Anti-tumor activity of new orally bioavailable 2-amino-5-(thiophen-2-yl) benzamide-series histone deacetylase inhibitors, possessing an aqueous soluble functional group as a surface recognition domain
Anti-tumor activity of new orally bioavailable 2-amino-5-(thiophen-2-yl) benzamide-series histone deacetylase inhibitors, possessing an aqueous soluble functional group as a surface recognition domain
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DOI：
10.1016/j.bmcl.2012.01.053
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发表时间：
2012-03-01
影响因子：
2.7
通讯作者：
Uesato, Shinichi
中科院分区：
文献类型：
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作者：
Hirata, Yoshiyuki;Hirata, Masahiko;Uesato, Shinichi
合成了新的口服生物有效的5-噻吩-2-基取代的2-氨基苯甲酰胺类组蛋白去乙酰化酶抑制剂。这些化合物具有吗啉或哌啶衍生的部分作为水溶性官能团。其中，具有4-乙基-2，3-二氧代哌嗪-1-甲酰胺基团作为表面识别结构域的8b显示出对HCT 116细胞生长和HDAC 1/2的有希望的抑制活性。值得注意的是，与MS-275不同，该化合物在细胞周期试验中不诱导细胞凋亡。因此，我们在裸鼠中进行了8b和MS-275对HCT 116细胞异种移植物的抗肿瘤试验。化合物8b在45和80 mg/kg下分别在16天内将肿瘤块的体积减小至T/C：60%和47%。这些值与MS-275的比率（T/C：45 mg/kg时为51%）相当。此外，8b在45或80 mg/kg剂量下均未诱导体重减轻，这在给予45 mg/kg MS-275的小鼠中观察到。(c)2012爱思唯尔有限公司保留所有权利。
New orally bioavailable 5-(thiophen-2-yl)-substituted 2-aminobenzamide-series histone deacetylase inhibitors were synthesized. These compounds possess a morpholine or piperadine-derived moiety as an aqueous soluble functional group. Among them, 8b, having a 4-ethyl-2,3-dioxopiperazine-1-carboxamide group as a surface recognition domain, showed promising inhibitory activities against HCT116 cell growth and HDAC1/2. Notably, unlike MS-275, this compound did not induce apoptosis in the cell cycle tests. We therefore conducted antitumor tests of 8b and MS-275 against HCT116 cell xenografts in nude mice. Compound 8b reduced the volume of tumor mass to T/C: 60% and 47% at 45 and 80 mg/kg over 16 days, respectively. These values were comparable to the rate (T/C: 51% at 45 mg/kg) for MS-275. Furthermore, 8b, at neither 45 nor 80 mg/kg, induced the weight loss which was observed in the mice given MS-275 at 45 mg/kg. (c) 2012 Elsevier Ltd. All rights reserved.