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

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2018
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Abstract
Cytochrome P450 family 1 (CYP1) enzymes catalyze the metabolic activation of environmental procarcinogens such as benzo[]pyrene, B[]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 , inhibits CYP1A1 enzyme with an IC 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 (). Claisen-Schmidt condensation of khellinone () with various aldehydes in presence of potassium hydroxide, at room temperature, provides a series of furanochalcones (khellinochalcones). Treatment of khellinone () with aryl aldehydes in the presence of piperidine, under reflux, affords the flavanone series of compounds (khellinoflavanones). The khellinoflavanone potently inhibited CYP1A1 with an IC value of 140 nM in live cells, with 170-fold selectivity over CYP1B1 (IC for CYP1B1 = 23.8 μM). Compound at 3× IC concentration for inhibition of CYP1A1 completely protected HEK293 cells from CYP1A1-mediated B[]P toxicity. Lung cancer cells, A549 (p53) and Calu-1 (p53-null), blocked in growth at the S-phase by B[]P were restored into the cell cycle by compound . The results presented herein strongly indicate the potential of these khellin derivatives for further development as cancer chemopreventive agents.
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Authors Sharma, Rajni;Williams, Ibidapo S;Gatchie, Linda;Sonawane, Vinay R;Chaudhuri, Bhabatosh;Bharate, Sandip B;
Journal ACS omega
Year 2018
DOI
10.1021/acsomega.8b01088
URL
Keywords
pharmacokinetics poloxamer sustained release in vitro release sd, standard deviation im, intramuscular atp, adenosine 5′ triphosphate auc80h, area under the analyte concentration versus time curve from time zero to 80 h auclast, area under the analyte concentration versus time curve from time zero to the time of the last measurable (non-below quantification level) concentration auc∞, area under the analyte concentration vs time curve from time zero to infinite time c0, analyte plasma concentration at time zero can, acetonitrile cmc, critical micellar concentration cmt, critical micellar temperature cmax, maximum observed analyte plasma concentration dn, dose normalized doe, design of experiments eo, ethylene oxide gpt, gel point temperature gel erosion h&e, hematoxylin and eosin iv, intravenous in situ forming gels k2.edta, potassium ethylenediaminetetraacetic acid lc–ms/ms, liquid chromatography-tandem mass spectrometry mdr-tb, multi-drug resistant tuberculosis mrm, multiple reaction monitoring nmp, n-methyl-2-pyrrolidone p338, poloxamer 338 p407, poloxamer 407 plga, poly-(dl-lactic-co-glycolic acid) po, propylene oxide tfa, trifluoroacetic acid uhplc, ultra-high performance liquid chromatography uv, ultraviolet n, sample size t1/2, apparent terminal elimination half-life tlast, sampling time until the last measurable (non-below quantification level) analyte plasma concentration tmax, sampling time to reach the maximum observed analyte plasma concentration

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