含吡咯结构的二芳氨基嘧啶类ALK抑制剂的设计合成及抗肿瘤活性研究

Design,synthesis and antitumor activities of diarylaminopyrimidine derivatives bearing pyrrolyl moiety as ALK inhibitors

目的设计并合成结构新颖的含吡咯结构的二芳氨基嘧啶类ALK抑制剂。方法基于色瑞替尼与ALK蛋白的共晶模型及其构效关系,设计含吡咯结构的二芳氨基嘧啶类化合物;以2,4,5-三氯嘧啶和5-氟-2-硝基苯甲醚为主要起始原料,经N-烃化、N-酰化、N-烃化、硝基还原和N-烃化5步反应得到目标化合物I1;I1与多种脂肪胺经Mannich反应得到目标化合物I2~I16。采用MTT法及HTRF激酶测试法,评价目标化合物的体外抗肿瘤活性。结果与结论合成了16个未见文献报道的二芳氨基嘧啶类化合物,其结构经MS、1H-NM R谱确证;大部分化合物显示出较强的活性,其中化合物I4的活性最佳,其抑制人间变性淋巴瘤细胞Karpas299和人肺腺癌细胞H2228的IC50值分别为0.021、0.12μmol·L^-1,化合物I4抑制ALK激酶的IC50值为8.7 nmol·L^-1,与色瑞替尼活性相当,有进一步研究的价值。

To develop novel anaplastic lymphoma kinase(ALK)inhibitors,a series of novel diarylaminopyrimidine derivatives bearing pyrrolyl moiety were designed and synthesized.Based on the cocrystal structure of ceritinib with ALK(PDB ID code:4 MKC)as well as the structure-activity relationships(SARs)of ceritinib,modifications were focused on the benzenesulfonyl(A),substituted phenyl(B)and hydrophilic handle(C)regions.With 2,4,5-trichloropyrimidine and 4-fluoro-2-methoxy-1-nitrobenzene as the starting material,the target compound I1 was synthesized via N-alkylation,N-acylation,N-alkylation,reduction reaction and N-alkylation.Subsequently,target compounds I2-I16 were obtained through M annich reaction from compound I1 and a variety of aliphatic amines.M ost compounds exhibited moderate to excellent potency in cellular and enzymatic assays.Compound I4 bearing 1-methylpiperazine moiety showed significant inhibitory activities against ALK-dependent cell lines Karpas299 and H2228 with IC50 of 0.021μmol·L^-1 and 0.12μmol·L^-1,respectively,which were equal to those of ceritinib(IC50=0.022μmol·L^-1 and 0.13μmol·L^-1).The preliminary SARs suggested that different hydrophilic groups on the pyrrolyl motif had significant impacts on anti-proliferative activity.■.