Synthesis, in vitro anti-inflammatory and cytotoxic evaluation, and mechanism of action studies of 1-benzoyl-β-carboline and 1-benzoyl-3-carboxy-β-carboline derivatives

Mei Lin Yang, Ping Chung Kuo, Tsong Long Hwang, Wen Fei Chiou, Keduo Qian, Chin Yu Lai, Kuo Hsiung Lee, Tian Shung Wu

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)

Abstract

In the present study, various 1-substituted and 1,3-disubstituted β-carboline derivatives were synthesized by a modified single-step Pictet-Spengler reaction. The compounds were examined for cytotoxicity and anti-inflammatory activity, as measured by the inhibition of prostaglandin E 2 (PGE 2) production and nitric oxide (NO) production. While only two compounds (28 and 31) showed marginal cytotoxicity against four human cancer cell lines, most of the tested compounds exhibited potent inhibitory activity of both NO and PGE 2 production. Moreover, compounds 6 and 16 significantly reduced the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2), suggesting that β-carboline analogs can inhibit NO and PGE 2 production at the translational level. In addition, several of the β-carboline derivatives (1, 2, 4-8, 11, 13, 22, 25, 27, 31, and 41-43) displayed significant inhibitory activity of superoxide anion (O2·-) generation or elastase release compared to the reference compound, with 6 being the most potent. N-Formyl-l-methionyl-phenylalanine (FMLP)-induced phosphorylation of c-Jun N-terminal kinase (JNK) and protein kinase B (AKT) were also inhibited by 6, suggesting that it suppresses human neutrophil functions by inhibiting the activation of JNK and AKT signaling pathways. Therefore, the synthetic 1-benzoyl-3-carboxy β-carboline analogs may have great potential to be developed as anti-inflammatory agents.

Original languageEnglish
Pages (from-to)1674-1682
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number5
DOIs
Publication statusPublished - 2011 Mar 1

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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