Ethynylflavones, Highly Potent, and Selective Inhibitors of Cytochrome P450 1A1

Abstract

The flavone backbone is a well-known pharmacophore present in a number of substrates and inhibitors of various P450 enzymes. In order to find highly potent and novel P450 family I enzyme inhibitors, an acetylene group was incorporated into six different positions of flavone. The introduction of an acetylene group at certain locations of the flavone backbone lead to time-dependent inhibitors of P450 1A1. 3′-Ethynylflavone, 4′-ethynylflavone, 6-ethynylflavone, and 7-ethynylflavone (KI values of 0.035–0.056 μM) show strong time-dependent inhibition of P450 1A1, while 5-ethynylflavone (KI value of 0.51 μM) is a moderate time-dependent inhibitor of this enzyme. Meanwhile, 4′-ethynylflavone and 6-ethynylflavone are highly selective inhibitors toward this enzyme. Especially, 6-ethynylflavone possesses a Ki value of 0.035 μM for P450 1A1 177- and 15-fold lower than those for P450s 1A2 and 1B1, respectively. The docking postures observed in the computational simulations show that the orientation of the acetylene group determines its capability to react with P450s 1A1 and 1A2. Meanwhile, conformational analysis indicates that the shape of an inhibitor determines its inhibitory selectivity toward these enzymes.

A Ligand-Based Drug Design. Discovery of 4-Trifluoromethyl-7,8-pyranocoumarin as a Selective Inhibitor of Human Cytochrome P450 1A2

“…The reaction was initiated by the addition of 200 μ L of an NADPH regenerating solution. 29 The final assay volume was 2.0 mL. The production of resorufin anion was monitored by a spectrofluorimeter (OLIS DM 45 spectrofluorimetry system) at 535 nm excitation and 585 nm emission, with a slit width of 2 nm.…”

“…For the controls, 10 μL of pure DMSO was added in place of the inhibitor solution. The reaction was initiated by the addition of 200 μL of an NADPH regenerating solution . The final assay volume was 2.0 mL.…”

Flavonoids and Naphthoflavonoids: Wider Roles in the Modulation of Cytochrome P450 Family 1 Enzymes

“…In contrast to monohydroxylated flavones, the corresponding flavonyl propargyl ethers displayed higher activity, and 3′‐propargyloxyflavone ( A2 ) was characterized as the strongest inhibitor of all compounds tested in this study. Similarly, a series of ethynylflavones were prepared and evaluated by Goyal and colleagues ( B1 – B6 ) . They incorporated an acetylene group into the flavone backbone, as an acetylene group could react with CYP1s and lead to their deactivation.…”

“…[47] In contrast to monohydroxylated flavones, the corresponding flavonyl propargyl ethers displayed higher activity,a nd 3'-propargyloxyflavone (A2)w as characterized as the strongest inhibitor of all compounds tested in this study.S imilarly,aseries of ethy- www.chemmedchem.org nylflavonesw ere prepareda nd evaluated by Goyal and colleagues (B1-B6). [52] They incorporated an acetylene group into the flavoneb ackbone,a sa na cetylene group could react with CYP1s and lead to their deactivation. Among these six compounds examined, ethynylflavones, bearing the an acetylene functional group at positions 3',4 ',6 ,a nd 7, were found to possess much stronger suppressive activities against CYP1A1 (B2-B5, K i range:0 .024-0.041 mm), and 6-ethynylflavone (B4) was notable for its capacity to selectively inhibit CYP1A1 (K i : 0.035 mm for CYP1A1, 177-and 15-foldl ower than that for CYP1A2a nd 1B1, respectively).…”

Structure-Based Drug Design for Cytochrome P450 Family 1 Inhibitors

“…Only 2′-ethynylflavone demonstrated another orientation in the CYP1A1 cavity; this compound appeared to be a selective inhibitor of CYP1A2. In all the studied ethynylflavones docked to CYP1A2, acetylene groups were oriented away from the heme [ 54 ].…”