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3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a potent inhibitor of xanthine oxidase: a potential therapeutic agent for treatment of hyperuricemia and gout.
Biochem Pharmacol. 2013 Nov 01; 86(9):1328-37.BP

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+Show Affiliations

Molecular Surgeon Research Center, Division of Surgical Research, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23994369

Citation

Lü, Jian-Ming, et al. "3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) Is a Potent Inhibitor of Xanthine Oxidase: a Potential Therapeutic Agent for Treatment of Hyperuricemia and Gout." Biochemical Pharmacology, vol. 86, no. 9, 2013, pp. 1328-37.
Lü JM, Yao Q, Chen C. 3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a potent inhibitor of xanthine oxidase: a potential therapeutic agent for treatment of hyperuricemia and gout. Biochem Pharmacol. 2013;86(9):1328-37.
Lü, J. M., Yao, Q., & Chen, C. (2013). 3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a potent inhibitor of xanthine oxidase: a potential therapeutic agent for treatment of hyperuricemia and gout. Biochemical Pharmacology, 86(9), 1328-37. https://doi.org/10.1016/j.bcp.2013.08.011
Lü JM, Yao Q, Chen C. 3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) Is a Potent Inhibitor of Xanthine Oxidase: a Potential Therapeutic Agent for Treatment of Hyperuricemia and Gout. Biochem Pharmacol. 2013 Nov 1;86(9):1328-37. PubMed PMID: 23994369.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a potent inhibitor of xanthine oxidase: a potential therapeutic agent for treatment of hyperuricemia and gout. AU - Lü,Jian-Ming, AU - Yao,Qizhi, AU - Chen,Changyi, Y1 - 2013/08/30/ PY - 2013/06/12/received PY - 2013/08/04/revised PY - 2013/08/06/accepted PY - 2013/9/3/entrez PY - 2013/9/3/pubmed PY - 2013/12/18/medline KW - 3,4-Dihydroxy-5-nitrobenzaldehyde KW - Antioxidant KW - Gout KW - Hyperuricemia KW - Xanthine oxidase inhibitor SP - 1328 EP - 37 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 86 IS - 9 N2 - 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. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/23994369/34_Dihydroxy_5_nitrobenzaldehyde__DHNB__is_a_potent_inhibitor_of_xanthine_oxidase:_a_potential_therapeutic_agent_for_treatment_of_hyperuricemia_and_gout_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(13)00497-8 DB - PRIME DP - Unbound Medicine ER -