Khellinoflavanone, a Semisynthetic Derivative of Khellin, Overcomes Benzo[ a]pyrene Toxicity in Human Normal and Cancer Cells That Express CYP1A1

Sharma, Rajni; Williams, Ibidapo S.; Gatchie, Linda; Sonawane, Vinay R.; Chaudhuri, Bhabatosh; Bharate, Sandip B.

Abstract

Copyright © 2018 American Chemical Society. Cytochrome P450 family 1 (CYP1) enzymes catalyze the metabolic activation of environmental procarcinogens such as benzo[a]pyrene, B[a]P, into carcinogens, which initiates the process of carcinogenesis. Thus, stopping the metabolic activation of procarcinogens can possibly prevent the onset of cancer. Several natural products have been reported to show unique ability in inhibiting CYP1 enzymes. We found that khellin, a naturally occurring furanochromone from Ammi visnaga, inhibits CYP1A1 enzyme with an IC50 value of 4.02 μM in CYP1A1-overexpressing human HEK293 suspension cells. To further explore this natural product for discovery of more potent and selective CYP1A1 inhibitors, two sets of semisynthetic derivatives were prepared. Treatment of khellin with alkali results in opening of a pyrone ring, yielding khellinone (2). Claisen-Schmidt condensation of khellinone (2) with various aldehydes in presence of potassium hydroxide, at room temperature, provides a series of furanochalcones 3a-v (khellinochalcones). Treatment of khellinone (2) with aryl aldehydes in the presence of piperidine, under reflux, affords the flavanone series of compounds 4a-p (khellinoflavanones). The khellinoflavanone 4l potently inhibited CYP1A1 with an IC50 value of 140 nM in live cells, with 170-fold selectivity over CYP1B1 (IC50 for CYP1B1 = 23.8 μM). Compound 4l at 3× IC50 concentration for inhibition of CYP1A1 completely protected HEK293 cells from CYP1A1-mediated B[a]P toxicity. Lung cancer cells, A549 (p53+) and Calu-1 (p53-null), blocked in growth at the S-phase by B[a]P were restored into the cell cycle by compound 4l. The results presented herein strongly indicate the potential of these khellin derivatives for further development as cancer chemopreventive agents. ©

Citation

Sharma, R., Williams, I. S., Gatchie, L., Sonawane, V. R., Chaudhuri, B., & Bharate, S. B. (2018). Khellinoflavanone, a Semisynthetic Derivative of Khellin, Overcomes Benzo[ a]pyrene Toxicity in Human Normal and Cancer Cells That Express CYP1A1. ACS Omega, 3(8), 8553-8566. https://doi.org/10.1021/acsomega.8b01088

• Journal Article Type: Article
• Acceptance Date: Jul 14, 2018
• Publication Date: Aug 31, 2018
• Deposit Date: Aug 3, 2018
• Publicly Available Date: Aug 7, 2019
• Journal: ACS Omega
• Electronic ISSN: 2470-1343
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 3
• Issue: 8
• Pages: 8553-8566
• DOI: https://doi.org/10.1021/acsomega.8b01088
• Keywords: khellin, cytochrome P50 family 1 enzymes, CYP1A1; khellinone, flavanones, polycyclic aromatic hydrocarbons
• Public URL: https://uwe-repository.worktribe.com/output/863344
• Publisher URL: http://dx.doi.org/10.1021/acsomega.8b01088
• Related Public URLs: https://cdn-pubs.acs.org/doi/suppl/10.1021/acsomega.8b01088