bufadienolide and Prostatic-Neoplasms

Molecular docking studies have shown that Δ(8,14)-anhydrobufalin (1) exhibited more potent binding affinity on androgen receptor (AR) than Δ(14,15)-anhydrobufalin (2) and bufalin (3). To validate the docking results, compounds 1 and 2 were synthesized. The AR competitive binding assay indicated that the IC50 values of 1-3 were 1.9, >50 and >50μM (relative binding affinity), respectively, which confirmed that our theoretical binding mode was reliable and predictable. Furthermore, compound 1 was found to show more potent inhibitory activity against the androgen dependent LNCaP cancer cells than the androgen independent PC3 cancer cells, but exhibited less inhibition on the Na(+)/K(+) ATPase as compared with the parent compound 3. To the best of our knowledge, compound 1 represented the first AR antagonist derived from bufadienolide discovered through a series of combined approaches of molecular docking and actual experimental validation.

Topics: Amino Acid Sequence; Androgen Receptor Antagonists; Binding, Competitive; Bufanolides; Cell Line, Tumor; Chromatography, High Pressure Liquid; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Hydrophobic and Hydrophilic Interactions; Male; Models, Molecular; Molecular Sequence Data; Prostatic Neoplasms; Receptors, Androgen; Sequence Alignment