Design and synthesis of benzodiazepine analogs as isoform-selective human lysine deacetylase inhibitors.
Design and synthesis of benzodiazepine analogs as isoform-selective human lysine deacetylase inhibitors.
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作为异构体选择性人赖氨酸脱乙酰酶抑制剂的苯二氮卓类似物的设计和合成。
DOI：
10.1016/j.ejmech.2016.12.032
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发表时间：
2017
影响因子：
6.7
通讯作者：
Marshall,GarlandR
中科院分区：
文献类型：
--
作者：
Reddy,DRajasekhar;Ballante,Flavio;Zhou,NancyJ;Marshall,GarlandR
本研究对新型苯二氮卓类（BZD）衍生物进行了全面的研究，以确定其为有效的和选择性的人赖氨酸脱乙酰酶抑制剂（hKDAC）。共设计、合成了108个BZD化合物，并从其中104个化合物对人赖氨酸脱乙酰酶（hKDAC）1、3和8（I类）和6（IIb类）进行了生物学评价。最具活性的化合物显示出对hKDAC 1、3和6的中纳摩尔效力和对hKDAC 8的微摩尔活性，而有希望的化合物（6 q）在不同的酶同种型中显示出对hKDAC 3的选择性。通过分子动力学模拟产生了一个hKDAC 6同源性模型，并进行了分子对接研究，以合理化主要的配体-残基相互作用以及定义结构-活性关系。实验结果证实了苯并二氮杂部分在追求hKDAC亚型选择性抑制时作为封端基团的有用性，表明其在设计新的hKDAC时继续使用。
A comprehensive investigation was performed to identify new benzodiazepine (BZD) derivatives as potent and selective human lysine deacetylase inhibitors (hKDACis). A total of 108 BZD compounds were designed, synthesized and from that 104 compounds were biologically evaluated against human lysine deacetylases (hKDACs) 1, 3 and 8 (class I) and 6 (class IIb). The most active compounds showed mid-nanomolar potencies against hKDACs 1, 3 and 6 and micromolar activity against hKDAC8, while a promising compound (6q) showed selectivity towards hKDAC3 among the different enzyme isoforms. An hKDAC6 homology model, refined by molecular dynamics simulation was generated, and molecular docking studies performed to rationalize the dominant ligand-residue interactions as well as to define structure-activity-relationships. Experimental results confirmed the usefulness of the benzodiazepine moiety as capping group when pursuing hKDAC isoform-selectivity inhibition, suggesting its continued use when designing new hKDACis.