trans-Stilbenoids: potent and selective inhibitors for human cytochrome P450 1B1

Abstract

On the basis of our previous insights into the structural requirements of stilbenoids for the inhibition of cytochrome P450 1B1 (CYP1B1), a series of 2,4-dimethoxy group-containing stilbenes was prepared and evaluated for their inhibitory effects on the activity of CYP1s with the ultimate goal of identifying a potent and selective CYP1B1 inhibitor. Among the thirteen derivatives prepared, five compounds exhibited similar or greater potency compared to the previous lead compound, 2,4,3 0 ,5 0 -tetramethoxystilbene (2,4,3 0 ,5 0 -TMS), in inhibiting CYP1B1. In particular, 2,2 0 ,3 0 ,4,6 0 -pentamethoxystilbene was found to be a more selective and more potent CYP1B1 inhibitor than 2,4,3 0 ,5 0 -TMS. 2,4,2 0 ,6 0 -TMS showed remarkably potent inhibitory activity against CYP1B1 (IC 50 ¼ 1.77 AE 0.14 nM) and also had a very high selectivity toward CYP1 isoenzymes. Molecular modeling was performed to determine the key molecular interactions with the CYP1B1 and CYP1A2 structures. On the basis of these structural and biological studies, the design of more potent and more selective druglike derivatives can be envisaged.

3,4,2′-Trimethoxy-trans-stilbene – a potent CYP1B1 inhibitor

“…For the most active CYP1B1 inhibitor 5b, the double bond C7-C8 in the conjugated linkage is in the trans conguration [torsion angle C(4)-C(7)-C(8)-C(9), 177.67 (13) ]. Furthermore, the value for the observed double The aromatic rings do not deviate signicantly from a coplanar arrangement, with a dihedral angle of 3.07 (9) between the planes. Among the three methoxy substituents on the aromatic ring, only the one at C2 is not exactly coplanar with the benzene ring (10.54 ).…”

“…In the last decade the inhibitory activity of resveratrol and its derivatives against cytochrome P450 enzymes has been extensively investigated. [4][5][6][7][8][9][10][11][12][13] Cytochromes P450 of family 1, cytochrome P450 1A1 (CYP1A1), cytochrome P450 1A2 (CYP1A2) and cytochrome P450 1B1 (CYP1B1), are involved in the activation of potential carcinogens. Recently, CYP1B1 has attracted increasing attention as a drug target.…”

New Perspectives of CYP1B1 Inhibitors in the Light of Molecular Studies

“…Stilbene and flavonoid derivatives were designed, synthesized, and evaluated as substrates and inhibitors of CYP1 isozymes with special regard to their molecular interactions in the enzyme binding sites. The high potency of trans-stilbene methoxy derivatives as selective inhibitors of CYP1B1 activity was analyzed with the use of computational methods, among others stilbene derivatives: 2,4,3 ,5 -tetramethoxy-trans-stilbene (TMS) and 2,2 ,4,6 -tetramethoxy-transstilbene [87][88][89]. In our studies, 2,3 ,4 -trimethoxy-trans-stilbene was the most effective and selective CYP1B1 inhibitor among the studied series of poly-methoxystilbenes [63].…”

Structure-Based Drug Design for Cytochrome P450 Family 1 Inhibitors

“…The positions of some substituents influence the ligand orientation and interactions with amino acid residues in the enzyme active site, affecting the distance to the heme, which determines the course of enzymatic reaction. In the studies of Chun et al [ 75 , 112 – 114 ], 3,5,2′,4′-tetramethoxy- trans -stilbene and 2,4,2′,6′-tetramethoxy- trans -stilbene were identified as very potent CYP1B1 inhibitors, indicating a distinctive role of methoxy substituents in positions 2 and 4, as well as 2 and 6 in the inhibition of CYP1B1 activity.…”