NSC-319745异羟肟酸衍生物作为DNMT和HDAC抑制剂的设计，合成和抗癌潜力,European Journal of Medicinal Chemistry

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NSC-319745异羟肟酸衍生物作为DNMT和HDAC抑制剂的设计，合成和抗癌潜力
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2017-04-16 13:01:31
Zigao Yuan, Qinsheng Sun, Dan Li, Shuangshuang Miao, Shaopeng Chen, Lu Song, Chunmei Gao, Yuzong Chen, Chunyan Tan, Yuyang Jiang

DNA甲基转移酶（DNMT）和组蛋白脱乙酰基酶（HDAC）是抗癌药物开发过程中重要的表观遗传学靶标。最近的研究表明，DNMT抑制剂和HDAC抑制剂在某些癌症中显示出协同作用，因此，靶向DNMT和HDAC的分子的开发对这些癌症具有治疗优势。根据DNMT抑制剂NSC-319745的结构和HDAC抑制剂的药效团特性，设计并合成了一系列NSC-319745异羟肟酸衍生物，作为DNMT和HDAC多功能抑制剂。大多数化合物显示出潜在的DNMT抑制能力和有效的HDAC抑制活性，尤其是化合物15a表现出比NSC-319745更好的DNMT1抑制能力，并以IC ₅₀抑制HDAC1，HDAC6值分别为57、17 nM。此外，合成的化合物对人癌细胞K562和U937表现出显着的细胞毒性。进一步的机理研究表明，U937中的15a处理可增加组蛋白H3K9和H4K8的乙酰化，促使P16 CpG岛脱甲基并上调P16表达，在细胞水平上调节凋亡相关蛋白的表达，并诱导显着的U937凋亡。此外，评估了代表性化合物的遗传毒性。总而言之，我们的研究提供了针对多种酶的实用药物设计策略，而15a代表了一种新型且有前途的先导化合物，可用于开发新型表观遗传抑制剂作为抗肿瘤药。

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Design, synthesis and anticancer potential of NSC-319745 hydroxamic acid derivatives as DNMT and HDAC inhibitors

DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) are important epigenetic targets during anticancer drug development. Recent study indicates that DNMT inhibitors and HDAC inhibitors display synergistic effects in certain cancers, therefore, development of molecules targeting both DNMT and HDAC is of therapeutic advantage against these cancers. Based on the structure of DNMT inhibitor NSC-319745 and the pharmacophore characteristics of HDAC inhibitors, a series of hydroxamic acid derivatives of NSC-319745 were designed and synthesized as DNMT and HDAC multifunctional inhibitors. Most compounds displayed potential DNMT inhibitory potency and potent HDAC inhibitory activity, especially compound 15a showed much better DNMT1 inhibitory potency than NSC-319745, and inhibited HDAC1, HDAC6 with IC₅₀ values of 57, 17 nM, respectively. Furthermore, the synthesized compounds exhibited significant cytotoxicity against human cancer cells K562 and U937. Further mechanistic studies demonstrated that 15a treatment in U937 increased histones H3K9 and H4K8 acetylation, prompted P16 CpG islands demethylation and upregulated P16 expression, regulated apoptosis-related protein expression on the cellular level and induced remarkable U937 apoptosis. Moreover, genotoxicity of representative compounds was evaluated. In summary, our study provided a practical drug design strategy targeting multiple enzymes, and 15a represents a novel and promising lead compound for the development of novel epigenetic inhibitors as antitumor agents.

更新日期：2017-04-17

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