期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 24, 期 4, 页码 1071-1074出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2014.01.008
关键词
PCA-1; ALKBH3; Inhibitor; Anti-prostate cancer drug; Small compound; Bioavailability
资金
- Program for Promotion of Fundamental Sciences in Health Sciences of the National Institute of Biomedical Innovation (NIBIO)
- Knowledge Cluster Initiative (Second Stage) of the Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Grants-in-Aid for Scientific Research [25430114, 23701037, 23510284] Funding Source: KAKEN
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. (C) 2014 Elsevier Ltd. All rights reserved.
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