新型Cdc25B抑制剂邻菲啰啉并1,2,4-三嗪衍生物及Co~(3+)配合物的合成及其对DNA的荧光识别
|
摘要
细胞分裂周期25磷酸酯酶B(缩写为Cdc25B)在各种人类癌症中过度表达,成为抗癌治疗的重要靶标.含有邻菲啰啉组块的分子因优良的荧光性能和生物活性,成为DNA荧光探针或新型治疗剂构筑的主要研究对象.设计合成了12个邻菲啰啉并-1,2,4-三嗪新型分子ARTP1～ARTP12,经IR和NMR等对其进行了结构表征,评价了其对Cdc25B的抑制活性.结果发现,9个分子抑制活性优良,4个分子活性优于阳性参照物,有望成为Cdc25B抑制剂.选择具有代表性、不同结构的三种配合物与Co~(3+)配位,制备了新型的配合物Co-ARTP-5, Co-ARTP-6和Co-ARTP-10,并借助IR,UV-Vis, 1H NMR及荧光光谱等,确定了配合物的成功构筑,探究了其与小牛胸腺DNA (CT-DNA)的作用方式.结果发现配合物的紫外吸收峰减色红移,结合常数Kb分别为(2.12±0.20)×10~5、(3.29±0.20)×10~5和(1.50±0.20)×10~5L·mol~(-1),发生强烈的荧光淬灭,表明配合物以插入方式与CT-DNA结合,可作为潜在的DNA荧光探针.
Cdc25B has become the important target for curing cancer owing to its over expression in kinds of cancers. Compounds containing phenanthroline moiety have become research objectives on the DNA fluorescence probes or the new curing agents for their excellent fluorescence property and bioactivities. Twelve novel 1,2,4-triazine scheleton phenanthroling derivatives ARTP1～ARTP12 were first designed and synthesized, the structures of ARTP1～ARTP12 were characterized successfully by means of IR and NMR. The inhibitory activities of ARTP1～ARTP12 against Cdc25B were evaluated. The results show that nine target molecules exhibit excellent inhibitories, four molecules behave better activities than the contrast reference Na_3VO_4 indicating that they may be used as Cdc25 B inhibitors. Meanwhile, three novel complexes Co-ARTP-5,Co-ARTP-6 and Co-ARTP-10 were first afforded by the reaction of the excellent inhibitory active compounds ARTP5, ARTP6 and ARTP10 with Co~(3+) respectively. The structures of the three complexes were confirmed through IR, UV-Vis, ~1 H NMR and fluorescence spectra. The interaction modes between the complexes and CT-DNA were explored. As a result, the excitation peaks of the complexes show a red shift and the complexes interact with CT-DNA through the insert mode. The binding constants Kb are(2.12±0.20)×105,(3.29±0.20)×10~5 and(1.50±0.20)×10~5 L·mol~(-1), respectively, and it occurs strong fluorescene quenching. The complexes are expected to be the DNA fluorescence probes.
Cdc25B has become the important target for curing cancer owing to its over expression in kinds of cancers. Compounds containing phenanthroline moiety have become research objectives on the DNA fluorescence probes or the new curing agents for their excellent fluorescence property and bioactivities. Twelve novel 1,2,4-triazine scheleton phenanthroling derivatives ARTP1～ARTP12 were first designed and synthesized, the structures of ARTP1～ARTP12 were characterized successfully by means of IR and NMR. The inhibitory activities of ARTP1～ARTP12 against Cdc25B were evaluated. The results show that nine target molecules exhibit excellent inhibitories, four molecules behave better activities than the contrast reference Na_3VO_4 indicating that they may be used as Cdc25 B inhibitors. Meanwhile, three novel complexes Co-ARTP-5,Co-ARTP-6 and Co-ARTP-10 were first afforded by the reaction of the excellent inhibitory active compounds ARTP5, ARTP6 and ARTP10 with Co~(3+) respectively. The structures of the three complexes were confirmed through IR, UV-Vis, ~1 H NMR and fluorescence spectra. The interaction modes between the complexes and CT-DNA were explored. As a result, the excitation peaks of the complexes show a red shift and the complexes interact with CT-DNA through the insert mode. The binding constants Kb are(2.12±0.20)×105,(3.29±0.20)×10~5 and(1.50±0.20)×10~5 L·mol~(-1), respectively, and it occurs strong fluorescene quenching. The complexes are expected to be the DNA fluorescence probes.
