2. Academic Validation
  3. Synthesis and evaluation of Na+/K+-ATP-ase inhibiting and cytotoxic in vitro activities of oleandrigenin and its selected 17β-(butenolidyl)- and 17β-(3-furyl)- analogues

Synthesis and evaluation of Na+/K+-ATP-ase inhibiting and cytotoxic in vitro activities of oleandrigenin and its selected 17β-(butenolidyl)- and 17β-(3-furyl)- analogues

  • Eur J Med Chem. 2020 Sep 15:202:112520. doi: 10.1016/j.ejmech.2020.112520.
Karol Michalak 1,  Lucie Rárová 2,  Martin Kubala 3,  Tereza Štenclová 4,  Miroslav Strnad 5,  Jerzy Wicha 6
Affiliations

Affiliations

  • 1 Institute of Organic Chemistry, Polish Academy of Sciences, Ul. Marcina Kasprzaka 44/52, 01-224, Warsaw, Poland.
  • 2 Laboratory of Growth Regulators, Institute of Experimental Botany of the Czech Academy of Sciences, and Faculty of Science, Palacký University, Šlechtitelů 27, CZ-783 71, Olomouc, Czech Republic; Department of Neurology, University Hospital in Olomouc, I. P. Pavlova 6, CZ-775 20, Olomouc, Czech Republic.
  • 3 Department of Experimental Physics, Faculty of Science, Palacký University, Šlechtitelů 27, CZ-783 41, Olomouc, Czech Republic.
  • 4 Laboratory of Growth Regulators, Institute of Experimental Botany of the Czech Academy of Sciences, and Faculty of Science, Palacký University, Šlechtitelů 27, CZ-783 71, Olomouc, Czech Republic.
  • 5 Laboratory of Growth Regulators, Institute of Experimental Botany of the Czech Academy of Sciences, and Faculty of Science, Palacký University, Šlechtitelů 27, CZ-783 71, Olomouc, Czech Republic; Department of Neurology, University Hospital in Olomouc, I. P. Pavlova 6, CZ-775 20, Olomouc, Czech Republic. Electronic address: miroslav.strnad@upol.cz.
  • 6 Institute of Organic Chemistry, Polish Academy of Sciences, Ul. Marcina Kasprzaka 44/52, 01-224, Warsaw, Poland. Electronic address: jerzy.wicha@icho.edu.pl.
PMID: 32645647 DOI: 10.1016/j.ejmech.2020.112520
Abstract

Natural cardiac-active principles built upon the 14,16β-dihydroxy-5β,14β-androstane core and bearing a heterocyclic substituent at 17β, in particular, a cardenolide - oleandrin and a bufadienolide - bufotalin, are receiving a great deal of attention as potential Anticancer drugs. The densely substituted and sterically shielded ring D is the particular structural feature of these compounds. The first synthesis of oleandrigenin from easily available steroid starting material is reported here. Furthermore, selected 17β-(4-butenolidyl)- and 17β-(3-furyl)-14,16β-dihydroxy-androstane derivatives were en route synthesized and examined for their Na+/K+-ATP-ase inhibitory properties as well as cytotoxic activities in normal and Cancer cell lines. It was found that the furyl-analogue of oleandrigenin/bufatalin (7) and some related 17-(3-furyl)- derivatives (19, 21) show remarkably high Na+/K+-ATP-ase inhibitory activity as well as significant cytotoxicity in vitro. In addition, oleandrigenin 2 compared to derivatives 21 and 25 induced strong Apoptosis in human cervical carcinoma HeLa cells after 24 h of treatment.

Keywords

ATP-ase inhibition; Apoptosis; Cardenolides; Cytotoxicity; Furan transformation; Partial synthesis.

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