Antioxidant and Anti-Inflammatory Activity of Aryl-Acetic and Hydroxamic Acids as Novel Lipoxygenase Inhibitors

Abstract

Lipoxygenase plays an essential role in the biosynthesis of the leukotrienes. Leukotrienes, as LO metabolites of arachidonic acid (AA), have been implicated as mediators in the pathophysiology of inflammatory diseases, host defense reactions and to play important role in the propagation of the diseases states, exacerbating the local events and ultimately leading to tissue damage. Simple stable molecules containing the hydroxamic acid functionality have been shown to inhibit 5-lipoxygenase. In fact, several hydroxamates are orally active inhibitors of the enzyme as determined by their ability to block the biosynthesis of leukotriene in vivo. In order to establish the inhibitory utility of simple hydroxamates several omega-phenylalkyl and omega-naphthylalkyl hydroxamic acids were synthesized. In an attempt to expand and delineate these results we tried to synthesize some more for a further pharmacochemical study. Since lipophilicity is a significant physicochemical property determining distribution, bioavailability, metabolic activity and elimination, we tried to determine experimentally their lipophilicity from RPTLC method. The compounds are tested in vitro on: a) soybean lipoxygenase inhibition, b) interaction with 1,1-diphenyl-2-picryl-hydrazyl (DPPH) stable free radical, c) the HO* radical mediated oxidation of DMSO, d) inhibition of lipid peroxidation, e) scavenging of superoxide anion radicals f) interaction with glutathione and g) in vivo for the inhibition of carrageenin induced rat paw edema. The compounds have shown important antioxidant activity, medium anti-inflammatory activity and potent inhibition of soybean lipoxygenase as a result of their physichochemical features.

Novel Cinnamic Acid Derivatives as Antioxidant and Anticancer Agents: Design, Synthesis and Modeling Studies

“…The evaluation of the novel acids against soybean lipoxygenase LOX was accomplished by the UV-based enzyme assay of Pontiki and Hadjipavlou-Litina [23][24][25]. This assay may be used as a qualitative or semi-quantitative screen for such activity [36].…”

“…Several LOX inhibitors proved to be excellent ligants for Fe 3+ . Lipophilicity is referred [23][24][25] to as an important physicochemical property for LOX inhibition. However, herein highly lipophilic compounds 4i and 3i resulted less active than compounds 1i and 2i (Table 2).…”

“…Previous studies of our group have shown that cytotoxic and antiinflammatory effects of antioxidant cinnamic acids are associated with their pro-oxidant effects [23][24][25][26]. The antioxidant, anti-inflammatory and anticancer properties of cinnamic acids are known to be influenced to a great extent by the substitutions of the aryl ring and the double bond.…”

Minor iridoids from Scutellaria albida ssp. albida. Inhibitory potencies on lipoxygenase, linoleic acid lipid peroxidation and antioxidant activity of iridoids from Scutellaria sp.

“…Ethanolic solution of the tested compound was incubated with sodium linoleate (0.1 mM) and 0.2 mL of soybean lipoxygenase solution (1/9 × 10 -4 w/v in saline) at room temperature. The conversion of sodium linoleate to 13-hydroperoxylinoleic acid was recorded at 234 nm and compared with the standard inhibitor caffeic acid according to the procedure previously reported 23 .…”

“…After 20 and 60 min the absorbance was recorded at 517 nm and compared with the appropriate standard NDGA. Ethanol was used as a control 23 .…”