探索新的组蛋白脱乙酰酶6抑制剂及其逆转甲基苯丙胺引起的α-微管蛋白脱乙酰化和细胞形态变化的作用。

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL
Sunil K. Gupta, Khan Hashim Ali, Sooyeun Lee, Young Ho Seo
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引用次数: 0

摘要

合成了具有新的锌结合修饰的基于吲唑的HDAC6抑制剂,并对其进行了评估,以确定其抑制HDAC6的潜力。对类似物进行组蛋白脱乙酰酶(HDAC)测定,从而鉴定化合物3a和3b。这两种化合物作为HDAC6抑制剂表现出更高的效力和选择性,IC50值分别为9.1 nM和9.0 nM,并突出了异羟肟酸部分在HDAC酶的催化袋内与Zn2+结合的重要性。在神经母细胞瘤SH-SY5Y细胞系中,在0.5µM的低浓度下,两种化合物都有效地乙酰化了α-微管蛋白,但没有乙酰化组蛋白H3。此外,化合物3a和3b有效地逆转了由甲基苯丙胺引起的SH-SY5 Y细胞系α-微管素的脱乙酰化,表明HDAC6选择性抑制通过逆转甲基苯丙胺诱导的脱乙酰作用在恢复血脑屏障完整性方面的潜在作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Exploring new histone deacetylase 6 inhibitors and their effects on reversing the α-tubulin deacetylation and cell morphology changes caused by methamphetamine

Exploring new histone deacetylase 6 inhibitors and their effects on reversing the α-tubulin deacetylation and cell morphology changes caused by methamphetamine

Indazole-based HDAC6 inhibitors with novel zinc-binding modifications were synthesized and evaluated to determine their potential to inhibit HDAC6. The analogs were subjected to a histone deacetylase (HDAC) enzyme assay, which led to identification of compounds 3a and 3b. Both compounds demonstrated higher potency and selectivity as HDAC6 inhibitors with IC50 values of 9.1 nM and 9.0 nM, respectively, and highlighted the importance of the hydroxamic acid moiety for binding to Zn2+ inside the catalytic pocket of HDAC enzymes. In the neuroblastoma SH-SY5Y cell line, both compounds efficiently acetylated α-tubulin but not histone H3 at a low concentration of 0.5 µM. Moreover, compounds 3a and 3b effectively reversed the deacetylation of α-tubulin caused by methamphetamine in the SH-SY5Y cell line, suggesting the potential usefulness of HDAC6 selective inhibition in restoring blood brain barrier integrity by reversing methamphetamine-induced deacetylation.

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来源期刊
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
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