1. β-Carboline and N-hydroxycinnamamide hybrids as anticancer agents for drug-resistant hepatocellular carcinoma.
- Author
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Ling Y, Gao WJ, Ling C, Liu J, Meng C, Qian J, Liu S, Gan H, Wu H, Tao J, Dai H, and Zhang Y
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Carbolines chemistry, Carcinoma, Hepatocellular pathology, Cell Line, Tumor, Cell Proliferation drug effects, Cinnamates chemistry, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Liver Neoplasms pathology, Molecular Structure, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Carbolines pharmacology, Carcinoma, Hepatocellular drug therapy, Cinnamates pharmacology, Drug Resistance, Neoplasm drug effects, Liver Neoplasms drug therapy
- 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 IC
50 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., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)- Published
- 2019
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