301
• Main Authors: Ren, Yulin, Tan, Qingwei, Heath, Kimberly, Wu, Sijin, Wilson, James R., Ren, Jinhong, Shriwas, Pratik, Yuan, Chunhua, Ngoc Ninh, Tran, Chai, Hee-Byung, Chen, Xiaozhuo, Soejarto, Djaja D., Johnson, Michael E., Cheng, Xiaolin, Burdette, Joanna E., Kinghorn, A. Douglas
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - isolation & purification; Antineoplastic Agents, Phytogenic - pharmacology; Cardiac glycosides; Cardiac Glycosides - chemistry; Cardiac Glycosides - isolation & purification; Cardiac Glycosides - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cytotoxicity; Docking profiles; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - pharmacology; Flowers - chemistry; Glucose transport inhibition; Humans; Molecular Conformation; Molecular Docking Simulation; Moraceae - chemistry; Na+/K+-ATPase inhibition; Plant Leaves - chemistry; Plant Stems - chemistry; Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors; Sodium-Potassium-Exchanging ATPase - metabolism; Streblus asper; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.115301

[Display omitted] 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.