丹参酮类似物的设计、合成及抗肿瘤活性评价  

Design,synthesis,and antitumor activity evaluation of tanshinone analogues

作　　者：谭欣 余佳 骆衡 潘卫东 TAN Xin;YU Jia;LUO Heng;PAN Weidong(School of Pharmacy,Guizhou Medical University,Guiyang 550025,Guizhou,China;Guizhou Natural Products Research Center,Guiyang 550014,Guizhou,China;School of Pharmacy,Guizhou University,Guiyang 550025,Guizhou,China)

机构地区：[1]贵州医科大学药学院,贵州贵阳550025 [2]贵州省天然产物研究中心,贵州贵阳550014 [3]贵州大学药学院,贵州贵阳550025

出　　处：《贵州医科大学学报》2024年第7期947-956,共10页Journal of Guizhou Medical University

基　　金：国家自然科学基金(82273818)。

摘　　要：目的探讨丹参酮类似物的设计、合成及抗肿瘤活性。方法丙醛和吗啉反应得到化合物2与1,4-萘醌加成反应得到化合物4,用2 mol/L盐酸加热化合物4生成化合物5,通过2-碘酰基苯甲酸氧化得到化合物6,化合物6通过氯甲基化得到化合物7,与目标基团偶联得到丹参酮类似物(TC1~TC8、TE1~TE8、TF1~TF8);以阿霉素作为阳性对照组,目标化合物作为实验组,观察对宫颈癌细胞Hela、人慢性髓系白血病K562、人前列腺癌细胞LNCaP的体外抗肿瘤活性的筛选测试。结果成功合成24个丹参酮类似物(TC系列8个、TE系列8个及TF系列8个),化学结构经HR-MS、^(1)H NMR、^(13)C NMR表征及Scifinder检索均为新化合物,其中TC系列丹参酮类似物对肿瘤细胞有较好抑制作用;丹参酮类似物TC4、TC5、TC6、TC8对宫颈癌细胞Hela、人慢性髓系白血病K562、人前列腺癌细胞LNCaP 3种癌细胞株的增殖有较好的抑制作用,其中化合物TC4的半数抑制浓度值接近与阳性对照组阿霉素,活性最佳;TE及TF系列丹参酮类似物抗癌活性没有阳性药阿霉素好,但化合物TE2和TF8对人前列腺癌细胞LNCaP有一定的抗肿瘤活性、且硫代化合物TE2活性优于氧代化合物TF8,表明硫取代活性相比氧取代活性有一定的优势。结论设计合成的TC系列丹参酮类似物对肿瘤细胞有较好抑制作用,其中化合物TC4的活性最佳。Objective To investigate the design,synthesis and antitumor activity of tanshinone analogues.Methods The reaction of propionaldehyde and morpholine yielded compound 2 with 1,and the compound 4 was obtained by the 4-naphthoquinone addition reaction.The compound 5 was generated by heating the compound 4 with 2 mol/L hydrochloric acid,and the compound 6 was obtained by oxidation of 2-iodoyl benzoic acid.The compound 6 yielded the compound 7 by chloromethylation,which was coupled to the target group to obtain the tanshinone analogue(TC1-TC8,TE1-TE8,and TF1-TF8).Doxorubicin as the positive control group and target compounds as the experimental group were used to test the in vitro antitumor activity of cervical cancer cells Hela,human chronic myeloid leukemia K562,and human prostate cancer cell LNCaP.Results Twenty-four tanshinone analogues(8 in TC series,8 in TE series,and 8 in TF series)were successfully synthesized.The chemical structures were characterized by HR-MS,^(1)H NMR,^(13)C NMR characterization,and Scifinder search as new compounds,among which the TC series tanshinone analogues had a better inhibitory effect on tumor cells.Tanshinone analogues TC4,TC5,TC6,and TC8 had better inhibitory effects on the proliferation of cervical cancer cells Hela,human chronic myeloid leukemia K562,and human prostate cancer cells LNCaP 3 cancer cell lines,among which the half inhibitory concentration value of compound TC4 was close to that of the positive control group doxorubicin with the best activity.The anticancer activity of TE and TF series tanshinone analog was not as good as the positive drug doxorubicin,but the compounds TE2 and TF8 had some antitumor activity of LNCaP in human prostate cancer cells.The activity of the sulfur substitution compound TE2 was better than that of the oxygen substitution compound TF8,indicating that the sulfur substitution activity had some advantages over the oxygen substitution activity.Conclusion The synthetic TC series tanshinone analogue is designed to inhibit the tumor cells quite well

关 键 词：丹参酮类似物 胺类 1 3 4-噁二唑 合成 抗肿瘤 活性 

分 类 号：R931.2[医药卫生—生药学]