Structure–activity relationship studies of flavonoids as potent inhibitors of human platelet 12-hLO, reticulocyte 15-hLO-1, and prostate epithelial 15-hLO-2

Abstract

Human lipoxygenase (hLO) isozymes have been implicated in a number of disease states and have attracted much attention with respect to their inhibition. One class of inhibitors, the flavonoids, have been shown to be potent lipoxygenase inhibitors but their study has been restricted to those compounds found in nature, which have limited structural variability. We have therefore carried out a comprehensive study to determine the structural requirements for flavonoid potency and selectivity against platelet 12-hLO, reticulocyte 15-hLO-1, and prostate epithelial 15-hLO-2. We conclude from this study that catechols are essential for high potency, that isoflavones and isoflavonones tend to select against 12-hLO, that isoflavons tend to select against 15-hLO-1, but few flavonoids target 15-hLO-2.

In vitro analysis of iron chelating activity of flavonoids

“…The current research has been gradually changing this dogma by emphasizing their transition metals chelation properties and direct interaction with some enzymes and blood/vascular cells, which may have important roles in their influence on human being [1,2]. The metal chelation can be responsible, at least partly, both for the documented antioxidant capacity of flavonoids and for some other activities (e.g., inhibition of lipooxygenases by chelation/reduction of iron in their active site) [3]. The former includes inhibition of both iron based Fenton reaction with prevention of the production of the hydroxyl radical and lipid peroxidation initiated by trace levels of copper/iron although, particularly, the contribution of direct scavenging effect and metal chelation is very difficult to assess [4].…”

Coumarins of Haplopappus Multifolius and Derivative as Inhibitors of Lox: Evaluation in-Vitro and Docking Studies

“…2 has well interaction of alcoholic geranyl group with non-heme iron (Fe 3+ ) Besides a two hydrogen bridges interaction with amino acid residues, due to a flat structure of the aromatic system, causing inhibition of the enzyme. In contrast, in quercetin this rigidity is changed into a B ring that is flexible and whose conformation does not allow good interaction in the active site, and this takes place before the quercetin can degrade to 3,4-dihydroxybenzoic acid, which according to the literature is a potent inhibitor of 15-sLOX [21][22][23] .…”

Isoflavans Derivatives as Inhibitors of Soybean Lipoxygenase: In-Vitro and Docking Studies

“…Isoflavans 1a-1d, 2, 3a and 3b were prepared following a procedure reported previously [8]: after a Houben-Hoesch reaction of the appropriate phenol with a benzyl cyanide and HCl/ZnCl 2 in dry ethyl ether, the resulting hydroxylketone was cyclized to the isoflavones using MeSO 2 Cl/DMF in the presence of BF 3 .Et 2 O. Reduction of the obtained isoflavone through catalytic hydrogenation with Pd/C (10%) in acetic acid formed the corresponding isoflavans.…”

“…The search for new LOX inhibitors has led to the synthesis and evaluation of a series of 3-aryl-3,4-dihydro-2-H-1-benzopyran or isoflavans derivatives in our laboratories [8]. Some of these compounds were found to exhibit interesting activities as inhibitors of soybean lipoxygenase-1 (sLOX); their IC 50 values were comparable with those of other good lipoxygenase inhibitors like caffeic or benzoic acid derivatives [9,10].…”