新型异吲哚啉类组蛋白去乙酰化酶抑制剂的设计、合成及构效关系。
The design, synthesis and structure-activity relationships of novel isoindoline-based histone deacetylase inhibitors.
机构信息
Novartis Institutes for Biomedical Research, Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
出版信息
Bioorg Med Chem Lett. 2011 Aug 15;21(16):4909-12. doi: 10.1016/j.bmcl.2011.06.015.
The design, synthesis and biological evaluation of a novel series of isoindoline-based hydroxamates is described. Several analogs were shown to inhibit HDAC1 with IC(50) values in the low nanomolar range and inhibit cellular proliferation of HCT116 human colon cancer cells in the sub-micromolar range. The cellular potency of compound 17e was found to have greater in vitro anti-proliferative activity than several compounds in late stage clinical trials for the treatment of cancer. The in vitro safety profiles of selected compounds were assessed and shown to be suitable for further lead optimization.
本研究描述了一系列新型异吲哚啉类羟肟酸的设计、合成和生物评价。研究表明，几种类似物能够以低纳摩尔浓度抑制 HDAC1，并以亚微摩尔浓度抑制 HCT116 人结肠癌细胞的增殖。化合物 17e 的细胞效力被发现比几种处于临床后期的用于癌症治疗的化合物具有更强的体外抗增殖活性。对选定化合物的体外安全性概况进行了评估，结果表明它们适合进一步进行先导化合物优化。
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