含哌嗪基团DPP-Ⅳ抑制剂类似物的合成及体外活性研究

Synthesis and in vitro activity of DPP-IV inhibitor analogues containing piperazine

二肽基肽酶-Ⅳ(DPP-Ⅳ)抑制剂结构中含有伯胺或仲胺基团,与DPP-Ⅳ谷氨酸残基Glu205、Glu206形成氢键,被认为是抑制DPP-Ⅳ活性的重要因素。通过DPP-Ⅳ抑制剂分子对接计算研究发现,含有叔胺的DPP-Ⅳ抑制剂衍生物,通过活性氢原子也可以分别与Glu205、Glu206上羰基形成氢键。本研究设计并合成了14个含有叔胺的哌嗪双取代衍生物,其结构均经MS及1H NMR确证,测定了对DPP-Ⅳ的体外抑制活性,结果表明当被叔胺取代后,对DPP-Ⅳ抑制作用明显消失,因此伯胺和仲胺中氢原子对DPP-Ⅳ的抑制起着关键作用。

The functional group primary or secondary amines of DPP-IV inhibitors provide critical hydrogen bonds to Glu205/Glu206 of DPP-IV and constitute the key factor for an effective inhibition of the enzyms.A docking study showed that the active hydrogen at tertiary amine of DPP-IV inhibitor could interact with the carbonyl at Glu-motif（Glu205-Glu206） of the DPP-IV enzyme.Fourteen potential DPP-IV inhibitors containing piperazine group were synthesized,and determined by MS and 1H NMR.In vitro inhibitory activity of these compounds against DPP-IV was evaluated.The assay results indicated that the inhibitory activity of the tertiary amines compounds against DPP-IV enzyme was lost.Therefore,it seems that hydrogen atoms in the primary or secondary amines of DPP-IV inhibitors may play a crucial role for the inhibition of DPP-IV enzyme.