title: Design and synthesis of novel androgen receptor antagonists via molecular modeling.
abstract: Several androgen receptor (AR) antagonists are clinically prescribed to treat prostate cancer. Unfortunately, many patients become resistant to the existing AR antagonists. To overcome this, a novel AR antagonist candidate called DIMN was discovered by our research group in 2013. In order to develop compounds with improved potency, we designed novel DIMN derivatives based on a docking study and substituted carbons with heteroatom moieties. Encouraging in vitro results for compounds 1b, 1c, 1e, 3c, and 4c proved that the new design was successful. Among the newly synthesized compounds, 1e exhibited the strongest inhibitory effect on LNCaP cell growth (IC50=0.35μM) and also acted as a competitive AR antagonist with selectivity over the estrogen receptor (ER) and the glucocorticoid receptor (GR). A docking study of compound 1e fully supported these biological results. Compound 1e is considered to be a novel, potent and AR-specific antagonist for treating prostate cancer. Thus, our study successfully applied molecular modeling and bioisosteric replacement for hit optimization. The methods here provide a guide for future development of drug candidates through structure-based drug discovery and chemical modifications.
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: You Hee
authors.initials: YH
authors.lastname: Choi
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Daulat Bikram
authors.initials: DB
authors.lastname: Khadka
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Jin
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: kwanglee@jnu.ac.kr.
authors.forename: Kwang-Youl
authors.initials: KY
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: wjcho@jnu.ac.kr.
authors.forename: Won-Jea
authors.initials: WJ
authors.lastname: Cho
mesh_terms: D020816:Amino Acid Motifs; D059002:Androgen Receptor Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D015195:Drug Design; D015870:Gene Expression; D017930:Genes, Reporter; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009536:Niacinamide / Q000737:chemistry; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism; D017433:Protein Structure, Secondary; D011718:Pyrazinamide / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D011743:Pyrimidines; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D009536:Niacinamide; D011718:Pyrazinamide; D008156:Luciferases
keywords: AR antagonist; Bioisostere; Molecular modeling; Nicotinamide; Pyrazinamide; Pyrimidinamide