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
  • 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: [email protected].
  • 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: [email protected].
  • 5. School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, PR China. Electronic address: [email protected].
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.