引文
[1]Mak, L. H.; Knott, J.; Scott, K. A.; Scott, C.; Whyte, G. F.; Ye, Y.;Mann,D.J.;Ces,O.;Stivers,J.;Woscholski,R.Bioorg.Med.Chem. 2012, 20, 4371.
[2]He,X.P.;Deng,Q.;Gao,L.X.;Li,C.;Zhang,W.;Zhou,Y.B.;Tang, Y.; Shi, X. X.; Xie J.; Li J.; Chen, G. R.; Chen, K. X. Bioorg.Med. Chem. 2011, 19, 3892.
[3]Sarkis, M.; Tran, D. N.; Kolb, S.; Miteva, M. A.; Villoutreix, B. O.;Garbay, C.; Braud, E. Bioorg. Med. Chem. Lett. 2012, 22, 7345.
[4]B?urle,S.;Blume,T.;Günther,J.;Henschel,D.;Hillig,R.C.;Husemann, M.; Mengel, A.; Parchmann, C.; Schmid, E.; Skuballa,W. Bioorg. Med. Chem. Lett. 2004, 14, 1673.
[5]Barton,J.K.;Danishefsky,A.;Goldberg,J.J.Am.Chem.Soc.1984, 106, 2172.
[6]Demeunynck,M.;Bailly,C.;Wilson,W.D.DNAandRNABinders,FromSmallMoleculestoDrugs,Vol.1,Wiley-VCH,Weinheim, 2003.
[7]Masood, M. A.; Hodgson, D. J. Inorg. Chem. 1993, 32, 4839.
[8]Kalyanasundaram,K.;Gratzel,M.Coord.Chem.Rev.1998,77,347.
[9]Barton,J.K.;Danishefsky,A.T.;Goldberg,J.M.J.Am.Chem.Soc. 1984, 106, 2172.
[10]Juris,A.;Balzani,V.;Barigelletti,F.;Campagna,S.;Belser,P.;Von Zelewsky, A. Coord. Chem. Rev. 1988, 84, 85.
[11]Balzani,V.;Juris,A.;Venturi,M.;Campagna,S.;Serroni,S.Chem. Rev. 1996, 96, 759.
[12]Cola, L. D.; Belser, P. Coord. Chem. Rev. 1998, 177, 301.
[13]Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000, 100, 3553.
[14]Chao, H.; Ji, L. N. Bioinorg. Chem. Appl. 2005, 3, 15.
[15]Vos,J.G.;Kelly,J.M.J.Chem.Soc.,DaltonTrans.2006,41,4869.
[16]Tan, L. F.; Liu, J. H.; Wang, F.; Zhang, S. Chem. Biodiversity 2007,4, 2863.
[17]Liu, Y. J.; Wang, N.; Mei, W. J.; Chen, F.; He, L. X.; Jian, L. Q.;Wang, R. J. Transition. Met. Chem. 2007, 32, 332.
[18]Xu, H.; Deng, H.; Zhang, Q. L.; Huang, Y.; Liu, J. Z.; Li, L. L. Inorg. Chem. Commun. 2003, 6, 766.
[19]Tan,L.F.;Chao,H.;Liu,Y.J.;Li,H.;Sun,B.;Ji,L.N.Inorg.Chim. Acta 2005, 358, 2191.
[20]Cédric, M. R.; Eddy, D.; Francis, S. Chem. Commun. 2005, 345.
