Edwardson J M, Dean P M
Department of Pharmacology, University of Cambridge, U.K.
Biochem Pharmacol. 1992 Dec 1;44(11):2111-5. doi: 10.1016/0006-2952(92)90336-h.
In this study we have shown that a range of compounds that are structurally similar to alloxan are able to protect mice against the diabetogenic effect of alloxan. The compounds include a group of five barbiturates, a group of five hydantoins, the methylxanthines caffeine and theophylline, the related compound uric acid, and ethosuximide. They were injected intraperitoneally prior to intravenous injection of alloxan, and blood glucose concentration was used as an index of alloxan toxicity. The salient structural feature possessed by all of these protective compounds is a pair of carbonyl oxygen atoms separated by a distance of 4.5 A and projecting from an approximately planar heterocyclic five- or six-membered ring; in all cases the carbonyl groups are separated by a ring nitrogen. We suggest that this feature is required for the protective effect of these compounds. In order to test further the requirement for two ring carbonyl groups, we also examined the effects of two compounds containing hydroxyl groups projecting from a six-membered ring, inositol and glucuronic acid. In agreement with previous studies on hexoses, we found that the effects of compounds such as these are unpredictable, with inositol protecting against alloxan toxicity but glucuronic acid not. We are unable to identify the critical difference in structure between these two compounds.
在本研究中，我们已表明，一系列在结构上与四氧嘧啶相似的化合物能够保护小鼠免受四氧嘧啶的致糖尿病作用。这些化合物包括一组五种巴比妥酸盐、一组五种乙内酰脲、甲基黄嘌呤咖啡因和茶碱、相关化合物尿酸以及乙琥胺。在静脉注射四氧嘧啶之前，将它们腹腔注射，血糖浓度用作四氧嘧啶毒性的指标。所有这些具有保护作用的化合物所共有的显著结构特征是一对羰基氧原子，它们相隔4.5埃的距离，并从一个近似平面的五元或六元杂环中伸出；在所有情况下，羰基都被一个环氮隔开。我们认为这一特征是这些化合物产生保护作用所必需的。为了进一步测试对两个环羰基的需求，我们还研究了两种从六元环伸出含有羟基的化合物，即肌醇和葡萄糖醛酸的作用。与先前对己糖的研究一致，我们发现这类化合物的作用不可预测，肌醇可保护小鼠免受四氧嘧啶毒性，而葡萄糖醛酸则不能。我们无法确定这两种化合物在结构上的关键差异。
