含有黄嘌呤衍生物的N-杂环卡宾金属配合物的生物活性研究进展

N-杂环卡宾(NHC)是一类多功能的配体,能够与过渡金属形成稳定的配位化合物,在催化、药学和材料科学等领域有着广泛的应用。黄嘌呤衍生物具有抗肿瘤转移和抗血管生成等生物活性,且结构易于修饰。将黄嘌呤衍生的NHC配体与过渡金属相结合有望得到具有全新生物活性的金属配合物。综述黄嘌呤衍生物的生物活性,以及黄嘌呤衍生的NHC金属配合物的结构特点和生物活性,并对黄嘌呤NHC金属配合物的研究进行了总结和展望,以期为进一步的研究提供参考。     

Design,synthesis, and molecular docking studies of N‐(9,10‐anthraquinone‐2‐carbonyl)amino acid derivatives as xanthine oxidase inhibitors

A series of N‐(9,10‐anthraquinone‐2‐carbonyl)amino acid derivatives ( 1a–j ) was designed and synthesized as novel xanthine oxidase inhibitors. Among them, the L/D‐phenylalanine derivatives ( 1d and 1i ) and the L/D‐tryptophan derivatives ( 1e and 1j ) were effective with micromolar level potency. In particular, the L‐phenylalanine derivative 1d (IC₅₀ = 3.0 μm ) and the D‐phenylalanine derivative 1i (IC₅₀ = 2.9 μm ) presented the highest potency and were both more potent than the positive control allopurinol (IC₅₀ = 8.1 μm ). Preliminary SAR analysis pointed that an aromatic amino acid fragment, for example, phenylalanine or tryptophan, was essential for the inhibition; the D‐amino acid derivative presented equal or greater potency compared to its L‐enantiomer; and the 9,10‐anthraquinone moiety was welcome for the inhibition. Molecular simulations provided rational binding models for compounds 1d and 1i in the xanthine oxidase active pocket. As a result, compounds 1d and 1i could be promising lead compounds for further investigation.     

Design,synthesis, and biological evaluation of 5‐(4‐(pyridin‐4‐yl)‐1H‐1,2,3‐triazol‐1‐yl)benzonitrile derivatives as xanthine oxidase inhibitors

A series of 5‐(4‐(pyridin‐4‐yl)‐1H‐1,2,3‐triazol‐1‐yl)benzonitrile derivatives ( 1a–p ) was designed, synthesized, and identified as xanthine oxidase inhibitors with micromolar level potencies. Among them, the most promising compounds 1j and 1k were obtained with IC₅₀ values of 8.1 and 6.7 μm , respectively. The Lineweaver–Burk plot revealed that compound 1k acted as a mixed‐type xanthine oxidase inhibitor. SAR analysis revealed that a carbon atom occupying the X³ position is not as effective as a nitrogen atom, and an iso‐pentyloxy or a cyclopentyloxy at the 2‐position of benzonitrile moiety will benefit the inhibitory potency. The basis of xanthine oxidase inhibition by 1k was rationalized by molecular modeling studies.     

抗高尿酸血症药物研究进展

痛风是一种代谢性疾病,危害严重,近年来患病率呈上升趋势。尿酸排泄减少或生成增多所致的高尿酸血症是痛风的主要病因,而高尿酸又与多种疾病密切相关。降低血尿酸水平是治疗痛风,预防痛风复发的重要措施。目前,抗高尿酸血症药物主要有3类,分别是黄嘌呤氧化酶抑制剂、尿酸盐阴离子转运蛋白1(URAT1)抑制剂和尿酸氧化酶类似物。对现有抗高尿酸血症药物的现状以及研究进展进行总结,希望对其研发提供参考。     

Febuxostat for the treatment of gout

Introduction: Gout is a rheumatologic condition associated with elevated serum uric acid levels and deposition of monosodium urate crystals in joints and soft tissues. The xanthine oxidase inhibitor, allopurinol, has historically been the principle agent utilized for reducing elevated uric acid levels and treating underlying cause of gout symptoms; the availability of febuxostat, a newer non-purine selective xanthine oxidase inhibitor, represents an alternative therapy for those patients with contraindications or intolerance to allopurinol.

Areas covered: This article reviews the published literature on the pharmacologic characteristics and clinical safety and efficacy data on the use of febuxostat in the treatment of gout. A literature search of MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations Databases (1996–November 2014) was conducted utilizing the key words ‘febuxostat’, ‘allopurinol’, and ‘gout’. All published articles regarding febuxostat were evaluated. References of selected articles, data from poster presentations, and abstract publications were additionally reviewed.

Expert opinion: Febuxostat has shown benefit with respect to symptomatic relief and uric acid level reduction. The safety profile of this agent makes it an ideal alternative in those patients with contraindications to or who are intolerant of allopurinol.     

Biochemical investigation of a child with molybdenum cofactor deficiency

A girl aged eight months, who presented with developmental delay and dislocated optic lenses, was diagnosed as having combined sulfite oxidase and xanthine dehydrogenase deficiencies consistent with molybdenum cofactor deficiency. The diagnosis was confirmed by demonstrating the absence in urine of urothione, a molybdenum cofactor metabolite. Prenatal diagnosis excluded the disease in the mother's second pregnancy. A summary of an in vitro study of molybdenum cofactor synthesis in the patient is given.     

Acceleration of Hypertensive Cerebral Injury by the Inhibition of Xanthine-Xanthine Oxidase System in Stroke-Prone Spontaneously Hypertensive Rats

It is well-known that, in ischemic cerebral injury, a free radical and its byproducts are generated by xanthine-xanthine oxidase system and eliminated by scavengers such as superoxide dismutase (SOD), catalase, uric acid and ascorbic acid. To investigate the possible involvement of the xanthine-xanthine oxidase system in hypertensive cerebral injury, we examined chronological changes in uric acid level in the cerebral cortex and the effects of the inhibition of xanthine oxidase or catalase using stroke-prone spontaneously hypertensive rats (SHRSP).     

Hypouricemic effect of the methanol extract from Prunus mume fruit in mice

Context: The fruit of the Prunus mume Sieb. et Zucc (Rosaceae) is used as a health food or medicinal material in traditional herb medicine for a long time in Eastern Asian countries.

Objective: Our present study investigated the hypouricemic effect of the methanol extract from P. mume fruit (MPMF) in mice with potassium oxonate-induced hyperuremia.

Materials and methods: Effect of MPMF (35, 70 and 140 mg/kg, p.o.) administrated for 7 days on the serum, liver, urinary uric acid levels and liver xanthine oxidase (XO) activity were assessed in mice.

Results: Hyperuricemic mice induced by potassium oxonate demonstrated an elevation in serum and liver uric acid levels (11.0 mg/dL and 0.52 mg/g tissue) and a reduction in urinary uric acid levels (49.9 mg/dL). Oral administration of 140 mg/kg MPMF for 7 days reversed the abnormalities in serum, liver and urinary uric acid levels (7.1 mg/dL, 0.37 mg/g tissue and 69.7 mg/dL, respectively). In addition, 70 and 140 mg/kg MPMF (3.1 and 2.9 nmol/min per mg protein) inhibited liver XO activity compared with hyperuricemic mice (3.9 nmol/min per mg protein).

Discussion and conclusion: The results indicated that the beneficial hypouricaemic effect of MPMF may be mediated, at least in part, by inhibiting XO activity in the liver. Our study suggests that P. mume and its extracts may have a considerable potential for development as an anti-gout agent for clinical application.