Synthesis of spin-labelled bergamottin: A potent CYP3A4 inhibitor with antiproliferative activity

Balázs Zoltán Zsidó, Mária Balog, Nikolett Erős, Miklós Poór, Violetta Mohos, Eszter Fliszár-Nyúl, Csaba Hetényi, Masaki Nagane, Kálmán Hideg, Tamás Kálai, Balázs Bognár

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Abstract

Bergamottin (BM, 1), a component of grapefruit juice, acts as an inhibitor of some isoforms of the cytochrome P450 (CYP) enzyme, particularly CYP3A4. Herein, a new bergamottin containing a nitroxide moiety (SL-bergamottin, SL-BM, 10) was synthesized; chemically characterized, evaluated as a potential inhibitor of the CYP2C19, CYP3A4, and CYP2C9 enzymes; and compared to BM and known inhibitors such as ketoconazole (KET) (3A4), warfarin (WAR) (2C9), and ticlopidine (TIC) (2C19). The antitumor activity of the new SL-bergamottin was also investigated. Among the compounds studied, BM showed the strongest inhibition of the CYP2C9 and 2C19 enzymes. SL-BM is a more potent inhibitor of CYP3A4 than the parent compound; this finding was also supported by docking studies, suggesting that the binding positions of BM and SL-BM to the active site of CYP3A4 are very similar, but that SL-BM had a better ∆Gbind value than that of BM. The nitroxide moiety markedly increased the antitumor activity of BM toward HeLa cells and marginally increased its toxicity toward a normal cell line. In conclusion, modification of the geranyl sidechain of BM can result in new CYP3A4 enzyme inhibitors with strong antitumor effects.

Original languageEnglish
Article number508
JournalInternational journal of molecular sciences
Volume21
Issue number2
DOIs
Publication statusPublished - Jan 2 2020

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Keywords

  • Anticancer activity
  • Bergamottin
  • CYP3A4 inhibition
  • Nitroxide

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Zsidó, B. Z., Balog, M., Erős, N., Poór, M., Mohos, V., Fliszár-Nyúl, E., Hetényi, C., Nagane, M., Hideg, K., Kálai, T., & Bognár, B. (2020). Synthesis of spin-labelled bergamottin: A potent CYP3A4 inhibitor with antiproliferative activity. International journal of molecular sciences, 21(2), [508]. https://doi.org/10.3390/ijms21020508