乳香酸类似物的合成及其抗肿瘤活性研究

Studies on the synthesis and antitumor activities of boswellic acid analogues

目的以乳香的提取物 3 乙酰基 11 羰基 β 乳香酸 (AKBA)为先导化合物 ,通过 3位及 2 4位结构修饰合成 3 烷氧基 11 羰基 β 乳香酸酯类衍生物。初步评价其抗肿瘤活性。 方法以AKBA为起始原料通过氯化、水解、烃化共 3步反应制得目标产物。采用吖啶橙 (acridineorange ,AO)和溴化乙啶 (ethidiumbromide ,EB)双染色法 ,测定乳香酸类似物诱导人急性早幼粒白血病细胞 (NB4 )的凋亡活性 ;采用MTT检测法测定目标化合物对NB4细胞的细胞毒性。结果共合成 10个目标化合物 ,其结构经红外光谱、核磁共振谱及质谱确证。初步药理筛选结果表明 :化合物 2、3的活性较先导化合物有明显地提高 ;化合物 2、3的细胞存活率也较先导化合物AKBA有一定程度地提高。结论合成 8个未见文献报道的新化合物 ,其结构经IR ,1H NMR和MS确证。 2、3的凋亡活性和细胞毒性优于AKBA ,值得深入研究。

Aim To design and synthesize 3-alkoxy-11-oxo-β-boswellic ester derivatives using 3-acetyl-11-oxo-β-boswellic acid(AKBA)as leading compound,through the modification on position 3 and position 24 of the structure.Methods Using AKBA as the starting material,the target compounds were synthesized through three-step-process reactions,including chloration,hydrolyzation and alkylation.The ending up of the reaction was determined by TLC.The induced apoptosis activities of the target compounds to NB4 cell were evaluated through AO and EB double decoration assay in vitro and the cell toxicity to NB4 cell were also tested by the MTT assay.Results The chemical structures of the target compounds were confirmed by IR, 1H-NMR, 13C-NMR and MS.The preliminary pharmacological tests showed that compounds 2,3 displayed relatively higher apoptosis activities than that of the lead compound.The cell survival rate of compounds 2 and 3 were improved to some extent comparing with that of AKBA.Conclusion Eight unreported derivatives of boswellic acid were synthesized by this way.Compounds 2 and 3,which were on apoptosis activities and cell toxicity superior to AKBA,are worthy to be intensively studied.