新型吲哚鬼臼毒素衍生物的合成及抗癌活性研究
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摘要
该文根据药物设计拼合原理,以鬼臼毒素和5-羧酸吲哚为起始原料,在鬼臼毒素母核的基础上,在其C-4位引入了不同的吲哚取代基,设计合成了一系列吲哚鬼臼毒素衍生物,并对其体外抗肿瘤活性进行研究,以期提高该类化合物的抗肿瘤作用,筛选出高效低毒的化合物。设计并合成了6个目标化合物4a～4f,均未见文献报道,其结构经~1H-NMR,~(13)C-NMR,HRESI-MS及熔点测定分析确证。以依托泊苷为阳性对照药,采用MTT法测试所有的目标化合物对He La细胞,K562细胞,K562/A02细胞的体外抗肿瘤活性。抗肿瘤活性筛选结果表明4b,4e,4f对He La细胞和K562细胞的体外抗肿瘤活性均比阳性对照药VP-16强。此路线操作简单,结构设计合理,对进一步开展鬼臼毒素的结构改造和抗肿瘤活性研究具有一定的参考价值。
According to drug design flattening principle,a series of novel indole podophyllotoxin derivatives which were introduced different indole substituents in C-4 position on the basis of podophyllotoxin nucleus were synthesized with the starting material podophyllotoxin and 1 H-indole-5-carboxylic acid. Its anti-tumor activity in vitro was tested in order to screen for high-efficiency and low-toxic compounds. Six target compounds were synthesized,and were confirmed by~1 H-NMR,~(13)C-NMR,HR-ESI-MS and melting point determination analysis. All these target compounds were not reported by previous literature. Using etoposide as positive control drug,all the target compounds were screened for cytotoxicity against He La cells,K562 cells and K562/A02 cell in vitro by MTT method. The antitumor activity screening results showed that compounds 4 b,4 e,4 f exhibited higher inhibitory rate against He La cells and K562 cells than those of control drug VP-16. This route has the advantages on simple operation and reasonable design,provides some practical reference value for the further development on the structure modification of podophyllotoxin and study on anti-tumor activity.
According to drug design flattening principle,a series of novel indole podophyllotoxin derivatives which were introduced different indole substituents in C-4 position on the basis of podophyllotoxin nucleus were synthesized with the starting material podophyllotoxin and 1 H-indole-5-carboxylic acid. Its anti-tumor activity in vitro was tested in order to screen for high-efficiency and low-toxic compounds. Six target compounds were synthesized,and were confirmed by~1 H-NMR,~(13)C-NMR,HR-ESI-MS and melting point determination analysis. All these target compounds were not reported by previous literature. Using etoposide as positive control drug,all the target compounds were screened for cytotoxicity against He La cells,K562 cells and K562/A02 cell in vitro by MTT method. The antitumor activity screening results showed that compounds 4 b,4 e,4 f exhibited higher inhibitory rate against He La cells and K562 cells than those of control drug VP-16. This route has the advantages on simple operation and reasonable design,provides some practical reference value for the further development on the structure modification of podophyllotoxin and study on anti-tumor activity.
引文
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[7]唐啸威,谢文利,陈虹,等.吲哚草酰类鬼臼毒素衍生物的合成及其抗肿瘤活性[J].天津医科大学学报,2011,17(3):299.
[8]吕晶晶,张予阳,陈虹,等.鬼臼毒素衍生物CIP-36诱导KBV200细胞凋亡[J].中国药理学通报,2010,26(5):607.
[9]李楠,赵阳,魏菲,等.鬼臼毒素脲类衍生物的合成和体外抗癌活性的研究[J].天津医科大学学报,2016,22(3):199.
[2] Issell B F,Muggia F M. Etoposide current status and new developments[M]. New York:Academic Press Inc.,1984.
[3] Lee K H,Beers S A,Mori M,et al. Antitumor agents. 111. new-hydroxylated and 4-halogenated aniline derivatives of 4'-demethylepipodophyllotoxin as potent inhibitors of human DNA topoisomeraseⅡ[J]. J Med Chem,1990,33(5):1364.
[4] Kamal A,Suresh P,Ramaiah M J,et al. 4β-[4'-(1-(Aryl)ureido)benzamide] podophyllotoxins as DNA topoisomeraseⅠandⅡαinhibitors and apoptosis inducing agents[J]. Bioorg Med Chem,2013,21(17):5198.
[5] Cragg G M,Newman D J. A tale of two tumor targets:topoisoimerase I and tubulin. The Wall and Wani contribution to cancer chemotherapy[J]. J Nat Prod,2004,67(2):232.
[6]陆艳玲,左松,师少宇,等.新型鬼臼毒素衍生物的合成及其抗肿瘤活性[J].中国药物化学杂志,2010,20(2):90.
[7]唐啸威,谢文利,陈虹,等.吲哚草酰类鬼臼毒素衍生物的合成及其抗肿瘤活性[J].天津医科大学学报,2011,17(3):299.
[8]吕晶晶,张予阳,陈虹,等.鬼臼毒素衍生物CIP-36诱导KBV200细胞凋亡[J].中国药理学通报,2010,26(5):607.
[9]李楠,赵阳,魏菲,等.鬼臼毒素脲类衍生物的合成和体外抗癌活性的研究[J].天津医科大学学报,2016,22(3):199.