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

• Published in: European journal of medicinal chemistry 2020-09, Vol.202, p.112520, Article 112520
• Main Authors: Michalak, Karol, Rárová, Lucie, Kubala, Martin, Štenclová, Tereza, Strnad, Miroslav, Wicha, Jerzy
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; ATP-ase inhibition; Cardenolides; Cardenolides - chemical synthesis; Cardenolides - chemistry; Cardenolides - pharmacology; Cell Cycle - drug effects; Cell Line; Cell Proliferation - drug effects; Cytotoxicity; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Furan transformation; Humans; Molecular Conformation; Partial synthesis; Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors; Sodium-Potassium-Exchanging ATPase - metabolism; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112520

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. [Display omitted] •The first synthesis of oleandrigenin from easily available steroid developed.•17β-(4-butenolidyl)-, 17β-(3-furyl)-14,16β-dihydroxy-androstanes synthesized.•Na+/K+-ATP-ase inhibitory and cytotoxic activities in vitro of new compounds.•Derivatives 21 and 25 induced strong apoptosis in HeLa cells after 24 h.