2,4,6-三取代嘧啶衍生物的合成及体外抗肿瘤活性研究
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摘要
为了寻找更高效、更经济的抗肿瘤药物,以乙酰乙酸乙酯和苯甲酰乙酸乙酯为起始原料,经环合、取代、氯代等反应合成了一系列具有查尔酮官能团的2,4,6-三取代嘧啶衍生物,共40个化合物.这些目标化合物的分子结构均经过~1H NMR,~(13)C NMR和HRMS确证,并利用CCK-8方法测试它们对MGC-803人胃癌细胞、HepG-2人肝癌细胞、EC-109人食管癌细胞和MDA-MB-231乳腺癌细胞四种人类癌细胞系的抗肿瘤活性研究.其中N-(3,4,5-三甲氧苯乙烯基苯基酮)-2-(苯并咪唑-2-亚甲硫基)-6-甲基嘧啶-4-胺(13u)对MGC-803和MDA-MB-231细胞株抗肿瘤活性要优于对照品5-氟尿嘧啶,其IC50值分别为0.99和1.77μmol·L~(-1).
With the aim of obtaining potential antitumor candidates with more efficiency and more economic value. 402,4,6-trisubstituted pyrimidine derivatives bearing chalcone moiety were synthesized via cyclization, chlorination, substitution with benzoylacetate and ethylacetoacetate as the starting materials. The structures of target products were confirmed by ~1H NMR, ~(13)C NMR and HRMS. 2,4,6-Trisubstituted pyrimidine derivatives bearing chalcone moiety were evaluated for anticancer activity on four human cancer cell lines including EC-109, MGC-803, HepG-2 and MDA-MB-231 by CCK-8(cell counting Kit-8) assay. Among them,(E)-1-(4-((2-(((1 H-benzo[d]imidazol-2-yl)methyl)thio)-6-methylpyrimidin-4-yl)amino)-phenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one(13 u) were more cytotoxic against MGC-803 and MDA-MB-231 cell lines, with IC50 values of 0.99 and 1.77 μmol·L~(-1), respectively.
With the aim of obtaining potential antitumor candidates with more efficiency and more economic value. 402,4,6-trisubstituted pyrimidine derivatives bearing chalcone moiety were synthesized via cyclization, chlorination, substitution with benzoylacetate and ethylacetoacetate as the starting materials. The structures of target products were confirmed by ~1H NMR, ~(13)C NMR and HRMS. 2,4,6-Trisubstituted pyrimidine derivatives bearing chalcone moiety were evaluated for anticancer activity on four human cancer cell lines including EC-109, MGC-803, HepG-2 and MDA-MB-231 by CCK-8(cell counting Kit-8) assay. Among them,(E)-1-(4-((2-(((1 H-benzo[d]imidazol-2-yl)methyl)thio)-6-methylpyrimidin-4-yl)amino)-phenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one(13 u) were more cytotoxic against MGC-803 and MDA-MB-231 cell lines, with IC50 values of 0.99 and 1.77 μmol·L~(-1), respectively.
引文
[1]For statistical information about cancer,see:U.S.Food and Drug Administration.http://www.fda.gov/About FDA/Reports ManualsForms/Reports/ucm276385.htm.
[2]Sangthong,S.;Krusong,K.;Ngamrojanavanich,N.;Vilaivan,T.;Puthong,S.;Chandchawan,S.;Muangsin,N.Bioorg.Med.Chem.Lett.2011,21,4813.
[3]Cao,R.H.;Fan,W.X.;Guo,L.;Ma,Q.;Zhang,G.X.;Li,J.R.;Chen,X.M.;Ren,Z.H.;Qiu,L.Q.Eur.J.Med.Chem.2013,60,135.
[4]Kamal,A.;Tamboli,J.R.;Nayak,V.L.;Adil,S.F.;Vishnuvardhan,M.V.P.S.;Ramakrishna,S.Bioorg.Med.Chem.Lett.2013,23,3208.
[5]Kamal,A.;Dastagiri,D.;Ramaiah,M.J.;Reddy,J.S.;Bharathi,E.V.;Reddy,M.K.;Sagar,M.V.P.;Reddy,T.L.;Pushpavalli,S.N.C.V.L.;Pal-Bhadra,M.Eur.J.Med.Chem.2011,46,5817.
[6]Hamid,M.K.A.E.;Mihovilovic,M.D.;El-Nassan,H.B.Eur.J.Med.Chem.2012,57,323.
[7]Kassab,A.E.;Gedawy,E.M.Eur.J.Med.Chem.2013,63,224.
[8]Duschinsky,R.;Pleven,E.;Heidelberger,C.J.Am.Chem.Soc.1957,79,4559.
[9]Pecchi,S.;Renhowe,P.A.;Taylor,C.;Kaufman,S.;Merritt,H.;Wiesmann,M.;Shoemaker,K.R.;Knapp,M.;Ornelas,E.;Hendrickson,T.F.;Fantl,W.;Voliva,C.F.Bioorg.Med.Chem.Lett.2010,20,6895.
[10]Keche,A.P.;Hatnapure,G.D.;Tale,R.H.;Rodge,A.H.;Birajdar,S.S.;Kamble,V.M.Bioorg.Med.Chem.Lett.2012,22,3445.
