N-取代2-(5-氯-2-(金刚基-1-基)-1H-吲哚-3-基)-2-氧代乙酰胺衍生物的合成及其细胞毒活性
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摘要
以金刚烷甲酰氯为起始原料,经亲核取代、吲哚环合及酰化反应制得中间体2-(5-氯-2-金刚烷-1H-吲哚-3-基)-2-氧代乙酰(4); 4与取代胺反应合成了14个新的N-取代2-(5-氯-2-(金刚基-1-基)-1H-吲哚-3-基)-2-氧代乙酰胺衍生物(5a～5n),其结构经~1H NMR,~(13)C NMR和HR-MS(ESI)表征。采用MTT法研究了化合物对人子宫颈癌细胞(Hela)、乳腺癌细胞(MCF-7)和人肝癌细胞(HepG-2)的体外抗肿瘤活性。结果显示:化合物2-(5-氯-2-金刚烷-1H-吲哚-3-基)-N-(3-氯-4-氟苯基)-2-氧代乙酰胺(5e)的体外抑制活性最优,IC_(50)分别为14. 10、10. 56和8. 55μmol·L~(-1)。
The intermediate,2-( 5-chloro-2-amantade-1H-indol-3-group)-2-oxyacetyl( 4),was prepared by three steps of nucleophilic substitution,indol ring and acylation with amantadine formyl chloride as the starting material. Fourteen new N-substituted 2-( 5-chloro-2-( diamond-1-group)-1H-indole-3-group)-2-oxyacetamide derivatives( 5a ～ 5n) were synthesized by reaction of 4 with substituted amines. The structures were characterized by ~1H NMR,13 C NMR and HR-MS( ESI). The in vitro antitumor activities of 5a ～ 5n on human Cervical cancer( Hela),human breast cancer cells( MCF-7)and hepatoma cells( HepG-2) were studied by MTT assay. The results showed that the compound 5e exhibited the best inhibitory activities with IC_(50) of 14. 10,10. 56 and 8. 55 μmol·L~(-1).
The intermediate,2-( 5-chloro-2-amantade-1H-indol-3-group)-2-oxyacetyl( 4),was prepared by three steps of nucleophilic substitution,indol ring and acylation with amantadine formyl chloride as the starting material. Fourteen new N-substituted 2-( 5-chloro-2-( diamond-1-group)-1H-indole-3-group)-2-oxyacetamide derivatives( 5a ～ 5n) were synthesized by reaction of 4 with substituted amines. The structures were characterized by ~1H NMR,13 C NMR and HR-MS( ESI). The in vitro antitumor activities of 5a ～ 5n on human Cervical cancer( Hela),human breast cancer cells( MCF-7)and hepatoma cells( HepG-2) were studied by MTT assay. The results showed that the compound 5e exhibited the best inhibitory activities with IC_(50) of 14. 10,10. 56 and 8. 55 μmol·L~(-1).
引文
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[3] VELLASCO W T,RB GOMES C,RA VASCONCELOS T,et al. Chemistry and biological activities of 1,3-benzoxathiol-2-ones[J]. Mini-Reviews in Organic Chemistry,2011,8(1):103-109.
[4] DING S,DUDLEY E,PLUMMER S,et al. Fingerprint profile of Ginkgo biloba nutritional suppleme-nts by LC/ESI-MS/MS[J]. Phytochemistry,2008,69(7):1555-1564.
[5] AHUIJA P,SIDDIQUI N. Anticonvulsant evaluation of clubbed indole-1,2,4-triazine derivatives:A synthetic approach[J]. Eur J Med Chem,2014,80(10):509-522.
[6] ZHANG M Z,MULHOLLAND N,BEATTIE D,et al.Synthesis and antifungal activity of 3-(1,3,4-oxadiazol-5-yl)-indoles and 3-(1,3,4-oxadiazol-5-yl)methyl-indoles[J]. Eur J Med Chem,2013,63(41):22-32.
[7] ZHANG M Z,CHEN Q,YANG G F. A review on recent developments of indole-containing antiviral agents[J]. Eur J Med Chem,2015,89(6):421-441.
[8] HU H Y,WU J,AO M T,et al. Synthesis,structureactivity relationship studies and biological evaluation of novel 2,5-disubstituted indole derivatives as anticancer agents[J]. Chem Biol Drug Des,2016,88(5):766-778.
[9] HU H Y,YU X D,WANG F,et al. Novel N-substituted 2-(2-(adamantan-1-yl)-1H-Indol-3-yl)-2-oxoacetamide derivatives:Synthesis and biological evaluation[J]. Molecules,2016,21(5):1-15.
[10] HU H Y,LIN C R,AO M T,et al. Synthesis and biological evaluation of 1-(2-(adamantane-1-yl)-1Hindol-5-yl)-3-substituted urea/thiourea derivatives as anticancer agents[J]. Rsc Advances,2017,7(81):51640-51651.
[11] PERRYMAN A L,ZHANG Q,SOUTTER H H,et al. Fragment-based screen against HIV protease[J]. Chem Biol Drug Des,2010,75(3):257-268.
[12] MA J Y,QUAN Y C,JIN H G,et al. Practical synthesis,antidepressant and anticonvulsant activity of 3-phenyliminoindolin-2-one derivatives[J]. Chemical Biology&Drug Design,2016,87(3):342-351.
[13] HOULIHANW J,PARRINO V A,UIKE Y,et al.Lithiation of N-(2-alkylphenyl)alkanamides and related compounds. A modified Madelung indole synthesis[J]. J Org Chem,1981,46(22):4511-4515.
[14] THOMPSOM M J,BORSENBERGERV,LOUTH J C,et al. Design,synthesis,and structure-activity relationship of indole-3-glyoxylamide libraries possessing highly potent activity in a cell line model of prion disease[J]. Journal of Medicinal Chemistry,2009,52(23):7503-7511.
[15] THOMPSOM M J,LOUTHJ C,FERRARA S,et al.Discovery of 6-substituted indole-3-glyoxylamides as lead antiprion agents with enhanced cell line activity,improved microsomal stability and low toxicity[J].European Journal of Medicinal Chemistry,2011,46(9):4125-4132.
[16] GUGGILAPU S D,GUNTUKU L,REDDY T S,et al. Synthesis of thiazole linked indolyl-3-glyoxylamide derivatives as tubulin polymerization inhibitors[J].European Journal of Medicinal Chemistry,2017,138(1):83-95.
[17] LEE Y J,HAN Y R,PARK W,et al. Synthetic analogs of indole-containing natural products as inhibitors of sortase A and isocitrate lyase[J]. Bioorganic&Medicinal Chemistry Letters, 2010, 20(23):6882-6885.
[18]鹿慧燕,仝水田,张蕴,等.新型吡唑啉化合物的合成及抑菌活性研究[J].浙江师范大学学报自然科学版,2016,39(4):412-418.
[19]陈仕杰,龚显峰,王雪微,等.伊马替尼衍生物的合成及细胞毒活性研究[J].化学通报,2015,35(7):621-626.
[20]高慧,郑喜,祁燕,等.新型白藜芦醇-查尔酮酰胺衍生物的合成及其细胞毒活性[J].有机化学,2018,38(3):648-655.