[21]Mahajan, S. S.; Scian, M.; Sripathy, S.; Posakony, J.; Lao, U.; Loe,T. K.; Leko, V.; Thalhofer, A.; Schuler, A. D.; Bedalov, A.; Simon,J. A. J. Med. Chem. 2014, 57, 3283.
[22]Wang,Z.N.;Xue,S.J.Chin.J.Org.Chem.2002,22,174(in Chinese).(王仲南,薛思佳,有机化学, 2002, 22, 174.)
[23]Paul,K.;Sharma,A.;Luxami,V.Bioorg.Med.Chem.Lett.2014,24, 624.
[24]Khoshneviszadeh,M.;Ghahremani,M.H.;Foroumadi,A.;Miri,R.; Firuzi, O.; Madadkar-Sobhani, A.; Edraki, N.; Parsa, M.; Shafiee, A. Bioorg. Med. Chem. 2013, 21, 6708.
[25]El-Sayed Ali, T. S. Eur. J. Med. Chem. 2009, 44, 4385.
[26]Stefek, M.; Soltesova Prnova, M.; Majekova, M.; Rechlin, C.; Heine, A.; Klebe, G. J. Med. Chem. 2015, 58, 2649.
[27]Luo, R.; Liu, L.; Si, Y.; Fang, J. J.; Xu, H. R.; Zhao, L. L.; An, D.M.; Mu, J. Mod. Prev. Med. 2011, 38, 4550(in Chinese).(罗榕,刘凌,司洋,方嘉佳,徐鸿儒,赵丽莉,安冬梅,慕洁,现代预防医学, 2011, 38, 4550.)
[28]Guo,X.X.;Du,X.X.;Xue,S.S.Chin.J.Pharmacovigilance2011, 8, 212(in Chinese).(郭晓昕,杜晓曦,薛松林,中国药物警戒, 2011, 8, 212.)
[29]Li, J.; Li, X. M.; Wang, H. Y. Int. J. Intern. Med. 1999, 26, 107(in Chinese).(李健,李晓玫,王海燕,国外医学内科学分册, 1999, 26, 107.)
[30]Cui, X. Y.; Cao, M. F.; Sun, H.; Yu, B. L. Med. Lab. Sci. Clin. 2008,16, 71(in Chinese).(崔秀玉,曹美芳,孙华,于保玲,医学检验与临床,2008,16,71.)
[31]Sangshetti, J. N.; Shinde, D. B. Bioorg. Med. Chem. Lett. 2010, 20,742.
[32]Misra, U.; Hitkari, A.; Saxena, A. K.; Gurtu, S.; Shanker, K. Eur. J.Med. Chem. 1996, 31, 629.
[33]Lindsley, C. W.; Wisnoski, D. D.; Wang, Y.; Leister, W. H.; Zhao,Z. J. Tetrahedron Lett. 2003, 44, 4495.
[34]Thirumurugan, P.; Perumal, P. T. Dyes Pigm. 2011, 88, 403.
[35]Ghazvini Zadeh, E. H.; El-Gendy, B. E. M.; Popa, A. G.; Katritzky,A. R. Med. Chem. Commun. 2012, 3, 52.
[36]Chai,J.H.;Wang,Y.;Xu,D.Q.;Wang,X.;Zhu,C.A.;Guo,Y.;Zhang, C. L. Chem. J. Chin. Univ. 2014, 35, 750(in Chinese).(柴金华,王越,徐德青,王雪,朱长安,国阳,张成路,高等学校化学学报, 2014, 35, 750.)
[37]Zhang, C. L.; Wang, X.; Guo, Y.; Wu, Y. F.; Gao, L. N.; Sun, L. J.Chin. J. Org. Chem. 2014, 34, 2331(in Chinese).(张成路,王雪,国阳,吴一非,高丽娜,孙立杰,有机化学,2014, 34, 2331.)
