Planta Med 2017; 83(12/13): 1035-1043
DOI: 10.1055/s-0043-109557
Natural Product Chemistry and Analytical Studies
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Production of the Cytotoxic Cardenolide Glucoevatromonoside by Semisynthesis and Biotransformation of Evatromonoside by a Digitalis lanata Cell Culture[*]

Jennifer Munkert1, **, Marina Santiago Franco2, **, Elke Nolte3, Izabella Thaís Silva2, Rachel Oliveira Castilho2, Flaviano Melo Ottoni2, Naira F. Z. Schneider4, Mônica C. Oliveira2, Helge Taubert3, Walter Bauer5, Saulo F. Andrade6, Ricardo J. Alves2, Cláudia M. O. Simões4, Fernão C. Braga2, Wolfgang Kreis1, Rodrigo Maia de Pádua2
  • 1Department of Biology, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Germany
  • 2Department of Pharmacy, Universidade Federal of Minas Gerais, Belo Horizonte, Brazil
  • 3Department of Urology, Universitätsklinikum Erlangen, Erlangen, Germany
  • 4Department of Pharmaceutical Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil
  • 5Department of Chemistry and Pharmacy, Friedrich-Alexander Universität, Erlangen-Nürnberg, Germany
  • 6Department of Pharmaceutical Sciences, Universidade Federal de Rio Grande do Sul, Porto Alegre, Brazil
Further Information

Publication History

received 31 January 2017
revised 31 March 2017

accepted 12 April 2017

Publication Date:
09 May 2017 (eFirst)

Abstract

Recent studies demonstrate that cardiac glycosides, known to inhibit Na+/K+-ATPase in humans, have increased susceptibility to cancer cells that can be used in tumor therapy. One of the most promising candidates identified so far is glucoevatromonoside, which can be isolated from the endangered species Digitalis mariana ssp. heywoodii. Due to its complex structure, glucoevatromonoside cannot be obtained economically by total chemical synthesis. Here we describe two methods for glucoevatromonoside production, both using evatromonoside obtained by chemical degradation of digitoxin as the precursor. 1) Catalyst-controlled, regioselective glycosylation of evatromonoside to glucoevatromonoside using 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide as the sugar donor and 2-aminoethyldiphenylborinate as the catalyst resulted in an overall 30 % yield. 2) Biotransformation of evatromonoside using Digitalis lanata plant cell suspension cultures was less efficient and resulted only in overall 18 % pure product. Structural proof of products has been provided by extensive NMR data. Glucoevatromonoside and its non-natural 1–3 linked isomer neo-glucoevatromonoside obtained by semisynthesis were evaluated against renal cell carcinoma and prostate cancer cell lines.

* Dedicated to Professor Dr. Max Wichtl in recognition of his outstanding contribution to pharmacognosy research.


** These authors contributed equally to this manuscript.


Supporting Information