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Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines
Journal of Enzyme inhibition and Medicinal Chemistry ( IF 5.6 ) Pub Date : 2020-10-26 , DOI: 10.1080/14756366.2020.1835883
Susanna Nencetti 1 , Doretta Cuffaro 1 , Elisa Nuti 1 , Lidia Ciccone 1 , Armando Rossello 1, 2 , Marina Fabbi 3 , Flavio Ballante 4 , Gabriella Ortore 1 , Grazia Carbotti 3 , Francesco Campelli 3 , Irene Banti 1 , Rosaria Gangemi 3 , Garland R. Marshall 4 , Elisabetta Orlandini 2, 5
Affiliation  

Abstract

Uveal melanoma (UM) represents an aggressive type of cancer and currently, there is no effective treatment for this metastatic disease. In the last years, histone deacetylase inhibitors (HDACIs) have been studied as a possible therapeutic treatment for UM, alone or in association with other chemotherapeutic agents. Here we synthesised a series of new HDACIs based on the SAHA scaffold bearing an (arylidene)aminoxy moiety. Their HDAC inhibitory activity was evaluated on isolated human HDAC1, 3, 6, and 8 by fluorometric assay and their binding mode in the catalytic site of HDACs was studied by molecular docking. The most promising hit was the quinoline derivative VS13, a nanomolar inhibitor of HDAC6, which exhibited a good antiproliferative effect on UM cell lines at micromolar concentration and a capability to modify the mRNA levels of HDAC target genes similar to that of SAHA.



中文翻译:

葡萄膜黑色素瘤细胞系中具有(芳基)氨氧基支架的组蛋白脱乙酰基酶抑制剂的鉴定

摘要

葡萄膜黑色素瘤(UM)代表一种侵略性癌症,目前,尚无针对这种转移性疾病的有效治疗方法。在过去的几年中,已经研究了组蛋白脱乙酰基酶抑制剂(HDACIs)作为UM的一种可能的治疗方法,可以单独使用或与其他化学治疗剂联合使用。在这里,我们基于带有(亚芳基)氨氧基部分的SAHA支架合成了一系列新的HDACI。通过荧光测定法对分离的人类HDAC1、3、6和8评估了它们的HDAC抑制活性,并通过分子对接研究了它们在HDAC催化位点的结合模式。最有希望的产品是喹啉衍生物VS13,一种HDAC6的纳摩尔抑制剂,在微摩尔浓度下对UM细胞系表现出良好的抗增殖作用,并且具有与SAHA类似的修饰HDAC靶基因mRNA水平的能力。

更新日期:2020-11-25
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