Cytotoxic and non-cytotoxic cardiac glycosides isolated from the combined flowers, leaves, and twigs of Streblus asper.
Ren Y, Tan Q, Heath K, Wu S, Wilson JR, Ren J, Shriwas P, Yuan C, Ngoc Ninh T, Chai HB, Chen X, Soejarto DD, Johnson ME, Cheng X, Burdette JE, Kinghorn AD.
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<sup>+</sup>/K<sup>+</sup>-ATPase. Compound 3 docks deeply in the Na<sup>+</sup>/K<sup>+</sup>-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<sup>+</sup>/K<sup>+</sup>-ATPase, respectively. However, 1 fits the cation binding sites with at least three different poses, which all depotentiate the binding between 1 and Na<sup>+</sup>/K<sup>+</sup>-ATPase. Thus, 3 was found to inhibit Na<sup>+</sup>/K<sup>+</sup>-ATPase, but 1 did not. In addition, the cytotoxic and Na<sup>+</sup>/K<sup>+</sup>-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<sup>+</sup>/K<sup>+</sup>-ATPase but not by interacting with glucose transporters.