新型高活性泛组蛋白去乙酰化酶（pan-HDAC）抑制剂的设计与合成。
Design and synthesis of novel and highly-active pan-histone deacetylase (pan-HDAC) inhibitors.
机构信息
Nippon Pharmaceutical Chemicals Co., Ltd, 2-8-18 Chodo, Higashi-Osaka, Osaka 577-0056, Japan.
Nippon Pharmaceutical Chemicals Co., Ltd, 2-8-18 Chodo, Higashi-Osaka, Osaka 577-0056, Japan.
出版信息
Bioorg Med Chem. 2014 Jul 15;22(14):3720-31. doi: 10.1016/j.bmc.2014.05.001. Epub 2014 May 14.
Histone deacetylase (HDAC) inhibitions are known to elicit anticancer effects. We designed and synthesized several HDAC inhibitors. Among these compounds, compound 40 exhibited a more than 10-fold stronger inhibitory activity compared with that of suberoylanilide hydroxamic acid (SAHA) against each human HDAC isozyme in vitro (IC50 values of 40: HDAC1, 0.0038μM; HDAC2, 0.0082μM; HDAC3, 0.015μM; HDAC8, 0.0060μM; HDAC4, 0.058μM; HDAC9, 0.0052μM; HDAC6, 0.058μM). The dose of the administered HDAC inhibitors that contain hydroxamic acid as the zinc-binding group may be reduced by 40. Because the carbostyril subunit is a time-tested structural component of drugs and biologically active compounds, 40 most likely exhibits good absorption, distribution, metabolism, excretion, and toxicity (ADMET). Thus, compound 40 is expected to be a promising therapeutic agent or chemical tool for the investigation of life process.
组蛋白去乙酰化酶（HDAC）抑制剂已被证实具有抗癌作用。我们设计并合成了几种 HDAC 抑制剂。在这些化合物中，化合物 40 对体外的每一种人源 HDAC 同工酶的抑制活性均比丁酸钠（SAHA）强 10 多倍（IC50 值为 40：HDAC1，0.0038μM；HDAC2，0.0082μM；HDAC3，0.015μM；HDAC8，0.006μM；HDAC4，0.058μM；HDAC9，0.0052μM；HDAC6，0.058μM）。含有作为锌结合基团的羟肟酸的 HDAC 抑制剂的给药剂量可能会降低 40。由于卡波斯坦部分是药物和生物活性化合物的经过时间考验的结构组成部分，因此 40 很可能具有良好的吸收、分布、代谢、排泄和毒性（ADMET）。因此，化合物 40 有望成为研究生命过程的有前途的治疗剂或化学工具。
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