利用甘草次酸和齐墩果酸研究空间位阻对五环三萜类羧基酰化反应的影响
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摘要
目的以甘草次酸和齐墩果酸为例探讨空间位阻对五环三萜类羧基酰化反应的影响。方法选取甘草次酸与齐墩果酸两种羧基位(非角位和角位)空间位阻不同的母核;与四元环或五元环和氮原子在环内或环外存在差异的环戊胺、环己胺、哌啶、吡咯烷四种含氮结构通过酰化反应的结果来进行对比实验分析,以期探明影响酰化反应的原因。结果甘草次酸可以和4种含氮结构正常进行酰化化反应,得到4个未见报道新结构,而齐墩果酸与其只能生成"齐墩果酸-HOBt"中间体活化酯,无法得到最终目标物。结论本实验揭示三萜类羧基酰化主要与其自身母核的空间位阻有关,而含氮杂环对酰化反应影响较小,本实验对今后三萜类羧基开展类似的酰化反应具有借鉴意义。
OBJECTIVE To investigate the effect of steric hindrance on the acylation reaction of pentacyclic triterpenoids,taking glycyrrhetinic acid and oleanolic acid as examples. METHODS The parent nucleus of glycyrrhetinic acid and oleanolic acid were selected,for which the steric hindrance is different at the two carboxyl sites: one is non-angle,another is angle. The parent nucleus were combined with cyclopentylamine,cyclohexylamine,piperidine,and pyrrolidine,respectively. The four simple nitrogen-containing heterocycles are distinct from the four-membered or five-membered ring and the nitrogen atom is inside or outside the ring. By means of comparing and analyzing the acylation reaction results,the reasons influencing acylation reactions were explored. RESULTS Glycyrrhetinic acid had acylation reaction with four simple nitrogen-containing heterocycles normally,whereas oleanolic acid only formed a kind of intermediate active ester,"oleanolic acid-HOBt",and no final target object could be obtained. CONCLUSION The effect of nitrogen-containing heterocycles on the acylation reaction is almost negligible,while the steric hindrance of different parent nucleuses has significant influence on the acylation reaction. This study is of reference significance for the acylation reaction of triterpenoid carboxyl groups.
OBJECTIVE To investigate the effect of steric hindrance on the acylation reaction of pentacyclic triterpenoids,taking glycyrrhetinic acid and oleanolic acid as examples. METHODS The parent nucleus of glycyrrhetinic acid and oleanolic acid were selected,for which the steric hindrance is different at the two carboxyl sites: one is non-angle,another is angle. The parent nucleus were combined with cyclopentylamine,cyclohexylamine,piperidine,and pyrrolidine,respectively. The four simple nitrogen-containing heterocycles are distinct from the four-membered or five-membered ring and the nitrogen atom is inside or outside the ring. By means of comparing and analyzing the acylation reaction results,the reasons influencing acylation reactions were explored. RESULTS Glycyrrhetinic acid had acylation reaction with four simple nitrogen-containing heterocycles normally,whereas oleanolic acid only formed a kind of intermediate active ester,"oleanolic acid-HOBt",and no final target object could be obtained. CONCLUSION The effect of nitrogen-containing heterocycles on the acylation reaction is almost negligible,while the steric hindrance of different parent nucleuses has significant influence on the acylation reaction. This study is of reference significance for the acylation reaction of triterpenoid carboxyl groups.
引文
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[2] XU B,CHU F,ZHANG Y,et al. A series of new ligustrazinetriterpenes derivatives as anti-tumor agents:design,synthesis,and biological evaluation[J]. Int J Mol Sci,2015,16(9):21035-21055.
[3] YANG S J,LIU M C,ZHAO Q,et al. Synthesis and biological evaluation of betulonic acid derivatives as antitumor agents[J].Eur J Med Chem,2015,96(8):58-65.
[4] WU X L,ZHUANG P P,HAO J N,et al. Regulation of 18β-glycyrrhetinic acid on apoptosis of U937 cell through activation of Wnt/β-catenin signal[J]. Chin Pharm J(中国药学杂志),2014,49(19):1710-1715.
[5] GINER-LARZA E M,MEZ S,RECIO M C,et al. Oleanonic acid,a 3-oxotriterpene from Pistacia,inhibits leukotriene synthesis and has anti-inflammatory activity[J]. Eur J Pharmacol,2001,428(1):137-143.
[6] CHANG S,LI L. Research progress on the pharmacological action of oleanolic acid[J]. Guangzhou Chem Ind(广州化工),2011,39(14):30-31.
[7] FAN X F,WANG P L,DU H Y,et al. Effect of new oleanolic acid derivative on proliferation and apoptosis in SMMC-7721 cell[J]. Chin Pharm J(中国药学杂志),2016,51(24):2114-2118.
[8] YAN R Y,CHEN R Y. Discovery and optimization of lead compounds in natural products[J]. Chin J Nat Med(中国天然药物),2005,3(6):18-21.
[9] LIU H L,WANG L,LIN D Z. Optimization strategy of lead compound structure(2)-structural modification reduces potential toxicity[J]. Acta Pharm Sin(药学学报),2014,49(1):1-15.
[10] CHU F,XU X,LI G,et al. Amino acid derivatives of ligustrazine-oleanolic acid as new cytotoxic agents[J]. Molecules,2014,19(11):18215-18231.
[11] CHU F,ZHANG W,GUO W,et al. Oleanolic acid-amino acids derivatives:design,synthesis,and hepatoprotective evaluation in vitro and in vivo[J]. Molecules,2018,23(2):332-346.
[12] WANG P,CHENG Y,XU K,et al. Synthesis and antitumor evaluation of one novel tetramethylpyrazine-rhein derivative[J].Asian J Chem,2013,25(9):4885-4888.
[13] WANG P,SHE G,YANG Y,et al. Synthesis and biological evaluation of new ligustrazine derivatives as anti-tumor agents[J].Molecules,2012,17(5):4972-4985.
[14] XU K,XU X,CHU F,et al. Synthesis and biological evaluation of T-OA analogues as the cytotoxic agents[J]. Res Chem Int,2015,41(9):6257-6269.
[15] GUO C. Drug Synthetic Reactions(药物合成反应)[M]. Beijing:People's Medical Publishing House,2014:120.