吲哚啉-2-酮和小檗胺衍生物的设计、合成及其生物活性研究
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摘要
蛋白激酶介导许多信号传导通路从而调节细胞的生长、分化、迁移和凋亡等各个方面。蛋白激酶的过量表达和/或活性调节紊乱等都能引发许多疾病例如恶性肿瘤。酪氨酸蛋白激酶和丝氨酸/苏氨酸蛋白激酶是最主要的两类蛋白激酶。近年来,酪氨酸蛋白激酶抑制剂应用于临床是肿瘤治疗上取得的令人鼓舞的重要进展之一。酪氨酸蛋白激酶主要分为两大类:受体酪氨酸激酶和非受体酪氨酸激酶。3-磷酸肌醇依赖蛋白激酶-1(PDK-1)和蛋白激酶B(PKB)是丝/苏氨酸蛋白激酶,它们在细胞信号传导途径中发挥关键作用。在多种人类肿瘤中发现蛋白激酶(例如EGFR、PDK-1或PKB)过表达或者活性失调。蛋白激酶是良好的抗肿瘤药物作用靶点。本论文第一部分介绍了几类蛋白激酶及其抑制剂。
本论文以已知的吲哚啉-2-酮酪氨酸激酶抑制剂SU5416为先导化合物,设计了三类的吲哚啉-2-酮衍生物。以巯甲基树脂为载体,采用固相合成法,无痕迹(traceless)平行合成了三取代的吲哚啉-2-酮衍生物并分离得到16个单体化合物;在固相合成吲哚啉-2-酮的基础上,在溶液中平行合成了109个吲哚啉-2-酮衍生物;对所合成的吲哚啉-2-酮衍生物进行了体外抗肿瘤活性测试,结果显示,吲哚啉-2-酮衍生物对所选肿瘤细胞株具有一定的抑制活性。发现3个化合物2.94,2.96和2.171对K562抑制活性强于阳性对照药Sunitinib。所有化合物中,对K562细胞和HepG2细胞抑制活性最强的是2.94,IC_(50)为0.089μM和1.7μM,均强于阳性对照药Sunitinib,而且2.94还显示出较好的选择性,其对A549细胞和PC-3细胞抑制活性较弱;对前列腺癌PC-3细胞抑制活性最强的是2.171,IC_(50)为9.0μM。
天然产物的结构修饰与改造一直是药物化学研究的重点和热点之一。小檗胺是从小檗属植物中提取分离得到的双苄基异喹啉型生物碱,近年的研究发现,虚薨范园籽∠赴乇鹗悄鸵┑陌籽∠赴允玖肆己玫囊种苹钚浴１韭畚囊孕￠薨肺奘味韵?在保留其双苄基异喹啉核心结构的基础上,对其游离的酚羟基作了醚化、酯化和磺酸酯化三类修饰,合成了30个小檗胺衍生物;对合成的小檗胺衍生物进行了耐药白血病细胞株K562-R细胞毒活性测试,发现大部分化合物均显示出良好的体外抗白血病活性,其中有14个化合物的IC_(50)小于1.0μM,化合物3.6,3.8,3.19和3.29具有较好的抑制活性,对K562-R细胞的IC_(50)分别为0.36μM,0.40μM,0.40μM和0.46μM;流式细胞术检测发现,衍生物3.16可以有效的诱导K562-R白血病细胞凋亡,并且能够抑制处于静止期(G0/G1)的白血病细胞,显示其可能具有杀死白血病干细胞的能力;测试了小檗胺衍生物对NF-κB的抑制活性,结果显示,化合物3.14,3.15,3.16和3.17可以显著的降低白血病细胞核内NF-κB p65的水平,NF-κB p65对于白血病干细胞的存活发挥重要作用。
Most of the signal transduction pathways are mediated by protein kinases regulating every aspect of cell function including cell growth,differentiation,migration, and apoptosis.Protein kinases were overexpressed or their function displayed aberrant activation or both result in many diseases such as cancers.There are two main subdivisions within the protein kinases superfamily:the protein tyrosine kinases(PTKs) and the protein serine/threonine kinases.One of the most exciting developments in cancer research in recent years has been the clinical validation of molecularly targeted drugs that inhibit the action of pathogenic tyrosine kinases.There are two classes of PTKs present in cells:the receptor protein tyrosine kinases and the nonreceptor protein tyrosine kinases.3-phosphoinositide-dependent protein kinase-1(PDK-1)and protein kinase B(PKB)are serine/threonine kinases,they play key roles in cell signal transduction pathways.In multiple human tumours,protein kinases(e.g.:EGFR,PDK-1 or PKB)are overexpressed and/or protein kinases signalling are upregulated,promoting tumour invasiveness,angiogenesis,and progression.Protein kinases are considered as significant anti-cancer drug targets.The partⅠof this thesis reviewed on several protein kinases and the current advance of the small molecular protein kinases inhibitors.
