2. Academic Validation
  3. Discovery of novel antitumor dibenzocyclooctatetraene derivatives and related biphenyls as potent inhibitors of NF-κB signaling pathway

Discovery of novel antitumor dibenzocyclooctatetraene derivatives and related biphenyls as potent inhibitors of NF-κB signaling pathway

  • Bioorg Med Chem. 2014 Jan 1;22(1):325-33. doi: 10.1016/j.bmc.2013.11.018.
Fang-Lin Yu 1,  Xiao-Yang He 2,  Chunping Gu 3,  Emika Ohkoshi 4,  Li-Ting Wang 4,  Sheng-Biao Wang 1,  Chin-Yu Lai 4,  Le Yu 3,  Susan L Morris-Natschke 4,  Kuo-Hsiung Lee 5,  Shuwen Liu 6,  Lan Xie 7
Affiliations

Affiliations

  • 1 Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
  • 2 Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China; Beijing Institute of Radiation Medicine, Beijing 100850, China.
  • 3 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 4 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 5 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan. Electronic address: khlee@unc.edu.
  • 6 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: liusw@smu.edu.cn.
  • 7 Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: lanxieshi@yahoo.com.
PMID: 24315191 DOI: 10.1016/j.bmc.2013.11.018
Abstract

Several dibenzocyclooctatetraene derivatives (5-7) and related biphenyls (8-11) were designed, synthesized, and evaluated for inhibition of Cancer cell growth and the NF-κB signaling pathway. Compound 5a, a dibenzocyclooctatetraene succinimide, was discovered as a potent inhibitor of the NF-κB signaling pathway with significant antitumor activity against several human tumor cell lines (GI₅₀ 1.38-1.45 μM) and was more potent than paclitaxel against the drug-resistant KBvin cell line. Compound 5a also inhibited LPS-induced NF-κB activation in RAW264.7 cells with an IC₅₀ value of 0.52 μM, prevented IκB-α degradation and p65 nuclear translocation, and suppressed LPS-induced NO production in a dose-dependent manner. The antitumor data in cellular assays indicated that relative positions and types of substituents on the dibenzocyclooctatetraene or acyclic biphenyl as well as torsional angles between the two phenyls are of primary importance to antitumor activity.

Keywords

Anticancer agents; Dibenzocyclooctatetraene derivatives; NF-κB inhibitor; Unsymmetrical biphenyls.

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