Synthesis and Pharmacological Evaluation of Selective Histone Deacetylase 6 Inhibitors in Melanoma Models.
Synthesis and Pharmacological Evaluation of Selective Histone Deacetylase 6 Inhibitors in Melanoma Models.
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黑色素瘤模型中选择性组蛋白脱乙酰酶 6 抑制剂的合成和药理学评价。
DOI：
10.1021/acsmedchemlett.7b00223
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发表时间：
2017
影响因子：
4.2
通讯作者：
Kozikowski,AlanP
中科院分区：
文献类型：
--
作者：
Tavares,MaurícioT;Shen,Sida;Knox,Tessa;Hadley,Melissa;Kutil,Zsófia;Bařinka,Cyril;Villagra,Alejandro;Kozikowski,AlanP
只有少数疗法能显著改善黑色素瘤的总体生存率，这种癌症的发病率在过去30年中持续上升。在我们努力鉴定作为黑色素瘤治疗方法的有效的和亚型选择性组蛋白脱乙酰酶（HDAC）抑制剂的过程中，制备了一系列基于nexturastat A支架的新HDAC 6抑制剂。新的类似物4d、4 e和7 b带有添加的亲水性取代基，以便在HDAC 6催化口袋的边缘上建立额外的氢键，表现出改善的针对HDAC 6的效力并保持对HDAC 1的选择性。化合物4对几种类型的黑色素瘤和淋巴瘤细胞具有抗增殖作用。进一步的研究表明，4d选择性地增加体外乙酰化微管蛋白水平，并通过下调细胞因子IL-10来增强免疫应答。一项体内药效研究表明，4d具有更好的抑制黑色素瘤生长的能力，这种作用是基于炎症和免疫反应的调节。
Only a handful of therapies offer significant improvement in the overall survival in cases of melanoma, a cancer whose incidence has continued to rise in the past 30 years. In our effort to identify potent and isoform-selective histone deacetylase (HDAC) inhibitors as a therapeutic approach to melanoma, a series of new HDAC6 inhibitors based on the nexturastat A scaffold were prepared. The new analogues4d,4e, and7bbearing added hydrophilic substituents, so as to establish additional hydrogen bonding on the rim of the HDAC6 catalytic pocket, exhibit improved potency against HDAC6 and retain selectivity over HDAC1. Compound4dexhibits antiproliferative effects on several types of melanoma and lymphoma cells. Further studies indicates that4dselectively increases acetylated tubulin levelsin vitroand elicits an immune response through down-regulating cytokine IL-10. A preliminaryin vivoefficacy study indicates that4dpossesses improved capability to inhibit melanoma tumor growth and that this effect is based on the regulation of inflammatory and immune responses.