School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, PR China; The Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, PR China.
School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, PR China.
Eur J Med Chem. 2019 Apr 15;168:515-526. doi: 10.1016/j.ejmech.2019.02.054. Epub 2019 Feb 21.
In an effort to develop anticancer agents that may overcome drug resistance, the number one reason in caner death, we have developed a series of novel hybrids of β-carboline and N-hydroxycinnamamide as histone deacetylase (HDAC) inhibitors. Most of the hybrids 13a-p showed strong antiproliferative effects with low-micromolar IC values against four human cancer cells. The most potent compound of series 13p exhibited high HDAC1/6 inhibitory effects, and also increased the acetylation levels of histone H3, H4 and α-tubulin. Importantly, 13p demonstrated high anticancer potency against drug-sensitive HepG2 and Bel7402 cells and drug-resistant Bel7402/5FU cells. Hybrid 13p triggered significant apoptosis by regulating apoptotic relative proteins expression in these Bel7402/5FU cells. Finally, 13p induced a substantial amount of autophagic flux activity by the accretion of the expression of LC3-II and the degeneration of expression of p62 and LC3-I in Bel7402/5FU cells. Overall, 13p is a novel β-carboline/N-hydroxycinnamamide hybrid with significant anticancer potency that warrants further evaluation for the treatment of drug-resistant hepatocellular carcinoma.
为了开发可能克服癌症耐药性的抗癌药物（癌症死亡的首要原因），我们设计并合成了一系列新型β-咔啉与 N-羟基肉桂酰胺的杂合体作为组蛋白去乙酰化酶（HDAC）抑制剂。大多数杂合体 13a-p 对四种人癌细胞表现出强烈的增殖抑制作用，其 IC50 值均在低微摩尔范围内。该系列中活性最强的化合物 13p 对 HDAC1/6 具有高抑制作用，同时增加了组蛋白 H3、H4 和 α-微管蛋白的乙酰化水平。重要的是，化合物 13p 对敏感的 HepG2 和 Bel7402 细胞以及耐药的 Bel7402/5FU 细胞均表现出高抗癌活性。化合物 13p 通过调节 Bel7402/5FU 细胞中凋亡相关蛋白的表达，引发了显著的细胞凋亡。最后，化合物 13p 通过 LC3-II 的表达增加和 p62、LC3-I 的表达减少，在 Bel7402/5FU 细胞中诱导了大量自噬流活性。总之，化合物 13p 是一种具有显著抗癌活性的新型β-咔啉/N-羟基肉桂酰胺杂合体，值得进一步研究用于治疗耐药性肝癌。