[38]Zhu, C. A.; Wu, F. Y.; Wang, X.; Gao, L. N.; Weng, Q. F.; Shi, L.; Zhang, C. L. Chin. J. Appl. Chem. 2014, 31, 455(in Chinese).(朱长安,武飞宇,王雪,高丽娜,翁前锋,石丽,张成路,应用化学, 2014, 31, 455.)
[39]Zhang, C. L.; Guo, Y.; Chen, Y.; Sun, L. J.; Cheng, A. Q.; Zhao, N.;Zhao, B. C.; Tang, J.; Xi, H. Chin. J. Org. Chem. 2015, 35, 1665(in Chinese).(张成路,国阳,陈莹,孙立杰,程安琪,赵娜,赵宝成,唐杰,袭焕,有机化学, 2015, 35, 1665.)
[40]Shui, Y. H. J. Chengdu Text. Coll. 2000, 17, 61(in Chinese).(税永红,成都纺织高等专科学校学报, 2000, 17, 61.)
[41]Wang, G. Z.; Wang, Q. X. Stud. Trace Elem. Health 2004, 21, 54(in Chinese).(王根志,王秋霞,微量元素与健康研究, 2004, 21, 54.)
[42]Park, H.; Bahn, Y. H.; Jung, S. K.; Jeong, D. G.; Lee, S. H.; Seo, I.;Yoon, T. S.; Kim, S. J.; Ryu, S. E. J. Med. Chem. 2008, 51, 5533.
[43]Vl?ek, A. A. Inorg. Chem. 1967, 6, 1425.
[44]HeinrichW,MilenaT.Collect.Czech.Chem.Commun.2003,68,965.
[45]Akritopoulou-Zanze,I.;Wang,Y.;Zhao,H.;Djuric,S.W.Tetrahedron Lett. 2009, 50, 5773.
[46]Zou,X.H.;Ye,B.H.;Li,H.;Liu,J.G.;Xiong,Y.;Ji,L.N.J.Chem. Soc., Dalton Trans. 1999, 9, 1423.
[47]Pabst,G.R.;Pfüller,O.C.;Sauer,J.TetrahedronLett.1998,39,8825.
[48]Chao, H.; Qiu, Z. R.; Cai, L. R.; Zhang, H.; Li, X. Y.; Wong, K. S.;Ji, L. N. Inorg. Chem. 2003, 42, 8823.
[2]He,X.P.;Deng,Q.;Gao,L.X.;Li,C.;Zhang,W.;Zhou,Y.B.;Tang, Y.; Shi, X. X.; Xie J.; Li J.; Chen, G. R.; Chen, K. X. Bioorg.Med. Chem. 2011, 19, 3892.
[3]Sarkis, M.; Tran, D. N.; Kolb, S.; Miteva, M. A.; Villoutreix, B. O.;Garbay, C.; Braud, E. Bioorg. Med. Chem. Lett. 2012, 22, 7345.
[4]B?urle,S.;Blume,T.;Günther,J.;Henschel,D.;Hillig,R.C.;Husemann, M.; Mengel, A.; Parchmann, C.; Schmid, E.; Skuballa,W. Bioorg. Med. Chem. Lett. 2004, 14, 1673.
[5]Barton,J.K.;Danishefsky,A.;Goldberg,J.J.Am.Chem.Soc.1984, 106, 2172.
[6]Demeunynck,M.;Bailly,C.;Wilson,W.D.DNAandRNABinders,FromSmallMoleculestoDrugs,Vol.1,Wiley-VCH,Weinheim, 2003.
[7]Masood, M. A.; Hodgson, D. J. Inorg. Chem. 1993, 32, 4839.
[8]Kalyanasundaram,K.;Gratzel,M.Coord.Chem.Rev.1998,77,347.
[9]Barton,J.K.;Danishefsky,A.T.;Goldberg,J.M.J.Am.Chem.Soc. 1984, 106, 2172.
