title: A bufadienolide derived androgen receptor antagonist with inhibitory activities against prostate cancer cells.
abstract: 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.
authors.affiliation: Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Tian
authors.affiliation: Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Yuan
authors.affiliation: Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
authors.forename: Lu
authors.initials: L
authors.lastname: Jin
authors.affiliation: Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.affiliation: Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China. Electronic address: chyewc@gmail.com.
authors.forename: Wen-Cai
authors.initials: WC
authors.lastname: Ye
authors.affiliation: Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China. Electronic address: trwjiang@jnu.edu.cn.
authors.forename: Ren-Wang
authors.initials: RW
authors.lastname: Jiang
mesh_terms: D000595:Amino Acid Sequence; D059002:Androgen Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002018:Bufanolides / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions / Q000187:drug effects; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D059002:Androgen Receptor Antagonists; D002018:Bufanolides; D011944:Receptors, Androgen; C087925:bufadienolide
keywords: Androgen receptor; Antagonist; Bufadienolide; Molecular docking; Na(+)/K(+) ATPase