Novel nitric oxide-releasing derivatives of pyranocarbazole as antitumor agents: Design, synthesis, biological evaluation, and nitric oxide release studies

Eur J Med Chem. 2022 Dec 15:244:114832. doi: 10.1016/j.ejmech.2022.114832. Epub 2022 Oct 7.

Abstract

In this study, a series of novel furoxan-based nitric oxide (NO) releasing derivatives of pyranocarbazole alkaloids were designed, synthesized, and biologically evaluated against human cancer cell lines. The derivatives showed considerable antiproliferative activities (IC50 = 0.05-7.55 μM) and most compounds showed higher activity in MDA-MB-231 than H460 and HeLa. Especially, the most active derivative 7a (IC50 = 0.05 μM) against MDA-MB-231 was about 60 times stronger than lead compound, as well as equivalent to positive control taxol, and produced high levels of NO in MDA-MB-231. Furthermore, 7a could significantly inhibit the growth of MDA-MB-231 tumors in vivo with low toxicity and the PI3K/Akt signaling pathway. These results indicated that compound 7a could be a promising lead for further studies.

Keywords: Antitumor; NO releasing; pyranocarbazole alkaloids.

MeSH terms

  • Alkaloids* / chemistry
  • Alkaloids* / pharmacology
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Carbazoles* / chemistry
  • Carbazoles* / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Nitric Oxide Donors* / chemistry
  • Nitric Oxide Donors* / pharmacology
  • Nitric Oxide* / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Nitric Oxide
  • Phosphatidylinositol 3-Kinases
  • Nitric Oxide Donors
  • Carbazoles
  • Alkaloids