Design and Synthesis of New α-Naphthoflavones as Cytochrome P450 (CYP) 1B1 Inhibitors To Overcome Docetaxel-Resistance Associated with CYP1B1 Overexpression

Abstract

CYP1B1 is recognized as a new target in cancer prevention and therapy. Taking α-naphthoflavone as a lead, a series of 6,7,10-trimethoxy-α-naphthoflavones (4a-o) were synthesized and evaluated for their inhibitory potency against CYP1B1 and selectivity over CYP1A1 and 1A2. SAR analysis indicated that introducing methoxy groups at C(6), C(7), and C(10) on the naphthalene part and a fluoro atom at C(3') on the B-ring, could sharply increase the efficiency toward CYP1B1 inhibition. Among the prepared derivatives, compound 4c is the most potent and selective CYP1B1 inhibitor ever reported. More effort was taken to acquire water-soluble α-naphthoflavone derivatives for further cell-based study of overcoming anticancer drug-resistance. Finally, we obtained water-soluble naphthoflavone (11f) which could obviously eliminate the docetaxel-resistance caused by the enhanced expression of CYP1B1 in MCF-7/1B1 cells. It could be envisaged that the discovery of new α-naphthoflavones as CYP1B1 inhibitors is clinically important for overcoming CYP1B1-mediated drug-resistance in cancer therapeutics.

Potential role of CYP1B1 in the development and treatment of metabolic diseases

“…Chang, et al, 2015). Consistent with this study, a new water-soluble α-naphthoflavone derivative which shows highly selective inhibitory activity toward CYP1B1 (IC 50 = 0.043 nM) can eliminate the docetaxel-resistance caused by the enhanced CYP1B1expression in MCF-7/1B1 cells (Cui, et al, 2015). Taken together, these studies suggest that CYP1B1 inhibitors could overcome anticancer drug resistance.…”

“…Shimada, et al, 1998). More recently, a potent inhibitor of CYP1B1 (IC 50 = 0.043 nM) was synthesized from α-naphthoflavone, and its water-soluble derivative can eliminate the resistance of docetaxel in MCF-7/1B1 cells (Cui, et al, 2015). Several flavonoids from St. John’s wort also show inhibitory activity on CYP1B1, including quercetin, rutin, apigenin, and amentoflavone (Chaudhary & Willett, 2006).…”

“…However, the fact that Cyp1b1 -null mice are normal, other than an increase in IOP suggest that inhibition of or CYP1B1 would not result in toxicities (Jeroen TM Buters, et al, 1999). An increasing number of CYP1B1 inhibitors have developed and patented (Cui, et al, 2015; Kumar & Gupta, 2016). In addition, ZYC300 is a CYP1B1-based vaccine which stimulates the immune system to elicit a cytotoxic T lymphocyte response against tumor cells expressing CYP1B1 (Maecker, et al, 2003).…”

Genomic signatures for paclitaxel and gemcitabine resistance in breast cancer derived by machine learning

“…This SVM contains 8 paclitaxel resistance genes. Predictions of docetaxel sensitivity might be improved by rederiving a specific SVM using taxane pathway genes (Oshiro et al., 2009), and those known to be associated with resistance to doclitaxel (such as CYP1B1 (Chang et al., 2015; Cui et al., 2015), miR‐141 or EIF4E (Yao et al., 2015), DKK3 (Tao et al., 2015), ABCB1 (Hansen et al., 2015; Kato et al., 2015), BIRC5 (Ghanbari et al., 2014), ABCC10 (Domanitskaya et al., 2014), miR‐452 (Hu et al., 2014), and PAWR (Pereira et al., 2013)). The approach that we have introduced could aid in rational selection of other therapeutic regimens that evade or at least minimize the effects of chemoresistance.…”

Synthesis, biological evaluation and docking studies of trans‐stilbene methylthio derivatives as cytochromes P450 family 1 inhibitors

“…The cytochrome P450 family 1 (CYP1) represents isoforms CYP1A1, CYP1A2 and CYP1B1, which are responsible for the phase I metabolism of endogenous and exogenous substrates including drug compounds and procarcinogens, for example polycyclic aromatic hydrocarbons and aromatic and heterocyclic amines. [3,4] Transresveratrol (3,4′,5-trihydroxytrans-stilbene) is a natural polyphenol found in grapes, berries and peanuts, showing well-characterized beneficial bioactivities. [1] Recently, the role of CYP1B1 in cancer progression and metastasis was reported.…”