title: 3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a potent inhibitor of xanthine oxidase: a potential therapeutic agent for treatment of hyperuricemia and gout.
abstract: Hyperuricemia, excess of uric acid in the blood, is a clinical problem that causes gout and is also considered a risk factor for cardiovascular disease. The enzyme xanthine oxidase (XO) produces uric acid during the purine metabolism; therefore, discovering novel XO inhibitors is an important strategy to develop an effective therapy for hyperuricemia and gout. We found that 3,4-dihydroxy-5-nitrobenzaldehyde (DHNB), a derivative of the natural substance protocatechuic aldehyde, potently inhibited XO activity with an IC₅₀ value of 3 μM. DHNB inhibited XO activity in a time-dependent manner, which was similar to that of allopurinol, a clinical XO inhibitory drug. DHNB displayed potent mixed-type inhibition of the activity of XO, and showed an additive effect with allopurinol at the low concentration. Structure-activity relationship studies of DHNB indicated that the aldehyde moiety, the catechol moiety, and nitration at C-5 were required for XO inhibition. DHNB interacted with the molybdenum center of XO and was slowly converted to its carboxylic acid at a rate of 10⁻¹⁰ mol/L/s. In addition, DHNB directly scavenged free radical DPPH and ROS, including ONOO⁻ and HOCl. DHNB effectively reduced serum uric acid levels in allantoxanamide-induced hyperuricemic mice. Furthermore, mice orally given a large dose (500 mg/kg) of DHNB did not show any side effects, while 42% of allopurinol (500 mg/kg)-treated mice died and their offspring lost their fur. Thus, DHNB could be an outstanding candidate for a novel XO inhibitory drug that has potent activity and low toxicity, as well as antioxidant activity and a distinct chemical structure from allopurinol.
authors.affiliation: Molecular Surgeon Research Center, Division of Surgical Research, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Lü
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Yao
authors.forename: Changyi
authors.initials: C
authors.lastname: Chen
mesh_terms: D000284:Administration, Oral; D000493:Allopurinol / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001547:Benzaldehydes / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002396:Catechols / Q000737:chemistry; D002474:Cell-Free System; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006074:Gout Suppressants / Q000494:pharmacology*; D033461:Hyperuricemia / Q000188:drug therapy*; D020128:Inhibitory Concentration 50; D051379:Mice; D008810:Mice, Inbred C57BL; D008982:Molybdenum / Q000737:chemistry / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D014527:Uric Acid / Q000097:blood; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
chemical_list: D000975:Antioxidants; D001547:Benzaldehydes; D002396:Catechols; D004791:Enzyme Inhibitors; D006074:Gout Suppressants; D017382:Reactive Oxygen Species; D014527:Uric Acid; C585071:3,4-dihydroxy-5-nitrobenzaldehyde; C005581:protocatechualdehyde; D000493:Allopurinol; D008982:Molybdenum; D014969:Xanthine Oxidase
keywords: 3,4-Dihydroxy-5-nitrobenzaldehyde; Antioxidant; Gout; Hyperuricemia; Xanthine oxidase inhibitor