基于 3-羟基吡啶-2-硫酮的组蛋白去乙酰化酶抑制剂的合成与构效关系研究。
Synthesis and structure-activity relationship of 3-hydroxypyridine-2-thione-based histone deacetylase inhibitors.
机构信息
School of Chemistry and Biochemistry, ‡Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology , Atlanta, Georgia 30332-0400, United States.
出版信息
J Med Chem. 2013 Dec 27;56(24):9969-81. doi: 10.1021/jm401225q. Epub 2013 Dec 12.
Abstract
We previously identified 3-hydroxypyridine-2-thione (3HPT) as a novel zinc binding group for histone deacetylase (HDAC) inhibition. Early structure-activity relationship (SAR) studies led to various small molecules possessing selective inhibitory activity against HDAC6 or HDAC8 but devoid of HDAC1 inhibition. To delineate further the depth of the SAR of 3HPT-derived HDAC inhibitors (HDACi), we have extended the SAR studies to include the linker region and the surface recognition group to optimize the HDAC inhibition. The current efforts resulted in the identification of two lead compounds, 10d and 14e, with potent HDAC6 and HDAC8 activities that are inactive against HDAC1. These new HDACi possess anticancer activities against various cancer cell lines including Jurkat J.γ1 for which SAHA and the previously disclosed 3HPT-derived HDACi were inactive.
摘要
我们之前发现 3-羟基吡啶-2-硫酮（3HPT）是一种新型锌结合基团，可抑制组蛋白去乙酰化酶（HDAC）。早期的结构-活性关系（SAR）研究导致了各种具有选择性抑制 HDAC6 或 HDAC8 活性但不抑制 HDAC1 的小分子。为了进一步阐明 3HPT 衍生的 HDAC 抑制剂（HDACi）的 SAR 深度，我们扩展了 SAR 研究，包括连接区域和表面识别基团，以优化 HDAC 抑制。目前的努力确定了两种先导化合物 10d 和 14e，它们对 HDAC6 和 HDAC8 具有很强的抑制活性，对 HDAC1 没有活性。这些新的 HDACi 对包括 Jurkat J.γ1 在内的各种癌细胞系具有抗癌活性，而 SAHA 和之前公开的 3HPT 衍生的 HDACi 对 Jurkat J.γ1 没有活性。
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8
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10
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