Balasubramaniam Sivaraman, Vijayan Sajith, Goldman Liam V, May Xavier A, Dodson Kyra, Adhikari Sweta, Rivas Fatima, Watkins Davita L, Stoddard Shana V
Department of Chemistry and Biochemistry, University of Mississippi, University, MS 38677-1848, USA.
Department of Chemistry, Rhodes College, Memphis, TN 38112, USA.
Beilstein J Org Chem. 2020 Apr 7;16:628-637. doi: 10.3762/bjoc.16.59. eCollection 2020.
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 , , and whose biological evaluation confirmed the strength of HDAC8 inhibition with 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.
在计算分析的指导下，我们在此报告了四种新型基于二嗪的组蛋白脱乙酰酶抑制剂（HDACi）的设计、合成和评估。感兴趣的靶点（TOI）是帕比司他的类似物，帕比司他是已报道的最有效和用途最广泛的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HDAC2和HDAC8的对接研究表明，这四种类似物表现出与帕比司他相当的抑制活性。多步合成得到了可视化的靶点、、和，其生物学评估证实了HDAC8抑制的强度，在不同浓度下表现出最大的疗效。本研究结果为未来针对HDAC8同工酶设计更有效的HDACi以及神经母细胞瘤的进一步治疗应用奠定了基础。
