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

Bioorg Med Chem. 2020 Feb 15;28(4):115301. doi: 10.1016/j.bmc.2019.115301.

Yulin Ren ¹, Qingwei Tan ¹, Kimberly Heath ², Sijin Wu ¹, James R Wilson ¹, Jinhong Ren ³, Pratik Shriwas ⁴, Chunhua Yuan ⁵, Tran Ngoc Ninh ⁶, Hee-Byung Chai ¹, Xiaozhuo Chen ⁷, Djaja D Soejarto ⁸, Michael E Johnson ⁹, Xiaolin Cheng ¹, Joanna E Burdette ², A Douglas Kinghorn ¹⁰

Affiliations

1 Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States.
2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States.
3 Center for Biomolecular Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States.
4 Department of Biological Sciences, Ohio University, Athens, OH 45701, United States; Edison Biotechnology Institute, Ohio University, Athens, OH 45701, United States; Molecular and Cellular Biology Program, Ohio University, Athens, OH 45701, United States.
5 Campus Chemical Instrument Center, The Ohio State University, Columbus, OH 43210, United States.
6 Institute of Ecology and Biological Resources, Vietnam Academy of Science and Technology, Hoang Quoc Viet, Cau Giay, Hanoi, Viet Nam.
7 Department of Biological Sciences, Ohio University, Athens, OH 45701, United States; Edison Biotechnology Institute, Ohio University, Athens, OH 45701, United States; Molecular and Cellular Biology Program, Ohio University, Athens, OH 45701, United States; Department of Biomedical Sciences, Ohio University, Athens, OH 45701, United States.
8 Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States; Science and Education, Field Museum of Natural History, Chicago, IL 60605, United States.
9 Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States; Center for Biomolecular Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States.
10 Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States. Electronic address: kinghorn.4@osu.edu.

PMID: 31953129 DOI: 10.1016/j.bmc.2019.115301

Abstract

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.

Keywords

Cardiac glycosides; Cytotoxicity; Docking profiles; Glucose transport inhibition; Na(+)/K(+)-ATPase inhibition; Streblus asper.

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