1. Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs
- Author
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Naoko Shigi, Yuko Ueda, Kentaro Jinguji, Akito Tanaka, Kazutake Tsujikawa, Miyuki Mabuchi, Ikumi Ohshio, Masahiro Ueda, Shunji Aoki, Hiroaki Mizuno, Tadashi Shimizu, Tatsuhiko Furukawa, Syuhei Nakao, Yoshihiro Itoh, Masatatsu Yamamoto, and Yuko Takeuchi
- Subjects
Male ,Clinical Biochemistry ,Pharmaceutical Science ,Administration, Oral ,Antineoplastic Agents ,Pharmacology ,Biochemistry ,law.invention ,Prostate Cancer Antigen 1 ,Prostate cancer ,Structure-Activity Relationship ,DU145 ,law ,Oral administration ,In vivo ,Antigens, Neoplasm ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Molecular Biology ,Cell Proliferation ,Dose-Response Relationship, Drug ,Chemistry ,Organic Chemistry ,Prostatic Neoplasms ,medicine.disease ,In vitro ,Bioavailability ,Rats ,Drug Design ,Recombinant DNA ,Molecular Medicine ,Pyrazoles ,Drug Screening Assays, Antitumor - Abstract
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.
- Published
- 2013