抗肿瘤中药活性成分千金子素L1的单酰化修饰研究
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摘要
为了考察千金子素L1(1)中的3-苯乙酰基、5-乙酰基及15-乙酰基对抗肿瘤活性的影响,本文以碳酸钾为碱,甲醇为溶剂,将1的3、5、15位酯键水解得脱酰基中间体2,对2的羟基进行选择性乙酰化、丙酰化、苯甲酰化、琥珀单酰化修饰,预期得5-酰基-3,15-二羟基千金子素L1衍生物(3)。经TLC、HPLC、MS检测,结果显示单酰化产物不稳定,化合物3可通过分子内酯交换生成相应的化合物4。
In order to investigate the effects of 3-phenylacetyl, 5-acetyl and 15-acetyl groups in Euphorbia factor L1(1) on anticancer activity, it was designed to synthesize a series of derivatives(3) of compound 1 possessing 5-acyl and 3,15-dihydroxyl. Exposed to potassium carbonate in methanol, compound 1 could be transformed to 3,5,15-trihydroxyl intermediate 2, which was used to synthesize compounds 3 through selective acetylation, propionylation, benzoylation and succinylation of the 5-hydroxyl group of 2. However, the obtained compounds 3 were indicated being instable and could convert into corresponding compounds 4 through intramolecular ester exchange.
In order to investigate the effects of 3-phenylacetyl, 5-acetyl and 15-acetyl groups in Euphorbia factor L1(1) on anticancer activity, it was designed to synthesize a series of derivatives(3) of compound 1 possessing 5-acyl and 3,15-dihydroxyl. Exposed to potassium carbonate in methanol, compound 1 could be transformed to 3,5,15-trihydroxyl intermediate 2, which was used to synthesize compounds 3 through selective acetylation, propionylation, benzoylation and succinylation of the 5-hydroxyl group of 2. However, the obtained compounds 3 were indicated being instable and could convert into corresponding compounds 4 through intramolecular ester exchange.
引文
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[9]Wei Jiao,Zhongmin Wan,Shuang Chen,et al.Lathyrol Diterpenes as Modulators of P?Glycoprotein Dependent Multidrug Resistance:Structure-Activity Relationship Studies on Euphorbia Factor L3Derivatives[J].J.Med.Chem.,2015,58,3720-3738.
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[2]Shi Qingwen,Su Xioahui,Kiyota Hiromasa.Chemical and pharmacological research of the plants in genus Euphorbia[J].Chem Rev.,2008,108(10):4295-4327.
[3]Jiao Wei,Dong Weiwei,Li Zhifeng,et al.Lathyrane diterpenes from Euphorbia lathyris as modulators of multidrug resistance and their crystal structures[J].Bioorg Med Chem.,2009,17(3):4786-4792.
[4]Hong Seongeun,Lee Jiae,Seo Donghyun,et al.Euphorbia factor L1inhibits osteoclastogenesis by regulating cellular redox status and induces Fas-mediated apoptosis in osteoclast[J].Free Radical Bio.Med.,2017,112,191-199.
[5]Jung Ujin,Seo Eungyeong,Hong Seongeun.Pharmaceutical composition containing euphorbia factor l1 or pharmaceutically acceptable salt thereof as an active ingredient for treatment or prevention of bone disease[P].Repub.Korea(2017),KR 1747775 B1 20170616.
[6]Zhang Jianye,Zhang Chao,Chen Hubiao,et al.Assignments of 1H and13C NMR signals of Euphorbia factor L1 and investigation of its anticancer activity in vitro[J].J.Med.Plant Res.,2010,4(4),335-338.
[7]Zhang Jianye,Mi Yanjun,Chen Shupeng,et al.Euphorbia factor L1reverses ABCB1-mediated multidrug resistance involving interaction with ABCB1 independent of ABCB1 down regualtion[J].J.Cell Biochem.,2011,112(4):1076-1083.
[8]Zhang Jianye,Lin Minting,Yi Tao,et al.Apoptosis sensitization by Euphorbia factor L1 in ABCB1-mediated multidrug resistant K562/ADRcells[J].Molecules,2013,18(10),12793-12808.
[9]Wei Jiao,Zhongmin Wan,Shuang Chen,et al.Lathyrol Diterpenes as Modulators of P?Glycoprotein Dependent Multidrug Resistance:Structure-Activity Relationship Studies on Euphorbia Factor L3Derivatives[J].J.Med.Chem.,2015,58,3720-3738.
[10]Ana M.Matos,Mariana Reis,Noe?lia Duarte,et al.Epoxylathyrol Derivatives:Modulation of ABCB1-Mediated Multidrug Resistance in Human Colon Adenocarcinoma and Mouse T?Lymphoma Cells[J].J.Nat.Prod.,2015,78,2215-2228.