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目的寻找新的烟酰胺磷酸核糖转移酶(Nampt)抑制剂,为进一步药物设计提供依据。方法以进入临床研究的APO866为先导化合物,设计合成一系列Nampt抑制剂。以哌嗪为原料,经取代、SN2反应、Gabriel反应、成胍、环合等多步反应得到关键中间体(7a7,b),该中间体再与酰氯衍生物反应,最终合成目标化合物。结果与结论合成了8个全新的Nampt抑制剂,化合物的结构经质谱和核磁共振氢谱确证;初步体外抗肿瘤实验结果表明,其中3个化合物(H1、H5、H7)具有一定的抗肿瘤活性,其活性与阳性对照APO866相当。
Objective To search for a new inhibitor of nalotonamide phosphoribosyltransferase (Nampt), which provides a basis for further drug design. Methods APO866 entered the clinical study as the lead compound, designed and synthesized a series of Nampt inhibitors. The key intermediate (7a7, b) was obtained from piperazine by reaction of substitution, SN2 reaction, Gabriel reaction, guanidine and cyclization to obtain the key intermediate (7a7, b). The intermediate was reacted with acid chloride derivative finally to synthesize the target compound. RESULTS AND CONCLUSION: Eight new Nampt inhibitors were synthesized and the structures of the compounds were confirmed by MS and 1H NMR. The preliminary in vitro antitumor experiments showed that three compounds (H1, H5 and H7) had certain anti-tumor activity , Its activity and the positive control APO866 quite.