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Open AccessArticle

Synthesis of Spin-Labelled Bergamottin: A Potent CYP3A4 Inhibitor with Antiproliferative Activity

1
Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Szigeti út 12, H-7624 Pécs, Hungary
2
Institute of Organic and Medicinal Chemistry, University of Pécs, Medical School, Honvéd utca 1, H-7624 Pécs, Hungary
3
Department of Pharmacology, University of Pécs, Faculty of Pharmacy, Szigeti út 12, H-7624 Pécs, Hungary
4
János Szentágothai Research Center, University of Pécs, Ifjúság útja 20, H-7624 Pécs, Hungary
5
Department of Biochemistry, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(2), 508; https://doi.org/10.3390/ijms21020508
Received: 19 December 2019 / Revised: 9 January 2020 / Accepted: 10 January 2020 / Published: 13 January 2020
(This article belongs to the Section Bioactives and Nutraceuticals)
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. View Full-Text
Keywords: bergamottin; nitroxide; CYP3A4 inhibition; anticancer activity bergamottin; nitroxide; CYP3A4 inhibition; anticancer activity
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Zsidó, B.Z.; Balog, M.; Erős, N.; Poór, M.; Mohos, V.; Fliszár-Nyúl, E.; Hetényi, C.; Nagane, M.; Hideg, K.; Kálai, T.; Bognár, B. Synthesis of Spin-Labelled Bergamottin: A Potent CYP3A4 Inhibitor with Antiproliferative Activity. Int. J. Mol. Sci. 2020, 21, 508.

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