摘要:
目的 合成(E)-6-甲氧基-1-(3,4,5-三甲氧基苯亚甲基)-1,2,3,4-四氢-2-萘醇及其对映异构体,测定其晶体结构,并考察其生物活性。 方法 以2,6-二甲氧基萘为起始原料,经还原及Knoevenael缩合制得中间体萘酮,再以CBS不对称催化还原分别制得R、S构型的目标化合物。采用单晶X-衍射测定其晶体结构,并测试其微管蛋白的抑制活性及体外抗肿瘤活性。 结果 目标化合物结构经MS、NMR及X-单晶衍射等确证。目标化合物的不对称还原反应收率达90.3%,e.e.%达99.04%,体外药理活性数据显示,S-构型目标化合物对微管蛋白聚合、HCT116和CCRF-CEM肿瘤细胞的抑制活性优于R-构型异构体及先导化合物22b,其IC50分别达到0.41、0.14 和0.001 μmol/L。 结论 采用CBS不对称催化还原的方法是一条制备高光学纯度的手性目标化合物的合成方法;高活性的S构型异构体具有进一步研究的价值。
Abstract:
Objective To synthesize the enantiomers of (E)-6-methoxy-1-(3,4,5-trimethoxybenzylidene)-1,2,3,4-tetrahydronaphthalen-2-ol,determine their structures by XRD and evaluate their anti-tumor activity in vitro. Methods The target compounds were prepared from 2,6-Dimethoxybenzoyl chloride. The key intermediate,(E)-6-methoxy-1-(3,4,5-trimethoxybenzylidene)-1,2,3,4-tetrahydronaphthalen-2-one,was obtained through Cornforth reduction and Knoevenael reaction,and the final R,S compounds were got by CBS asymmetric reduction.The structure of the target compounds were determined by XRD. The target compounds were rested by anti-tubulin and anti-tumor assay. Results The structure of the target compounds were determined by 1H NMR,13C NMR,MS,and XRD analysis.The yield of asymmetric reduction reaction was 90.3%,e.e.% was 99.04%,in vitro anti-tumor assay showed all of the S isomer had stronger anticancer activity than the R isomer,especially on CCRF-CEM cell(IC50=1 nmol/L),HCT-116 cell(IC50=0.14 μmol/L) and inhibition of tubulin polymerization (IC50=0.41 μmol/L). Conclusion The CBS asymmetric reduction was a good way to get high-yield and high optical purity compound. The S isomer with outstanding anticancer activity was worth further research.
点击查看大图
下载:
