A series of hydroxamic acid-based HDACIs with 4-aminoquinazolinyl moieties as capping groups was profiled. Most compounds showed more potent HDACs inhibition activity than clinically used drug SAHA. Among them, compounds 5f and 5h selectively inhibited HDAC 1,2 over HDAC8, and showed strong activity in several cellular assays, not possessing significant toxicity to primary human cells and hERG inhibition. Strikingly, 5f possessed acceptable pharmacokinetic characteristics and exhibited significant antitumor activity in an A549 xenograft model study at well tolerated doses.

中文翻译：

---

以4-氨基喹唑啉基系统为封端基团的新型组蛋白脱乙酰基酶抑制剂的设计，合成和生物学评价

分析了一系列以4-氨基喹唑啉基部分为封端基的基于异羟肟酸的HDACI。大多数化合物显示出比临床使用的药物SAHA更有效的HDAC抑制活性。其中，化合物5f和5h比HDAC8选择性抑制HDAC 1,2，并且在几种细胞试验中显示出强大的活性，对原代人细胞和hERG的抑制作用不具有明显的毒性。令人惊讶的是，在耐受性良好的A549异种移植模型研究中，5f具有可接受的药代动力学特征并表现出显着的抗肿瘤活性。