Costantino L, Del Corso A, Rastelli G, Petrash J M, Mura U
Dipartimento di Scienze Farmaceutiche, Modena e Reggio Emilia University, Via Campi 183, I-41100 Modena, Italy.
Eur J Med Chem. 2001 Sep;36(9):697-703. doi: 10.1016/s0223-5234(01)01272-7.
On the basis of the results of molecular modelling studies performed on the aldose reductase (ALR2) inhibitor 7-hydroxy-2-(4'-hydroxybenzyl)-4H-1-benzopyran-4-one (compound A) bound at the active site of the enzyme, we synthesised and tested on bovine and human ALR2 several derivatives modified at position 2 of the benzopyran moiety, in order to confirm the hypothesised binding mode of this compound. The substitution of the methylene bridge with the isosteric sulphur substituent gives an active derivative, while substitution with a polar NH causes a decrease in inhibitory activity; this is in accordance to the previously reported structure in which the methylene linker was found to be adjacent to a hydrophobic aminoacid (Leu300). Among the substituents at 4' position examined, the most favourable for inhibitory activity are those able to act as hydrogen bond donors, supporting the hypothesis of the importance of the interaction with Thr113 for the inhibition of the enzyme.
基于对与醛糖还原酶（ALR2）活性位点结合的醛糖还原酶抑制剂7-羟基-2-（4'-羟基苄基）-4H-1-苯并吡喃-4-酮（化合物A）进行的分子模拟研究结果，我们合成并在牛和人ALR2上测试了苯并吡喃部分2位修饰的几种衍生物，以证实该化合物假定的结合模式。用等排硫取代基取代亚甲基桥得到一种活性衍生物，而用极性NH取代则导致抑制活性降低；这与先前报道的结构一致，在该结构中发现亚甲基连接体与疏水氨基酸（Leu300）相邻。在所研究的4'位取代基中，对抑制活性最有利的是那些能够作为氢键供体的取代基，这支持了与Thr113相互作用对酶抑制作用重要性的假设。
