title: Discovery of novel 1,2,3,4-tetrahydrobenzo[4, 5]thieno[2, 3-c]pyridine derivatives as potent and selective CYP17 inhibitors.
abstract: The inhibition of CYP17 to block androgen biosynthesis is a well validated strategy for the treatment of prostate cancer. Herein we reported the design, synthesis and structure-activity relationship (SAR) study for a series of novel 1,2,3,4- tetrahydrobenzo[4,5]thieno[2,3-c]pyridine derivatives. Some analogs demonstrated a potent inhibition to both rat and human CYP17 protein and reduced testosterone production in human H295R cell line. Some analogs also showed high selectivity against other CYP enzymes such as 3A4, 1A2, 2C9, 2C19 and 2D6, which may limit side effects due to drug-drug interactions. Among these analogs, the most potent compound 9c showed 1.5 fold more potent against rat and human CYP17 protein than that of abiraterone (IC50= 16 nM and 20 nM vs. 25 nM and 36 nM respectively). In NCI-H295R cells, the inhibitory effect of compound 9c on testosterone production (52± 2%) was also more potent than that of abiraterone (74± 15%) at the concentration of 1 μM. Further, it was shown that 9c reduced plasma testosterone level in a dose-dependent manner in Sprague-Dawley rats. Thus, analog 9c maybe a potential agent used for the treatment of prostate cancer.
authors.affiliation: Department of Natural Products Chemistry, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Wang
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, PR China.
authors.forename: Yanjia
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, PR China.
authors.forename: Shoulai
authors.initials: S
authors.lastname: Gu
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, PR China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Chen
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, PR China.
authors.forename: Zhengjiang
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Natural Products Chemistry, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China; The Institutes of Integrative Medicine of Fudan University, 12 Middle Urumqi Road, Shanghai 200040, PR China. Electronic address: sunxunf@shmu.edu.cn.
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, PR China. Electronic address: zhujd@sioc.ac.cn.
authors.forename: Jidong
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000097:blood
chemical_list: D000736:Androstenes; D011725:Pyridines; D013739:Testosterone; D013254:Steroid 17-alpha-Hydroxylase; C089740:abiraterone
keywords: Abiraterone; Androgens; CYP17; CYP3A4; Prostate cancer