Okuda J, Miwa I, Inagaki K, Horie T, Nakayama M
Biochem Pharmacol. 1982 Dec 1;31(23):3807-22. doi: 10.1016/0006-2952(82)90297-0.
Thirty flavones, four isoflavones and thirteen coumarins were tested as inhibitors of lens aldose reductase, which is believed to participate in the initiation of cataract formation in diabetes. Many were found to be potent inhibitors, and the two most potent ones were axillarin (5,7,3',4'-tetrahydroxy-3,6-dimethoxyflavone) and 6,3',4'-trihydroxy-5,7,8-trimethoxyflavone (LARI 1). These two flavones inhibited aldose reductase purified from rat lens with IC50 values of 2.6 X 10(8) and 3.6 X 10(8) M respectively. They also inhibited aldose reductase purified from bovine lens with IC50 values of 1.8 X 10(7) M. The potencies of the two compounds were superior to those of all the previously reported inhibitors of aldose reductase. Inhibition of rat and bovine lens aldose reductases by the two compounds was of a non-competitive type with DL-glyceraldehyde as the variable substrate. Some flavones including axillarin and LARI 1 were found to be poorly or scarcely inhibitory against several adeninenucleotide-requiring enzymes, which are involved in glycolysis and other metabolic reactions. These results obtained show that the two flavones have some features which may be required in clinically useful drugs for diabetic patients. All the potent inhibitors of the compounds tested had a flavone skeleton, one (or two free) hydroxyl(s) in ring C, and more than three hydroxyls (free or methylated) in ring A. The possible relationships of structures to inhibitory potencies of the compounds tested are discussed.
测试了30种黄酮、4种异黄酮和13种香豆素作为晶状体醛糖还原酶的抑制剂，该酶被认为参与糖尿病性白内障形成的起始过程。发现许多化合物是有效的抑制剂，其中两种最有效的是腋花苷（5,7,3',4'-四羟基-3,6-二甲氧基黄酮）和6,3',4'-三羟基-5,7,8-三甲氧基黄酮（LARI 1）。这两种黄酮抑制从大鼠晶状体中纯化的醛糖还原酶，IC50值分别为2.6×10⁻⁸和3.6×10⁻⁸ M。它们还抑制从牛晶状体中纯化的醛糖还原酶，IC50值为1.8×10⁻⁷ M。这两种化合物的效力优于所有先前报道的醛糖还原酶抑制剂。以DL-甘油醛为可变底物时，这两种化合物对大鼠和牛晶状体醛糖还原酶的抑制作用属于非竞争性类型。发现包括腋花苷和LARI 1在内的一些黄酮对几种参与糖酵解和其他代谢反应的需腺嘌呤核苷酸的酶抑制作用较弱或几乎没有抑制作用。这些结果表明，这两种黄酮具有一些糖尿病患者临床可用药物可能需要的特性。所测试的所有有效抑制剂化合物都具有黄酮骨架，C环有一个（或两个游离）羟基，A环有三个以上羟基（游离或甲基化）。讨论了所测试化合物的结构与抑制效力之间可能的关系。
