Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran; Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran.
Carbohydr Res. 2013 Oct 18;380:81-91. doi: 10.1016/j.carres.2013.07.008. Epub 2013 Aug 6.
The synthesis of a set of pyrimidine-fused derivatives (L1-L8), resulting from the incorporation of different fragments on the pyrimidine-fused heterocycle (PFH) of the earlier reported α-glucosidase (α-Gls) inhibitor (C1-C5), allowed the discovery of new ligands with modest and selective inhibitory activity. The PFH core (substructure 2) was proved to play a significant role in their inhibitory properties. Additionally, the substituent on substructures 1 and 3 of the heterocyclic ring was demonstrated to be important in the enzyme inhibitory action of the pyrimidine-fused derivatives. Moreover, these ligands show selective inhibitory properties for α-Gls over porcine pancreatic α-amylase (α-Amy) which is important in terms of their reduced susceptibility for the possible development of intestinal disturbance side effects. Therefore, low to moderate α-Amy inhibition with effective α-Gls inhibitory action may offer a better therapeutic strategy. Overall, these compounds can potentially offer a new opportunity to develop novel antidiabetic drugs with selective inhibitory action against α-Gls.
我们合成了一组嘧啶稠合衍生物（L1-L8），这些衍生物是在先前报道的α-葡萄糖苷酶（α-Gls）抑制剂（C1-C5）的嘧啶稠合杂环（PFH）上引入不同片段得到的，从而发现了具有适度和选择性抑制活性的新配体。PFH 核心（结构 2）被证明在它们的抑制特性中起着重要作用。此外，杂环的 1 位和 3 位取代基在嘧啶稠合衍生物的酶抑制作用中也很重要。此外，这些配体对α-Gls 具有选择性抑制作用，而对猪胰腺α-淀粉酶（α-Amy）的抑制作用较弱，这对于降低可能引起肠道紊乱副作用的风险非常重要。因此，低至中度的α-Amy 抑制作用和有效的α-Gls 抑制作用可能提供一种更好的治疗策略。总的来说，这些化合物可能为开发具有选择性抑制α-Gls 作用的新型抗糖尿病药物提供新的机会。
