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Design, Synthesis, Characterization, and Crystal Structure Studies of Nrf2 Modulators for Inhibiting Cancer Cell

Prathima Chikkegowda1, Baburajeev C Pookunoth2, Venugopal R Bovilla3,4

  • 1Department of Pharmacology, JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India.

ACS Omega
|May 31, 2021
PubMed

Insights

This study explored Nrf2 inhibitors for colorectal cancer (CRC). Compound 5b, a novel tetrahydrocarbazole, effectively reduced cancer cell proliferation and tumor growth in mice, showing therapeutic promise.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key therapeutic target in various cancers, including colorectal cancers (CRCs).
  • Existing Nrf2 inhibitors have shown limited success in inhibiting CRC progression.
  • Targeting Nrf2 presents a potential strategy for novel cancer therapies.

Purpose of the Study:

  • To investigate the therapeutic potential of siRNA-mediated Nrf2 downmodulation on CRC cell proliferation.
  • To design, synthesize, and characterize novel tetrahydrocarbazoles (THCs) as Nrf2 modulators.
  • To evaluate the cytotoxic and anti-cancer effects of synthesized compounds, particularly compound 5b.

Main Methods:

  • siRNA-mediated Nrf2 downmodulation was performed on CRC cell lines.
  • A series of tetrahydrocarbazoles (THCs) were synthesized and characterized, including crystal structure determination.
  • Compounds were tested for their ability to modulate Nrf2 target gene NAD(P)H:quinone oxidoreductase (NQO1) activity in HCT-116 cells.
  • Cytotoxicity assays were conducted on various cancer cell lines with differing Nrf2 activity levels.
  • In vitro cell cycle progression and in vivo tumor growth inhibition (Ehrlich ascites carcinomas in mice) were assessed for the lead compound 5b.

Main Results:

  • siRNA-mediated Nrf2 downmodulation demonstrated a therapeutic effect on CRC cell proliferation.
  • Synthesized THCs were characterized, and their NQO1 modulatory activity was assessed.
  • Compound 5b showed significant cytotoxic effects and inhibited tumor growth in a mouse model.
  • Compound 5b exhibited a favorable therapeutic index compared to other tested compounds.

Conclusions:

  • Compound 5b, a novel tetrahydrocarbazole, is a promising candidate for targeting Nrf2 in cancer therapy.
  • The study validates Nrf2 as a viable therapeutic target and highlights compound 5b for further preclinical development.
  • Targeting Nrf2 with novel compounds like 5b offers a potential strategy for managing colorectal and other cancers.

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