2. Academic Validation
  3. β-Carboline and N-hydroxycinnamamide hybrids as anticancer agents for drug-resistant hepatocellular carcinoma

β-Carboline and N-hydroxycinnamamide hybrids as anticancer agents for drug-resistant hepatocellular carcinoma

  • Eur J Med Chem. 2019 Apr 15:168:515-526. doi: 10.1016/j.ejmech.2019.02.054.
Yong Ling 1,  Wei-Jie Gao 2,  Changchun Ling 3,  Ji Liu 2,  Chi Meng 2,  Jianqiang Qian 2,  Siqun Liu 2,  Huiling Gan 2,  Hongmei Wu 2,  Jinhua Tao 2,  Hong Dai 4,  Yanan Zhang 5
Affiliations

Affiliations

  • 1 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. Electronic address: Lyyy111@sina.com.
  • 2 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, PR China.
  • 3 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.
  • 4 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, PR China; College of Chemistry and Chemical Engineering, Nantong University, Nantong, 226019, PR China. Electronic address: dh123@ntu.edu.cn.
  • 5 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, PR China. Electronic address: zhangyanan@gmail.com.
PMID: 30851694 DOI: 10.1016/j.ejmech.2019.02.054
Abstract

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 IC50 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.

Keywords

Drug resistance; Histone deacetylase inhibitors; Hybrids; N-Hydroxycinnamamide; β-Carbolines.

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