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

别嘌呤醇是已知的抑制黄嘌呤氧化酶（XO），现在被广泛用于治疗痛风和高尿酸血症引起的尿酸。别嘌呤醇是相对无毒的。然而，一些别嘌呤醇毒性和危及生命的毒性综合征的报道后，其使用。虽然最近在一些合成化合物中发现了XO抑制活性，但自1963年别嘌呤醇被引入临床使用以来，还没有开发出临床有效的治疗高尿酸血症的XO抑制剂。本文建立了7- h -嘌呤、7-β- d -核糖呋喃基- 7h -[1,2,4]三唑[3,4 - i]嘌呤、9h - 1,2,4 -三唑[3,4 - i]嘌呤、1h -吡唑[3,4 -d]嘧啶和7h -吡唑[4,3 -e]- 1,2,4 -三唑[4,3 -c]嘧啶作为新型潜在的XO抑制剂的简便、通用合成方法。研究了这些化合物对牛乳黄嘌呤的体外抑制活性，结果表明，这些化合物的抑制活性大多是别嘌呤醇的几倍、几倍到几百倍。(1)在7H-嘌呤-2(3H)- 1的6位和1h -吡唑啉[3,4 -d]嘧啶-6(7H)- 1的4位上引入芳醛腙，其活性明显提高，比别嘌呤醇的活性高10 ~ 900倍。与嘌呤的2-氧基衍生物和吡唑嘧啶的6-氧基衍生物相比，在2位或6位上被氯、氨基或硫氧基取代的衍生物有降低活性的趋势。(2)三环杂环9h - 1,2,4 -三唑[3,4 - i]嘌呤总体上表现出比别嘌呤醇更强的抑制活性，但抑制活性低于嘌呤。(3)三环杂环7h -吡唑啉[4,3 -e]- 1,2,4 -三唑啉[4,3 -c]嘧啶-5(6H) -1具有较强的抑制活性，活性比别嘌呤醇高30 ~ 800倍，有的化合物活性比别嘌呤醇高760倍。结果表明，上述杂环上的氧基和芳基甲基肼基可能对抑制活性起重要作用。少

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