Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition
Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition
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DOI：
10.3762/bjoc.16.59
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发表时间：
2020-04-07
影响因子：
2.7
通讯作者：
Stoddard, Shana V.
中科院分区：
文献类型：
--
作者：
Balasubramaniam, Sivaraman;Vijayan, Sajith;Stoddard, Shana V.
在计算分析的指导下，本文报道了四个新的基于二嗪的组蛋白去乙酰化酶抑制剂（HDACis）的设计、合成和评价。感兴趣的靶标（TOI）是帕比司他的类似物，帕比司他是报道的最有效和通用的HDACi之一。通过简单地将帕比司他的苯基核心替换为二嗪衍生物的苯基核心，针对HDAC 2和HDAC 8的对接研究显示，这四种类似物表现出与帕比司他相当的抑制活性。多步合成提供了可视化的靶标TOI 1、TOI 2、TOI 3-rev和TOI 4，其生物学评价证实了HDAC 8抑制的强度，其中TOI 4在不同浓度下显示出最大功效。这项研究的结果奠定了基础，为未来的设计策略，以更有效的HDAC 8同工酶HDACis和进一步的神经母细胞瘤的治疗应用。
Guided by computational analysis, herein we report the design, synthesis and evaluation of four novel diazine-based histone deacetylase inhibitors (HDACis). The targets of interest (TOI) are analogues of panobinostat, one of the most potent and versatile HDACi reported. By simply replacing the phenyl core of panobinostat with that of a diazine derivative, docking studies against HDAC2 and HDAC8 revealed that the four analogues exhibit inhibition activities comparable to that of panobinostat. Multistep syntheses afforded the visualized targets TOI1, TOI2, TOI3-rev and TOI4 whose biological evaluation confirmed the strength of HDAC8 inhibition with TOI4 displaying the greatest efficacy at varying concentrations. The results of this study lay the foundation for future design strategies toward more potent HDACis for HDAC8 isozymes and further therapeutic applications for neuroblastoma.