Molecular design of purines and purine nucleosides for potential xanthine oxidase inhibitory activity

别嘌呤醇已知可抑制黄嘌呤氧化酶 (XO)，目前广泛用于治疗痛风和尿酸引起的高尿酸血症。别嘌呤醇相对无毒。然而，在使用后已有一些别嘌呤醇毒性和危及生命的毒性综合征的报道。尽管最近在一些合成化合物中发现了 XO 抑制活性，但自 1963 年别嘌呤醇引入临床以来，尚未开发出临床有效的治疗高尿酸血症的 XO 抑制剂。在这里，我们建立了 7H-嘌呤、7-β-D-呋喃核糖基-7H-[1, 2, 4]三唑并[3, 4-I]嘌呤、9H-1、 2, 4-三唑并[3, 4-I]嘌呤、1H-吡唑并[3, 4-d]嘧啶和7H-吡唑并[4, 3-e]-1, 2, 4-三唑并[4, 3-c]嘧啶作为新型潜在的XO抑制剂。研究了它们对牛乳黄嘌呤的体外抑制活性，本研究制备的上述化合物大多来自(1)在7H-嘌呤-2(3H)-one的6位和1H-吡唑并[3, 4-d]嘧啶-6(7H)-one的4位引入芳醛腙，其活性显着提高，比别嘌呤醇活性高10倍至900倍。相比之下，嘌呤的2-氧代衍生物和吡唑并嘧啶的6-xo衍生物，2位或6位被氯、氨基或硫代基取代的衍生物表现出活性降低的趋势。(2)三环杂环9H-1,2,4-三唑并[3,4-I]嘌呤通常表现出比(3) 三环杂环化合物7H-吡唑并[4, 3-e]-1, 2, 4-三唑并[4, 3-c]嘧啶-5(6H)-酮类化合物大多表现出较强的抑制活性，其活性比别嘌呤醇高30倍至800倍，有些化合物的抑制活性高达760倍。证明上述杂环上的氧代基团和芳基亚甲基肼基可能对其抑制活性很重要。较少的

Allopurinol is known to inhibit xanthine oxidase (XO) and is now widely employed in treatment of gout and hyperuricemia resulting from uric acid. Allopurinol is relatively non-toxic. However, some allopurinol toxicities and a life-threatening toxicity syndrome have been reported after its use. Although XO inhibitory activities have recently discovered in some synthetic compounds, no clinically effective XO inhibitors for the treatment of hyperuricemia have been developed since allopurinol was introduced for clinical use in 1963. Here we established new, convenient, and general syntheses of 7H-purines, 7-β-D-ribofuranosyl-7H-[1, 2, 4]triazolo[3, 4-I]purines, 9H-1, 2, 4-triazolo[3, 4-I]purines, 1H-pyrazolo[3, 4-d]pyrimidines and 7H-pyrazolo[4, 3-e]-1, 2, 4-triazolo[4, 3-c]pyrimidines as new class of potential XO inhibitors.Their inhibitory activities against bovine milk xanthine in vitro were investigated, and the above compounds prepared in this study exhibited mostly from several times … More to several hundred times more potent activities than allopurinol.(1) The introduction of arylaldehyde hydrazones at the 6-position of 7H-purine-2(3H)-one and at the 4-position of 1H-pyrazolo[3, 4-d]pyrimidin-6(7H)-one markedly increased their activities, being from 10-fold to 900-fold more active than allopurinol. In contrast the 2-oxo derivatives of the purine and the 6-xo derivatives of the pyrazolopyrimidine, the derivatives substituted by a chloro, amino or thioxo group at the 2-position or at the 6-position showed a tendency to decrease the activity.(2) The tricycle heterocycles, 9H-1, 2, 4-triazolo[3, 4-I]purines, generally showed more potent inhibitory activities than that of allopurinol, but less inhibitory activities compared with the purines.(3) The tricyclic heterocycles, 7H-pyrazolo[4, 3-e]-1, 2, 4-triazolo[4, 3-c]pyrimidin-5(6H)-ones, showed mostly potent inhibitory activities, being from 30-fold to 800-fold more active than allopurinol and some compound showed a 760-fold more potent activity than that of allopurinol.It was demonstrated that the oxo group and the arylmethylidenehydrazino group on the ring of the above heterocycles might be important for the inhibitory activity. Less