Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs

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• 作者：Syuhei Nakao ; Miyuki Mabuchi ; Tadashi Shimizu ; Yoshihiro Itoh ; Yuko Takeuchi ; Masahiro Ueda ; Hiroaki Mizuno ; Naoko Shigi ; Ikumi Ohshio ; Kentaro Jinguji ; Yuko Ueda ; Masatatsu Yamamoto ; Tatsuhiko Furukawa ; Shunji Aoki ; Kazutake Tsujikawa ; Akito Tanaka
• 关键词：PCA-1 ; ALKBH3 ; Inhibitor ; Anti-prostate cancer drug ; Small compound ; Bioavailability
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：15 February, 2014
• 年：2014
• 卷：24
• 期：4
• 页码：1071-1074
• 全文大小：353 K

文摘

A series of 1-aryl-3,4-substituted-1H-pyrazol-5-ol derivatives was synthesized and evaluated as prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors to obtain a novel anti-prostate cancer drug. After modifying 1-(1H-benzimidazol-2-yl)-3,4-dimethyl-1H-pyrazol-5-ol (1), a hit compound found during random screening using a recombinant PCA-1/ALKBH3, 1-(1H-5-methylbenzimidazol-2-yl)-4-benzyl-3-methyl-1H-pyrazol-5-ol (35, HUHS015), was obtained as a potent PCA-1/ALKBH3 inhibitor both in vitro and in vivo. The bioavailability (BA) of 35 was 7.2% in rats after oral administration. As expected, continuously administering 35 significantly suppressed the growth of DU145 cells, which are human hormone-independent prostate cancer cells, in a mouse xenograft model without untoward effects.