Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs
Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs
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DOI：
10.1016/j.bmcl.2014.01.008
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发表时间：
2014-02-15
影响因子：
2.7
通讯作者：
Tanaka, Akito
中科院分区：
文献类型：
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作者：
Nakao, Syuhei;Mabuchi, Miyuki;Tanaka, Akito
合成了一系列1-芳基-3，4-取代-1H-吡唑-5-醇衍生物，并对其作为前列腺癌抗原-1(PCA-1/ALKBH3)抑制剂进行了评价，以获得一种新型的抗前列腺癌药物。对1-(1H-benzimidazol-2-yl)-3，4-dimethyl-1H-pyrazol-5-ol(1)进行修饰后，得到了一种在体内外均能抑制PCa-1/ALKBH3的活性的化合物1-(1H-5-methylbenzimidazol-2-yl)-4-benzyl-3-methyl-1H-吡唑-5-醇(35，HUHS015)。大鼠口服35的生物利用度(BA)为7.2%。正如预期的那样，在小鼠异种移植模型中，连续注射35显著抑制了DU145细胞的生长，DU145细胞是人类激素非依赖性的前列腺癌细胞，没有不良反应。(C)2014爱思唯尔有限公司。保留所有权利。
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.