含苯并吲唑或吡唑并吲唑骨架的选择性组蛋白去乙酰化酶 6（HDAC6）抑制剂的设计、合成及生物评价作为表面识别基序。
Design, synthesis and biological evaluation of selective histone deacetylase 6 (HDAC6) inhibitors bearing benzoindazole or pyrazoloindazole scaffold as surface recognition motif.
机构信息
Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China.
出版信息
Bioorg Chem. 2021 Jun;111:104910. doi: 10.1016/j.bioorg.2021.104910. Epub 2021 Apr 20.
A series of compounds were designed and synthesized based on the compound 11i bearing phenylpyrazole scaffold with histone deacetylase 6 (HDAC6) inhibitory activity. Most of the compounds showed considerable inhibitory activity against HDAC6 and compound A16 with good inhibitory activity was found therein. We further found that A16 had an inhibitory effect on inflammatory mediators (NO, TNF-α, IL-6) involved in inflammatory response and neuroendocrine regulation. In addition, A16 has a certain neuroprotective effect on PC12 cells injured by hydrogen peroxide. Acute toxicity assay showed that the LD of A16 was 274.47 mg/kg in mouse model. Furthermore, A16 displayed good stability properties in microsomes and plasma.
基于具有组蛋白去乙酰化酶 6（HDAC6）抑制活性的化合物 11i 中的苯基吡唑骨架，设计并合成了一系列化合物。大多数化合物对 HDAC6 表现出相当大的抑制活性，并且发现其中化合物 A16 具有良好的抑制活性。我们进一步发现 A16 对炎症反应和神经内分泌调节中涉及的炎症介质（NO、TNF-α、IL-6）具有抑制作用。此外，A16 对过氧化氢损伤的 PC12 细胞具有一定的神经保护作用。急性毒性试验表明，A16 在小鼠模型中的 LD 为 274.47mg/kg。此外，A16 在微粒体和血浆中表现出良好的稳定性。
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