Phosphorus containing analogues of SAHA as inhibitors of HDACs.
Phosphorus containing analogues of SAHA as inhibitors of HDACs.
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DOI：
10.1080/14756366.2022.2063281
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发表时间：
2022-12
影响因子：
5.6
通讯作者：
Berkman CE
中科院分区：
文献类型：
--
作者：
Pun MD;Wu HH;Olatunji FP;Kesic BN;Peters JW;Berkman CE
组蛋白脱乙酰酶（HDAC）是负责通过调节DNA与组蛋白的结合来调节DNA转录的酶家族。HDAC在几种类型的癌症中过表达，并被认为是药物靶标。伏立诺他，或辛二酰异羟肟酸（SAHA），是一种组蛋白脱乙酰酶（HDAC）抑制剂，具有作为锌结合基团（ZBG）的异羟肟酸，已被FDA批准用于治疗T细胞淋巴瘤。在这项工作中，合成了基于磷的SAHA类似物，以评估其与SAHA的异羟肟酸相比的锌结合有效性。具体而言，我们研究了磷酸盐，氨基磷酸酯和硫代磷酸酯基团作为传统HDAC抑制剂的典型异羟肟酸基序的电子等排体。筛选化合物与来自HeLa细胞裂解物的HDAC酶的结合。然后针对HDAC 3和HDAC 8亚型筛选最有效的衍生物。HDAC抑制测定表明，这些基于磷的SAHA类似物表现出与HDAC的缓慢结合，但具有比先前检查的膦酸盐SAHA类似物更大的效力。所有化合物均抑制HDAC，最有效的IC50为50 µM。
Histone deacetylases (HDACs) are a family of enzymes responsible for regulating DNA transcription by modulating its binding to histone proteins. HDACs are overexpressed in several types of cancers and are recognised as drug targets. Vorinostat, or suberanilohydroxamic acid (SAHA), is an histone deacetylase (HDAC) inhibitor with a hydroxamic acid as a zinc-binding group (ZBG), and it has been FDA approved for the treatment of T-cell lymphoma. In this work, phosphorus-based SAHA analogues were synthesised to assess their zinc-binding effectiveness compared to the hydroxamic acid of SAHA. Specifically, we examined phosphate, phosphoramidate and phosphorothiolate groups as isosteres of the canonical hydroxamic acid motif of conventional HDAC inhibitors. The compounds were screened for binding to HDAC enzymes from HeLa cell lysate. The most potent derivatives were then screened against HDAC3 and HDAC8 isoforms. HDAC inhibition assays demonstrated that these phosphorus-based SAHA analogs exhibited slow binding to HDACs but with greater potency than phosphonate SAHA analogs examined previously. All compounds inhibited HDACs, the most potent having an IC50 of 50 µM.
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