Abstract
Leukotrienes are inflammatory mediators that actively participate in the inflammatory response and host defense against pathogens. However, leukotrienes also participate in chronic inflammatory diseases. 5-lipoxygenase is a key enzyme in the biosynthesis of leukotrienes and is thus a validated therapeutic target. As of today, zileuton remains the only clinically approved 5-lipoxygenase inhibitor; however, its use has been limited due to severe side effects in some patients. Hence, the search for a better 5-lipoxygenase inhibitor continues. In this study, we investigated structural analogues of caffeic acid phenethyl ester, a naturally-occurring 5-lipoxygenase inhibitor, in an attempt to enhance the inhibitory activity against 5-lipoxygenase and determine structure-activity relationships. These compounds were investigated for their ability to attenuate the biosynthesis of leukotrienes. Compounds 13 and 19, phenpropyl and diphenylethyl esters, exhibited significantly enhanced inhibitory activity when compared to the reference molecules caffeic acid phenethyl ester and zileuton.
Highlights
The 5-lipoxygenase (5-LO) enzyme catalyzes the first two steps of the conversion of arachidonic acid into leukotrienes (LTs) [1]
The production of LTs has been associated with several inflammatory diseases such as asthma [3], arthritis [4], atherosclerosis [2], and some types of cancers [5, 6]
Physiological and pharmacological regulation of LT biosynthesis remains a focal point of numerous research efforts investigating the control of inflammatory diseases [8, 9, 39]
Summary
The 5-lipoxygenase (5-LO) enzyme catalyzes the first two steps of the conversion of arachidonic acid into leukotrienes (LTs) [1]. LTs are potent lipid mediators that actively participate in numerous inflammatory diseases such as atherosclerosis [2], asthma [3], arthritis [4], and several types of cancers [5,6,7]. Honeybee propolis is a resinous substance composed of 50% plant resins, 30% wax, 10% essential and aromatic oils, 5% pollens, and 5% of other organic substances (reviewed in [15]). Caffeic acid phenethyl ester (CAPE (2, Figure 1)) is one of the major bioactive components of honeybee propolis [19]. We and others have shown that CAPE (2) and some structural analogues are potent inhibitors of the 5-LO pathway [20,21,22,23]
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