[11]Ni,L.;Meng,C.Q.;Sikorski,J.A.Expert.Opin.Ther.Pat.2004,14,1669.
[12]Dimmock,J.R.;Elias,D.W.;Beazely,M.A.Kandepu,N.M.Curr.Med.Chem.1999,6,1125.
[13]Domínguez,J.N.;León,C.;Rodrigues,J.;Gamboa,D.N.;Gut,J.;Rosenthal,P.J.J.Med.Chem.2005,48,3654.
[14]Gacche,R.;Dhole,N.A.;Kamble,S.G.;Bandgar,B.P.J.Enzyme Inhib.Med.Chem.2008,23,28.
[15]Sharma,V.;Kumar,P.;Pathak,D.J.Heterocycl.Chem.2010,47,491.
[16]Shao,K.P.;Zhang,X.Yao.;Chen,P.J.;Xue,D.Q.;He,P.;Ma,L.Y.;Zheng,J.X.;Zhang,Q.R.;Liu,H.M.Bioorg.Med.Chem.Lett.2014,24,3877.
[17]Chen,P.J.;Yang,A.;Gu,Y.F.;Zhang,X.S.;Shao,K.P.;Xue,D.Q.;He,P.;Jiang,T.F.;Zhang,Q.R.;Liu,H.M.Bioorg.Med.Chem.Lett.2014,24,2741.
[18]Tominaga,H.;Ishiyama,M.;Ohseto,F.;Sasamoto,K.;Hamamoto,T.;Suzuki,K.;Watanabe,M.Anal.Commun.1999,36,47.
[2]Sangthong,S.;Krusong,K.;Ngamrojanavanich,N.;Vilaivan,T.;Puthong,S.;Chandchawan,S.;Muangsin,N.Bioorg.Med.Chem.Lett.2011,21,4813.
[3]Cao,R.H.;Fan,W.X.;Guo,L.;Ma,Q.;Zhang,G.X.;Li,J.R.;Chen,X.M.;Ren,Z.H.;Qiu,L.Q.Eur.J.Med.Chem.2013,60,135.
[4]Kamal,A.;Tamboli,J.R.;Nayak,V.L.;Adil,S.F.;Vishnuvardhan,M.V.P.S.;Ramakrishna,S.Bioorg.Med.Chem.Lett.2013,23,3208.
[5]Kamal,A.;Dastagiri,D.;Ramaiah,M.J.;Reddy,J.S.;Bharathi,E.V.;Reddy,M.K.;Sagar,M.V.P.;Reddy,T.L.;Pushpavalli,S.N.C.V.L.;Pal-Bhadra,M.Eur.J.Med.Chem.2011,46,5817.
[6]Hamid,M.K.A.E.;Mihovilovic,M.D.;El-Nassan,H.B.Eur.J.Med.Chem.2012,57,323.
[7]Kassab,A.E.;Gedawy,E.M.Eur.J.Med.Chem.2013,63,224.
[8]Duschinsky,R.;Pleven,E.;Heidelberger,C.J.Am.Chem.Soc.1957,79,4559.
[9]Pecchi,S.;Renhowe,P.A.;Taylor,C.;Kaufman,S.;Merritt,H.;Wiesmann,M.;Shoemaker,K.R.;Knapp,M.;Ornelas,E.;Hendrickson,T.F.;Fantl,W.;Voliva,C.F.Bioorg.Med.Chem.Lett.2010,20,6895.
[10]Keche,A.P.;Hatnapure,G.D.;Tale,R.H.;Rodge,A.H.;Birajdar,S.S.;Kamble,V.M.Bioorg.Med.Chem.Lett.2012,22,3445.
[11]Ni,L.;Meng,C.Q.;Sikorski,J.A.Expert.Opin.Ther.Pat.2004,14,1669.
[12]Dimmock,J.R.;Elias,D.W.;Beazely,M.A.Kandepu,N.M.Curr.Med.Chem.1999,6,1125.
[13]Domínguez,J.N.;León,C.;Rodrigues,J.;Gamboa,D.N.;Gut,J.;Rosenthal,P.J.J.Med.Chem.2005,48,3654.
[14]Gacche,R.;Dhole,N.A.;Kamble,S.G.;Bandgar,B.P.J.Enzyme Inhib.Med.Chem.2008,23,28.
[15]Sharma,V.;Kumar,P.;Pathak,D.J.Heterocycl.Chem.2010,47,491.
[16]Shao,K.P.;Zhang,X.Yao.;Chen,P.J.;Xue,D.Q.;He,P.;Ma,L.Y.;Zheng,J.X.;Zhang,Q.R.;Liu,H.M.Bioorg.Med.Chem.Lett.2014,24,3877.
[17]Chen,P.J.;Yang,A.;Gu,Y.F.;Zhang,X.S.;Shao,K.P.;Xue,D.Q.;He,P.;Jiang,T.F.;Zhang,Q.R.;Liu,H.M.Bioorg.Med.Chem.Lett.2014,24,2741.
[18]Tominaga,H.;Ishiyama,M.;Ohseto,F.;Sasamoto,K.;Hamamoto,T.;Suzuki,K.;Watanabe,M.Anal.Commun.1999,36,47.