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Synthesis and Pharmacological Evaluation of Selective Histone Deacetylase 6 Inhibitors in Melanoma Models
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-09-11 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00223 Maurício T. Tavares 1 , Sida Shen 1 , Tessa Knox 2 , Melissa Hadley 2 , Zsófia Kutil 3 , Cyril Bařinka 3 , Alejandro Villagra 2 , Alan P. Kozikowski 4
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-09-11 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00223 Maurício T. Tavares 1 , Sida Shen 1 , Tessa Knox 2 , Melissa Hadley 2 , Zsófia Kutil 3 , Cyril Bařinka 3 , Alejandro Villagra 2 , Alan P. Kozikowski 4
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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 analogues 4d, 4e, and 7b bearing 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. Compound 4d exhibits antiproliferative effects on several types of melanoma and lymphoma cells. Further studies indicates that 4d selectively increases acetylated tubulin levels in vitro and elicits an immune response through down-regulating cytokine IL-10. A preliminary in vivo efficacy study indicates that 4d possesses improved capability to inhibit melanoma tumor growth and that this effect is based on the regulation of inflammatory and immune responses.
中文翻译：
黑色素瘤模型中选择性组蛋白去乙酰化酶6抑制剂的合成及药理评价
在黑色素瘤的病例中，只有少数几种疗法可显着改善整体生存率，而黑色素瘤的发病率在过去30年中持续上升。为了确定有效和同工型选择性组蛋白脱乙酰基酶（HDAC）抑制剂作为黑色素瘤的治疗方法，我们制备了一系列基于nexturastat A支架的新型HDAC6抑制剂。带有添加的亲水性取代基的新的类似物4d，4e和7b，以便在HDAC6催化腔的边缘上建立额外的氢键，显示出对HDAC6的增强效力，并保持了对HDAC1的选择性。复合4d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在体外选择性增加乙酰化微管蛋白的水平，并通过下调细胞因子IL-10引发免疫反应。初步的体内功效研究表明4d具有增强的抑制黑素瘤肿瘤生长的能力，并且这种作用是基于炎症和免疫反应的调节。
更新日期：2017-09-11
中文翻译：
黑色素瘤模型中选择性组蛋白去乙酰化酶6抑制剂的合成及药理评价
在黑色素瘤的病例中，只有少数几种疗法可显着改善整体生存率，而黑色素瘤的发病率在过去30年中持续上升。为了确定有效和同工型选择性组蛋白脱乙酰基酶（HDAC）抑制剂作为黑色素瘤的治疗方法，我们制备了一系列基于nexturastat A支架的新型HDAC6抑制剂。带有添加的亲水性取代基的新的类似物4d，4e和7b，以便在HDAC6催化腔的边缘上建立额外的氢键，显示出对HDAC6的增强效力，并保持了对HDAC1的选择性。复合4d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在体外选择性增加乙酰化微管蛋白的水平，并通过下调细胞因子IL-10引发免疫反应。初步的体内功效研究表明4d具有增强的抑制黑素瘤肿瘤生长的能力，并且这种作用是基于炎症和免疫反应的调节。
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