[10]Juris,A.;Balzani,V.;Barigelletti,F.;Campagna,S.;Belser,P.;Von Zelewsky, A. Coord. Chem. Rev. 1988, 84, 85.
[11]Balzani,V.;Juris,A.;Venturi,M.;Campagna,S.;Serroni,S.Chem. Rev. 1996, 96, 759.
[12]Cola, L. D.; Belser, P. Coord. Chem. Rev. 1998, 177, 301.
[13]Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000, 100, 3553.
[14]Chao, H.; Ji, L. N. Bioinorg. Chem. Appl. 2005, 3, 15.
[15]Vos,J.G.;Kelly,J.M.J.Chem.Soc.,DaltonTrans.2006,41,4869.
[16]Tan, L. F.; Liu, J. H.; Wang, F.; Zhang, S. Chem. Biodiversity 2007,4, 2863.
[17]Liu, Y. J.; Wang, N.; Mei, W. J.; Chen, F.; He, L. X.; Jian, L. Q.;Wang, R. J. Transition. Met. Chem. 2007, 32, 332.
[18]Xu, H.; Deng, H.; Zhang, Q. L.; Huang, Y.; Liu, J. Z.; Li, L. L. Inorg. Chem. Commun. 2003, 6, 766.
[19]Tan,L.F.;Chao,H.;Liu,Y.J.;Li,H.;Sun,B.;Ji,L.N.Inorg.Chim. Acta 2005, 358, 2191.
[20]Cédric, M. R.; Eddy, D.; Francis, S. Chem. Commun. 2005, 345.
[21]Mahajan, S. S.; Scian, M.; Sripathy, S.; Posakony, J.; Lao, U.; Loe,T. K.; Leko, V.; Thalhofer, A.; Schuler, A. D.; Bedalov, A.; Simon,J. A. J. Med. Chem. 2014, 57, 3283.
[22]Wang,Z.N.;Xue,S.J.Chin.J.Org.Chem.2002,22,174(in Chinese).(王仲南,薛思佳,有机化学, 2002, 22, 174.)
[23]Paul,K.;Sharma,A.;Luxami,V.Bioorg.Med.Chem.Lett.2014,24, 624.
[24]Khoshneviszadeh,M.;Ghahremani,M.H.;Foroumadi,A.;Miri,R.; Firuzi, O.; Madadkar-Sobhani, A.; Edraki, N.; Parsa, M.; Shafiee, A. Bioorg. Med. Chem. 2013, 21, 6708.
[25]El-Sayed Ali, T. S. Eur. J. Med. Chem. 2009, 44, 4385.
[26]Stefek, M.; Soltesova Prnova, M.; Majekova, M.; Rechlin, C.; Heine, A.; Klebe, G. J. Med. Chem. 2015, 58, 2649.
[27]Luo, R.; Liu, L.; Si, Y.; Fang, J. J.; Xu, H. R.; Zhao, L. L.; An, D.M.; Mu, J. Mod. Prev. Med. 2011, 38, 4550(in Chinese).(罗榕,刘凌,司洋,方嘉佳,徐鸿儒,赵丽莉,安冬梅,慕洁,现代预防医学, 2011, 38, 4550.)
[28]Guo,X.X.;Du,X.X.;Xue,S.S.Chin.J.Pharmacovigilance2011, 8, 212(in Chinese).(郭晓昕,杜晓曦,薛松林,中国药物警戒, 2011, 8, 212.)
[29]Li, J.; Li, X. M.; Wang, H. Y. Int. J. Intern. Med. 1999, 26, 107(in Chinese).(李健,李晓玫,王海燕,国外医学内科学分册, 1999, 26, 107.)
[30]Cui, X. Y.; Cao, M. F.; Sun, H.; Yu, B. L. Med. Lab. Sci. Clin. 2008,16, 71(in Chinese).(崔秀玉,曹美芳,孙华,于保玲,医学检验与临床,2008,16,71.)
