二氢吡啶酮类组蛋白去乙酰化酶抑制剂的设计、合成及抗肿瘤活性

Synthesis and anti-tumor activity of novel histone deacetylase inhibitors based on dihydropyridin-2-one scaffold

基于已有的先导结构二氢吡啶酮骨架,为了得到对组蛋白去乙酰化酶（HDAC）抑制活性更强、亚型选择性更高的二氢吡啶酮类HDAC抑制剂,本文利用点击化学合成了27个新型的具有三氮唑结构的二氢吡啶酮类HDAC抑制剂,其结构经过1H NMR和HR-MS确证,并完成了初步的药理活性评价。结果显示,这些化合物均展现出了较强的HDAC1和HDAC6抑制活性以及体外抗肿瘤活性,部分化合物对HDAC1的抑制活性和抗肿瘤活性与先导化合物1A和阳性药物SAHA相比均有提高。尤其是化合物18g不仅对HDAC1展现出了最强的抑制活性,同时对PC-3和Hep G2也有最强的抑制活性。此外,目标化合物对正常的RWPE-1和VERO细胞没有毒性,而SAHA有毒性。

To discover novel dihydropyridin-2-one derivatives with higher HDAC inhibitory activity and subtype selectivity, twenty-seven dihydropyridin-2-one derivatives containing triazole unit were synthesized via click chemistry. The structures of these compounds have been confirmed by IR, ^1H NMR and HR-MS spectra. Preliminary in vitro pharmacological tests showed that these compounds potently inhibited HDAC 1 and HDAC6, which also displayed significant antiproliferative effect on five cancer cells, and most of them were better than that of the parent compound 1A and drug SAHA. Specifically, compound 18g exhibited most potent anti-HDAC1 activity, and also showed the greatest potency against PC-3 and HepG2. Additionally, all compounds were nontoxic to health RWPE-1 and VERO cells, while SAHA showed essential toxicity.