Xanthine Oxidase Inhibition by 1,3-dipropyl-8-sulfophenyl-xanthine (DPSPX), an Antagonist of Adenosine Receptors

Abstract

Xanthine oxidase (XO), an enzyme involved in purine metabolism, is a source of either oxidants (superoxide radical) or antioxidants (uric acid). Interference with XO activity can lead to oxidative stress, thus contributing to the pathogenesis of cardiovascular diseases. The adenosine receptors antagonist, 1,3-dipropyl-8-sulfophenylxanthine (DPSPX), induces hypertension and cardiovascular injury in rats. Since DPSPX is a xanthine, we aimed at evaluating DPSPX's influence on XO activity to ascertain its contribution to DPSPX-induced hypertension. The activity of isolated XO in the presence of DPSPX was evaluated spectrophotometrically. Serum and urinary uric acid levels of DPSPX-treated rats were measured using a commercial kit. DPSPX inhibited XO activity in a concentration-dependent manner and reduced rat serum and urinary uric acid levels. It can be concluded that: DPSPX is an inhibitor of XO; decreased generation of uric acid may lead to oxidative stress, thus contributing to endothelial dysfunction and vascular morphological changes in DPSPX-treated rats.

The Role of Oxidative Stress in Hyperuricemia and Xanthine Oxidoreductase (XOR) Inhibitors

“…Among numerous inhibitors, Y-700 (1-(3-cyano-4-neopentyloxyphenyl)-1H-pyrazole-4-carboxylic acid) was identified as the compound with the best IC 50 (5.8 nM compared to 260 nM for allopurinol) and exhibited inhibitory activity of a mixed type. Similar to febuxostat, Y-700 exhibited more potent and longer-lasting hypouricemic activity than allo/oxypurinol [139,150]. Moreover, related results suggest that Y-700 is a useful agent for the prevention of colon tumorigenesis [151].…”

“…The introduction of new substituents to a natural substrate produces a better affinity towards the enzyme. Based on xanthine, new purine-like analogues were reported in some related studies such as the newly synthesized 8-(n-hexylthio) xanthine and the xanthine derivative 1,3-dipropylxanthine substituted benzenesulfonic acid, both of which showed better potency than allopurinol [139,140]. One of the best irreversible inhibitors of hypoxanthine derivatives was 8-(m-(p-fluorosulfonylbenzamido)benzylthio) hypoxanthine,…”

Inhibitors of Xanthine Oxidase: Scaffold Diversity and Structure‐Based Drug Design

“…Three years later the xanthine derivative 1,3‐dipropylxanthine substituted benzenesulfonic acid ( 5 ), already known as an adenosine receptor antagonist, was reported by Sousa et al. to be a good XO inhibitor, with an IC 50 value in the micromolar range. In vivo studies conducted in rats showed that this compound is able to decrease both the levels of uric acid and the generation of superoxide radicals.…”

“…In aw ork published in 2001 by Biagi et al [33] it was reported that the newly synthesized 8-(n-hexylthio)xanthine( 4)s howed more than six times better potencyt han allopurinol. Three years later the xanthine derivative 1,3-dipropylxanthine substituted benzenesulfonic acid (5), already knowna sa na denosine receptor antagonist, was reported by Sousa et al to be ag ood XO inhibitor, [34] with an IC 50 value in the micromolar range. In vivo studies conducted in rats showedt hat this compound is able to decrease both the levels of uric acid and the generation of superoxide radicals.…”