黄芩素含氮衍生物的合成Synthesis of nitrogen-containing baicalein analogues
费佳,冯锋,柳文媛,王军政
FEI Jia1,FENG Feng1,LIU Wen-yuan2,WANG Jun-zheng1(1.Department of Natural Medicinal Chemistry
摘要(Abstract)：
目的为开发黄芩素为母体的抗肿瘤药物奠定基础。方法首先制备卤代的含氮中间体R1R2N(CH2)nCl.HCl,使之与黄芩素的6位或7位酚羟基反应,引入氮原子到黄芩素的A环。并用四甲基偶氮唑盐微量酶反应比色法[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide,MTT]测定合成产物体外抑制人肝癌细胞HepG2和人肺腺癌细胞A549细胞的活性。结果合成了10个黄芩素含氮衍生物(4a-4f,5a-5d),并经波谱测试确证其结构,均为新化合物。初步活性测试显示4c,5d有较显著的细胞毒性提升。结论该方法提供了一类新的黄芩素衍生物,能够用来制备黄芩素衍生物有机酸盐,改善母体溶解度不佳的缺点,并在药理活性方面有开发潜力。
Objective To study the anti-tumor baicalein analogues.Methods Baicalein derivatives were synthesized from baicalein via alkylation with nitrogen-containing side chain(R1R2N(CH2)nCl·HCl).Cancer cell lines including HepG2 and A549 were incubated with baicalein analogues of various concentrations.The inhibition rate was examined by MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)assay.Results Ten new baicalein analogues(4a4f,5a5d)were prepared and their structures were confirmed by 1H-NMR and ESI-MS.Activity tests showed that 4c and 5b had more significant upgraded cytotoxicity.Conclusions Series of novel baicalein derivatives can be obtained by this synthetic route.The route can be used for the synthesis of water-soluble analogue of baicalein through the reaction with mineral acid or organic acid.
关键词(KeyWords)：
黄芩素;合成;黄酮
flavonoid analogue;baicalein;synthesis
基金项目(Foundation):
作者(Author):
费佳,冯锋,柳文媛,王军政
FEI Jia1,FENG Feng1,LIU Wen-yuan2,WANG Jun-zheng1(1.Department of Natural Medicinal Chemistry
DOI: 10.14066/j.cnki.cn21-1349/r.2010.11.006
参考文献(References)：
- [1]SEDLACEKH H.Pharmacological aspects of targetingcancer gene therapy to endothelial cells[J].CriticalReviews in Oncology/Hematology,2001,139(2):169-215.
- [2]HSU Shih-lan,HSIEH Yun-chih,HESIEH Wen-chiu-an,et al.Baicalein induces a dual growth arrest bymodulating multiple cell cycle regulatory molecules[J].Eur J Pharmacol,2001,425(3):165-171.
- [3]ZHANG Shi-xuan,MA Ji-gang,BAO Yong-ming,etal.Nitrogen-containing flavonoid analogues as CDK1/cyclin B inhibitors:Synthesis,SAR analysis,and bio-logical activity[J].Bioorg Med Chem,2008,16:7127-7132.
- [4]孙逊,胡昌奇,黄晓东,等.黄芩苷元的Mannich反应[J].有机化学,2003,23:81-85.
- [5]LEE Y,YEO H,LIU S H,et al.Increased anti-P-glyco-protein activity of baicalein by alkylation on the a ring[J].J Med Chem,2004,47:5555-5566.
- [6]向华,方维,何玲,等.大豆黄素衍生物的合成及其与雌激素受体亲和力的研究[J].中国药科大学学报,2006,37(1):23-27.