[31]Sangshetti, J. N.; Shinde, D. B. Bioorg. Med. Chem. Lett. 2010, 20,742.
[32]Misra, U.; Hitkari, A.; Saxena, A. K.; Gurtu, S.; Shanker, K. Eur. J.Med. Chem. 1996, 31, 629.
[33]Lindsley, C. W.; Wisnoski, D. D.; Wang, Y.; Leister, W. H.; Zhao,Z. J. Tetrahedron Lett. 2003, 44, 4495.
[34]Thirumurugan, P.; Perumal, P. T. Dyes Pigm. 2011, 88, 403.
[35]Ghazvini Zadeh, E. H.; El-Gendy, B. E. M.; Popa, A. G.; Katritzky,A. R. Med. Chem. Commun. 2012, 3, 52.
[36]Chai,J.H.;Wang,Y.;Xu,D.Q.;Wang,X.;Zhu,C.A.;Guo,Y.;Zhang, C. L. Chem. J. Chin. Univ. 2014, 35, 750(in Chinese).(柴金华,王越,徐德青,王雪,朱长安,国阳,张成路,高等学校化学学报, 2014, 35, 750.)
[37]Zhang, C. L.; Wang, X.; Guo, Y.; Wu, Y. F.; Gao, L. N.; Sun, L. J.Chin. J. Org. Chem. 2014, 34, 2331(in Chinese).(张成路,王雪,国阳,吴一非,高丽娜,孙立杰,有机化学,2014, 34, 2331.)
[38]Zhu, C. A.; Wu, F. Y.; Wang, X.; Gao, L. N.; Weng, Q. F.; Shi, L.; Zhang, C. L. Chin. J. Appl. Chem. 2014, 31, 455(in Chinese).(朱长安,武飞宇,王雪,高丽娜,翁前锋,石丽,张成路,应用化学, 2014, 31, 455.)
[39]Zhang, C. L.; Guo, Y.; Chen, Y.; Sun, L. J.; Cheng, A. Q.; Zhao, N.;Zhao, B. C.; Tang, J.; Xi, H. Chin. J. Org. Chem. 2015, 35, 1665(in Chinese).(张成路,国阳,陈莹,孙立杰,程安琪,赵娜,赵宝成,唐杰,袭焕,有机化学, 2015, 35, 1665.)
[40]Shui, Y. H. J. Chengdu Text. Coll. 2000, 17, 61(in Chinese).(税永红,成都纺织高等专科学校学报, 2000, 17, 61.)
[41]Wang, G. Z.; Wang, Q. X. Stud. Trace Elem. Health 2004, 21, 54(in Chinese).(王根志,王秋霞,微量元素与健康研究, 2004, 21, 54.)
[42]Park, H.; Bahn, Y. H.; Jung, S. K.; Jeong, D. G.; Lee, S. H.; Seo, I.;Yoon, T. S.; Kim, S. J.; Ryu, S. E. J. Med. Chem. 2008, 51, 5533.
[43]Vl?ek, A. A. Inorg. Chem. 1967, 6, 1425.
[44]HeinrichW,MilenaT.Collect.Czech.Chem.Commun.2003,68,965.
[45]Akritopoulou-Zanze,I.;Wang,Y.;Zhao,H.;Djuric,S.W.Tetrahedron Lett. 2009, 50, 5773.
[46]Zou,X.H.;Ye,B.H.;Li,H.;Liu,J.G.;Xiong,Y.;Ji,L.N.J.Chem. Soc., Dalton Trans. 1999, 9, 1423.
[47]Pabst,G.R.;Pfüller,O.C.;Sauer,J.TetrahedronLett.1998,39,8825.
[48]Chao, H.; Qiu, Z. R.; Cai, L. R.; Zhang, H.; Li, X. Y.; Wong, K. S.;Ji, L. N. Inorg. Chem. 2003, 42, 8823.