齐墩果酸-α-氨基膦酸酯衍生物的合成与抗肿瘤活性研究

Synthesis and Anti-tumor Activity Evaluation of Oleanolic Acid-α-aminophosphonate Derivatives

摘要:

目的：合成新型的齐墩果酸-α-氨基膦酸酯衍生物，并研究其抗肿瘤活性。方法：以齐墩果酸为原料，经乙酰化反应后，与草酰氯反应成酰氯，继而在三乙胺作为缚酸剂的条件下，与α-氨基膦酸酯进行反应，一共合成了9个齐墩果酸-α-氨基膦酸酯衍生物，并对其结构进行表征。采用体外抗肿瘤活性测试MTT法，在细胞培养密度为2~3×10⁴个/mL，药物测试浓度为50 μmol·L^-1，作用时间为48 h条件下测试合成的齐墩果酸-α-氨基膦酸酯衍生物对人肺癌细胞A549、人肝癌细胞HepG-2、人宫颈癌细胞Hela和人乳腺癌细胞MDA-MB-231的增殖抑制活性。结果：这些化合物对受试肿瘤细胞株表现出不同程度的抑制活性。其中化合物2，4，7，10对人肺癌细胞A549和人宫颈癌细胞Hela具有显著的增殖抑制活性（对A549的抑制率分别为87.5%，85.3%，87.1%，87.8%，对Hela的抑制率分别为85.7%，78.7%，83.6%，87.9%）；化合物2和10对人乳腺癌细胞MDA-MB-231的增殖抑制活性很好（抑制率分别为82.0%，88.1%）。结论：这些齐墩果酸-α-氨基膦酸酯衍生物表现出不同程度的抗肿瘤活性，其中，苯环上邻位有卤素取代的齐墩果酸-α-氨基膦酸酯衍生物对测试细胞的增殖抑制活性较好。

Abstract:

Objective: To synthesize and evaluate anti-tumor activity of oleanolic acid-α-aminophosphonate derivatives. Method: Oleanolic acid-α-aminophosphonate derivatives were synthesized from oleanolic acid, which was treated by acetylation, then the acetylated product was reacted with oxalyl chloride, followed by esterification with α-aminophosphonate under triethylamine to obtain nine target compounds. The structures of these compounds were identified. MTT method was used to assay the anti-tumor activity of synthesized compounds against human lung cancer cell lines A549, human hepatic cell lines HepG-2, human cervical carcinoma cell lines Hela and human breast cancer cell lines MDA-MB-231.The density of cell culture was 2-3×10⁴/mL, the concentration of drug was 50 μmol·L^-1 for 48 hours. Result: These target compounds showed varying degrees of inhibitory activity against tumor cell lines. Compounds 2, 4, 7 and 10 exhibited significant inhibitory activity against human lung tumor cell A549 and human cervical carcinoma Hela (the inhibition rate against A549 was respectively 87.5%, 85.3%, 87.1% and 87.8%;the inhibition rate against Hela was respectively 85.7%, 78.7%, 83.6% and 87.9%). Compounds 2 and 10 showed high inhibitory activity against human breast tumor cell MDA-MB-231 (the inhibition rate was respectively 82.0% and 88.1%). Conclusion: These oleanolic acid-α-aminophosphonate derivatives exhibited varying degrees of inhibitory activity against tumor cell lines. The compounds with ortho-substituted by halogen in phenyl ring showed better inhibitory activity.