一种茚酮衍生物的合成及其体内外抗肿瘤活性研究

摘要

目的:制备新型茚酮衍生物,研究其抗肿瘤活性.方法:以水合茚三酮、反式β-硝基苯乙烯和戊烯醛为原料,用仲胺催化的MBH-麦克加成-环化“一锅法”反应和后续的碘关环反应制备茚酮骨架与呋喃并吡喃骨架桥接的茚酮衍生物;用四甲基偶氮唑盐(MTT)法测定新型茚酮衍生物对人肿瘤细胞株MV4-11,THP-1,U87,H1975,A549,Lncap,DU145,Huh-7,Raji,HCT116,MDA-MB-231,MKN45,Capan-2,A2780,A2780/Taxol,A2780/CP,MCF7/ADR的增殖抑制作用;用人急性髓性白血病MV4-11细胞和人结肠癌HCT116细胞皮下注射小鼠建立小鼠肿瘤模型,考察新型茚酮衍生物对肿瘤体内生长的影响.结果:得到结构确证的茚酮骨架与呋喃并吡喃骨架桥接的产物;能抑制MV4-11,THP-1,U87,H1975,A549,Lncap,DU145,Huh-7,Raji,HCT116,MDA-MB-231,MKN45,Capan-2和A2780细胞增殖,半数抑制浓度(IC50)分别为1.31,3.23,3.88,3.23,3.46,2.57,2.86,4.17,4.34,4.18,4.63,3.25和3.26 mmol·L-1;能抑制耐药肿瘤细胞A2780/Taxol,A2780/CP,MCF7/ADR增殖,IC50分别为4.62,4.33和3.71 mmol·L-1;体内抗肿瘤研究中,茚酮衍生物抑制MV4-11(12.5,25和50 mg·kg-1,ig)和HCT116(12.5,25和50 mg·kg-1,ig)模型小鼠肿瘤生长,且抑制作用呈剂量依赖.结论:新型茚酮衍生物((3S,3aR,4S,5S,7aS)-3-碘-2,2-二甲基-5-硝基-苯基-2H,3H,3aH,4H,5H,7aH-螺[呋喃[2,3-b]吡喃-6,2'-茚]-1',3'-二酮)具有良好的体内外抗肿瘤活性,可作为新的抗肿瘤药物先导化合物进行进一步的研究与开发.%Objective:To synthesize a new type of spiroindanone derivative and determine its antitumor activity in vitro and in vivo.Methods:The new indanone derivative compound,(3S,3aR,4S,5S,7aS)-3-iodo-2,2-dimethyl-5-nitro-4-phenyl-2,3,3a,4,5,7a-hexahydrospiro [furo [2,3-b] pyran-6,2'-indene]-1',3'-dione,was synthesized by chiral secondary amine-catalyzed MBH-Michael-Acetalization cascade reaction and an iodine-mediated cyclization reaction.The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was used to determine inhibitory effect of the new indanone derivative on human carcinoma cell lines,MV4-11,THP-1,U87,H1975,A549,Lncap,DU145,Huh-7,Raji,HCT116,MDA-MB-231,MKN45 and Capan-2,and drugresistant human carcinoma cell lines,A2780/Taxol,A2780/CP and MCF7/ADR cells.Human leukemia cell line MV4-11 cells and human colorectal cancer cell line HCT116 cells were implanted in NOD-SCID mice and BALB/c nude mice to establish mouse tumor models.Results:A new type indanone derivative bearing five chiral centers with confirmed structure and excellent stereoselectivity was synthesized successfully.The new indanone derivative efficiently inhibited the proliferation of MV4-11,THP-1,U87,H1975,A549,Lncap,DU145,Huh-7,Raji,HCT116,MDA-MB-231,MKN45,Capan-2,A2780,A2780/Taxol,A2780/CP,and MCF7/ADR cells,with IC50 values of 1.31,3.23,3.88,3.23,3.46,2.57,2.86,4.17,4.34,4.18,4.63,3.25,3.26,4.62,4.33,and 3.71 mmol· L-1,respectively.The new indanone derivative significantly inhibited the growth of tumor in mouse tumor models of leukemia and colorectal cancer in dose-dependent manners.Conclusion:The new indanone derivative,(3 S,3 aR,4S,5 S,7 aS)-3-iodo-2,2-dimethyl-5-nitro-4-phenyl-2,3,3 a,4,5,7 a-hexahydrospiro [furo [2,3-b] pyran-6,2'-indene]-1',3'-dione,has a broad spectrum of anticancer activity in vitro.In addition,it also suppresses the growth of tumor in mouse tumor models of leukemia and colorectal cancer in vivo.