烟酰胺磷酸核糖转移酶抑制剂的设计合成及抗肿瘤细胞增殖活性

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。

Synthesis and antitumor activities of nicotiamide phosphoribosyl transferase inhibitors

Nowadays,nicotinamide phosphoribosyl transferase(Nampt) has studied as an important target in the area of tumor inhibition.As a result,it is necessary to find some better Nampt inhibitors.A Nampt inhibitor APO866(also known as FK866) which entered clinical trials was chosen as a lead compound,eight Nampt inhibitors derivatives were designed and synthesized.Using piperazine as raw materials,by seven steps including substitution reaction,SN2 reaction,Gabriel reaction,synthesis of guanidine,cyclization,deprotection and acylation,the target compounds were synthesized.Moreover,the structures of compounds were verified by MS and 1H-NMR,and preliminary in vitro antitumor assessment showed that three compounds(H1,H5,H7) had a certain antitumor activity(the IC50 value of H1 on MCF-7,HL-60 and A549 were 20.25 μmol · L-1,20.64 μmol · L-1 and 13.45 μmol · L-1;the IC50 value of H5 on MCF-7,HL-60 and A549 were 23.88 μmol · L-1,25.23 μmol · L-1 and 18.52 μmol · L-1;the IC50 value of H7 on MCF-7,HL-60 and A549 were 22.99 μmol · L-1,28.72 μmol · L-1 and 10.57 μmol · L-1),in which the biological activity of them nearly approaches the APO866(IC50 value of APO866 on MCF-7,HL-60 and A549 were 20.18 μmol · L-1,12.92 μmol · L-1 and 7.15 μmol · L-1).These data will provide certain reference for APO866 further structure transformation.