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

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.