熊果酸衍生物与查耳酮缀合物的合成及抗肿瘤活性研究

Synthesis and Antitumor Activity of Ursolic Acid Derivative-Chalcone Conjugates

目的设计、合成喹喔啉熊果酸-查耳酮缀合物。方法以喹喔啉熊果酸为先导化合物,将查耳酮通过酯化反应拼接到喹喔啉熊果酸得到了一系列喹喔啉熊果酸-查耳酮缀合物,并通过MTT法测试其抗癌活性。结果合成了6个喹喔啉熊果酸-查耳酮缀合物,其结构均通过1H NMR,13C NMR和HRMS加以确认。初步的生物活性结果表明,这些缀合物对MCF-7、PC-3、GBC-823和KB细胞均有抑制活性,尤其是对MCF-7细胞的抑制活性与熊果酸相比均有提高,其中化合物5(IC50=14.2μmol·L^(-1)),6(IC50=15.3μmol·L^(-1))和7(IC50=10.6μmol·L^(-1))对MCF-7细胞的抑制活性甚至强于临床上应用的药物他莫昔芬(IC_(50)=15.9μmol·L^(-1))。同时,这些缀合物对正常的乳腺上皮细胞MCF-10A没有毒性。结论本研究为开发高效、低毒的的熊果酸衍生物提供了信息和依据。

OBJECTIVE Design,synthesis of ursolic acid derivative-chalcone conjugates with anti-cancer activity.METHODS Esterification of quinoxaline ursolic acid with chalcone resulted in novel quinoxaline ursolic acidchalcone conjugates via natural product ursolic acid,and the anti-cancer activity was assessed by MTT.RESULTS6 conjugates were synthesized and their structures have been confirmed by -1H NMR,（13）C NMR and HRMS spectra.The preliminary biological results showed that these conjugates displayed significant antiproliferative effect on MCF-7,PC-3,GBC-823 and KB cells;specifically,they showed the more potency against MCF-7,which is about 2-fold greater potent than ursolic acid;most encouragingly,compounds 5（IC50=14.2μmol·L-1）,6（IC50=15.3μmol·L（-1）） and 7（IC50=10.6μmol·L（-1）） exhibited more potent antiproliferative activity than tamoxifen.Additionally,all conjugates were nontoxic to health MCF-10 A cells,while tamoxifen showed essential toxicity.CONCLUSION This study provided information and basis for development of ursolic acid derivatives with high active and low toxic.