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

别嘌醇可以抑制黄嘌呤氧化酶(XO)，现在被广泛用于治疗痛风和尿酸引起的高尿酸血症。别嘌醇相对无毒。然而，在使用别嘌醇后，已有一些别嘌醇毒性和危及生命的毒性综合征的报道。虽然最近在一些合成化合物中发现了XO抑制活性，但自1963年别嘌醇被引入临床使用以来，还没有开发出临床上有效的XO抑制剂来治疗高尿酸血症。本文建立了7H-嘌呤、7-β-D-呋喃核苷-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]嘧啶类化合物的合成方法，研究了它们对牛乳黄嘌呤的体外抑制活性。本研究中所制备的化合物大多为多次…的产物(1)在7H-嘌呤-2(~3H)-酮的6位和1H-吡唑并[3，4-d]嘧啶-6(7H)酮的4位引入芳醛肼后，活性显著提高，活性从10倍提高到900倍。相反，嘌呤的2-氧代衍生物和吡唑并嘧啶的6-氧代衍生物，在2-位或6-位被氯、氨基或硫氧基取代的衍生物表现出活性降低的趋势。(2)三环杂环化合物9H-1，2，4-三唑并[3，4-I]嘌呤通常表现出比别嘌醇更强的抑制活性，但抑制活性低于嘌呤。(3)三环杂环，7H-吡唑并[4，3-e]-1，2，4-三氮唑[4，3-e]-1，2，4-三唑[4，3-e]-1，2，4-三唑并[4，3-e]-1，2，4-三唑并[4，3-e]3-c]-嘧啶-5(6H)-酮类化合物具有较强的抑制活性，比别嘌醇高30~800倍，部分化合物的活性比别嘌醇高760倍，表明上述杂环上的氧基和芳亚甲基肼基团可能对抑制活性有重要作用。较少

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