基于二酮哌嗪骨架的选择性HDAC6抑制剂的设计、合成及生物活性研究

Malignant tumor is one of the diseases that severely harm the public health. Aberrant expression of histone deacetylase (HDAC) is closely associated with precancerous or malignant states. However, current clinical HDAC inhibitors are unselective which usually yield undesired toxic side effect. The selective inhibition of HDAC6 has proved to be an efficient approach for the cancer treatment and leads to less toxicity. In our previous study, a series of novel derivatives containing natural 2, 5-diketopiperazine (DKP) skeleton had been synthesized. Among these, compound I-2 exhibited distinct HDAC6 selectivity and obvious antiproliferative activity against several solid tumors. Further structural modification of I-2 is aimed to improve solubility and drug-likeness. Pharmacological and pharmacokinetic properties of I-2 will be evaluated to discovery an efficient and low-toxicity HDAC6 inhibitor for use in cancer treatment.

恶性肿瘤是当前危害人类健康的主要疾病之一，而组蛋白去乙酰化酶 （histone deacetylase,HDAC）的过度表达与肿瘤的发生和发展密切相关。目前临床上的HDAC抑制剂大部分为泛抑制剂，具有明显的毒副作用。研究表明选择性地抑制HDAC6既保证抗肿瘤效果，又能减少毒性。申请人在活性天然产物骨架2,5-二酮哌嗪的基础上，设计并合成了结构新颖的选择性HDAC6抑制剂。其中，化合物I-2展现了良好的亚型选择性，且对部分实体瘤细胞株具有明显的抗增殖活性。在此基础上，本项目拟对I-2进行结构修饰，改善溶解性，提高类药性，结合药理药代评价，以期发现高效低毒的HDAC6抑制剂应用于抗肿瘤研究。

组蛋白去乙酰化酶6（HDAC6）抑制剂广泛应用于癌症，抗炎，神经代谢性疾病等领域。本项目结合计算机辅助药物设计，类药性筛选，设计并合成了一类含有二酮哌嗪骨架的化合物。其中化合物21b对HDAC6的活性达到了0.73nM，且对HDAC亚型展现了良好的选择性。体外肝微粒体实验结果表明其具有较好的结构稳定性。体外细胞筛选表明其与阿霉素有协同抗癌作用。神经细胞活性结果表明二酮哌嗪类及衍生的吲哚哌嗪类化合物具有较好的神经营养作用，展现了较好的抗AD潜力。