Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, PR China.
J Med Chem. 2011 Aug 11;54(15):5532-9. doi: 10.1021/jm200577a. Epub 2011 Jul 11.
Histone deacetylase (HDAC) has emerged as an attractive target for the development of antitumor agents during the past decade. Previously tetrahydroisoquinoline-bearing hydroxamic acid analogue, ZYJ-25e (1), was identified and validated as a potent histone deacetylase inhibitor (HDACi) with marked in vitro and in vivo antitumor potency. In the present study, further modification of 1 led to another more potent, orally active HDACi, ZYJ-34c (4). Compared to FDA-approved drug suberoylanilide hydroxamic acid (SAHA), compound 4 exhibited higher in vivo antitumor potency in a human breast carcinoma (MDA-MB-231) xenograft model and in a mouse hepatoma-22 (H22) pulmonary metastasis model and similar in vivo antitumor potency in a human colon tumor (HCT116) xenograft model.
在过去的十年中，组蛋白去乙酰化酶 (HDAC) 已成为抗肿瘤药物开发的一个有吸引力的靶点。先前，带有四氢异喹啉的羟肟酸类似物 ZYJ-25e（1）被鉴定并验证为一种具有显著体外和体内抗肿瘤活性的强效组蛋白去乙酰化酶抑制剂 (HDACi)。在本研究中，对 1 进行了进一步修饰，得到了另一种更有效的、具有口服活性的 HDACi ZYJ-34c（4）。与美国食品和药物管理局批准的药物丙戊酰苯胺羟肟酸 (SAHA) 相比，化合物 4 在人乳腺癌（MDA-MB-231）异种移植模型和小鼠肝癌-22（H22）肺转移模型中表现出更高的体内抗肿瘤活性，并且在人结肠肿瘤（HCT116）异种移植模型中具有相似的体内抗肿瘤活性。
