ABSTRACT
Several diaryl triazene derivatives were synthesized and tested for their ability to inhibit cytochrome P450 1A1 and 1B1 as a potential means to prevent and treat cancer. These compounds are more planar than their conformational flexible aryl morpholino triazene counterparts that were previously shown to inhibit the above enzymes. As a result, the diaryl triazenes are more likely to exhibit increased binding to the enzyme active sites and inhibit these enzymes more strongly than the aryl morpholino triazenes. The data indicates that the diaryl triazenes inhibit cytochrome P450 1A1 and 1B1 one to two orders of magnitude more strongly than the aryl morpholino triazenes. Furthermore, compounds 8-10 strongly inhibited cytochrome P450 1B1 with IC50 values of 51 nM, 740 nM, and 590 nM respectively. Thus, diaryl triazenes should be further investigated as a potential chemopreventive agent.
Subject(s)
Cytochrome P-450 CYP1A1/antagonists & inhibitors , Cytochrome P-450 CYP1B1/antagonists & inhibitors , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Morpholinos/pharmacology , Triazenes/pharmacology , Cytochrome P-450 CYP1A1/metabolism , Cytochrome P-450 CYP1B1/metabolism , Cytochrome P-450 Enzyme Inhibitors/chemical synthesis , Cytochrome P-450 Enzyme Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Morpholinos/chemical synthesis , Morpholinos/chemistry , Structure-Activity Relationship , Triazenes/chemical synthesis , Triazenes/chemistryABSTRACT
Many cytochrome P450 1A1 and 1B1 (CYP1A1 and CYP1B1) inhibitors, such as resveratrol, have planar, hydrophobic, aromatic rings in their structure and exhibit anti-cancer activity. Aryl morpholino triazenes have similar structural features and in addition contain a triazene unit consisting of three consecutive, conjugated nitrogen atoms. Several aryl morpholino triazenes, including 4-[(E)-2-(3,4,5-trimethoxyphenyl)diazenyl]-morpholine (2), were prepared from a reaction involving morpholine and a diazonium ion produced from different aniline derivatives, such as 3,4,5-trimethoxyaniline. The aryl morpholino triazenes were then screened at 100µM for their ability to inhibit CYP1A1 and CYP1B1 using ethoxyresorufin as the substrate. Triazenes that inhibited the enzymes to less than 80% of the uninhibited enzyme activity were assayed to determine their IC50 value. Compound 2 was the only triazene to inhibit both CYP1A1 and CYP1B1 to the same degree as resveratrol with IC50 values of 10µM and 18µM, respectively. Compounds 3 and 6 selectively inhibited CYP1B1 over CYP1A1 with IC values of 2µM and 7µM, respectively. Thus, aryl morpholino triazenes are a new class of compounds that can inhibit CYP1A1 and CYP1B1 and potentially prevent cancer.