In this thesis,we chosed the protein tyrosine kinase inhibitor SU5416 as lead compound,three classes of novel indolin-2-ones were designed.Trisubsititued indolin-2-one derivatives were synthesized by using a traceless solid-phase approach with mercaptomethyl resin.109 Indolin-2-ones that designed based on SU5416 were synthesized in solution phase.Most of the synthesized compounds have been used for the biological evaluation in vitro.From the biological evaluation results,a series of indolin-2-ones were found to have moderate cytotoxic activity against the selected tumor cell lines.Compounds 2.94,2.96 and 2.171 were found to have more potent cytotoxicity against the K562 cell line compared to Sunitinib.Compound 2.94 exhibited the most potent inhibition activities against K562 and HepG2 cell lines with IC_(50)values of 0.089μM and 1.7μM.Compound 2.171 exhibited the most potent inhibition activities against PC-3 cell line with an IC_(50)value of 9.0μM.
Natural small molecules were considered as significant lead compounds in drug discoveries.Berbamine is a well-known bisbenzylisoquinoline alkaloid isolated from traditional Chinese herbal medicines such as berberis amurensis.Previous studies showed that berbamine was effective for inhibiting both Imatinib sensitive-and resistant-Ph~+ chronic myeloid leukemia(CML)cells.30 Berbamine derivatives were designed,synthesized and the anti-leukemia activity of them against imatinib-resistant K562 leukemia cell line was evaluated.From the biological evaluation results,most compounds displayed potent cytotoxic activity in vitro.14 derivatives were found have potent cytotoxic activity against K562-R cell line with IC_(50)values at 48 hours were in the submicromolar range.Compounds 3.6,3.8,3.19 and 3.29 showed the most potent inhibition activities against K562-R,whose IC_(50)values at 48 hours were 0.36μM,0.40μM,0.40μM and 0.46μM.The cell cycle analysis on K562-R cell line indicated that derivative 3.16 can reduce quiescent(G0/G1)phase cells,suggesting that berbamine derivatives may have potential to kill leukemia stem cells.In particular,compounds 3.14,3.15,3.16 and 3.17 also displayed potent inhibition of the cytoplasm-to-nucleus translocation of NF-κB p65 which is critical for survival of leukemia stem cells.
本论文以已知的吲哚啉-2-酮酪氨酸激酶抑制剂SU5416为先导化合物,设计了三类的吲哚啉-2-酮衍生物。以巯甲基树脂为载体,采用固相合成法,无痕迹(traceless)平行合成了三取代的吲哚啉-2-酮衍生物并分离得到16个单体化合物;在固相合成吲哚啉-2-酮的基础上,在溶液中平行合成了109个吲哚啉-2-酮衍生物;对所合成的吲哚啉-2-酮衍生物进行了体外抗肿瘤活性测试,结果显示,吲哚啉-2-酮衍生物对所选肿瘤细胞株具有一定的抑制活性。发现3个化合物2.94,2.96和2.171对K562抑制活性强于阳性对照药Sunitinib。所有化合物中,对K562细胞和HepG2细胞抑制活性最强的是2.94,IC_(50)为0.089μM和1.7μM,均强于阳性对照药Sunitinib,而且2.94还显示出较好的选择性,其对A549细胞和PC-3细胞抑制活性较弱;对前列腺癌PC-3细胞抑制活性最强的是2.171,IC_(50)为9.0μM。
天然产物的结构修饰与改造一直是药物化学研究的重点和热点之一。小檗胺是从小檗属植物中提取分离得到的双苄基异喹啉型生物碱,近年的研究发现,虚薨范园籽∠赴乇鹗悄鸵┑陌籽∠赴允玖肆己玫囊种苹钚浴１韭畚囊孕￠薨肺奘味韵?在保留其双苄基异喹啉核心结构的基础上,对其游离的酚羟基作了醚化、酯化和磺酸酯化三类修饰,合成了30个小檗胺衍生物;对合成的小檗胺衍生物进行了耐药白血病细胞株K562-R细胞毒活性测试,发现大部分化合物均显示出良好的体外抗白血病活性,其中有14个化合物的IC_(50)小于1.0μM,化合物3.6,3.8,3.19和3.29具有较好的抑制活性,对K562-R细胞的IC_(50)分别为0.36μM,0.40μM,0.40μM和0.46μM;流式细胞术检测发现,衍生物3.16可以有效的诱导K562-R白血病细胞凋亡,并且能够抑制处于静止期(G0/G1)的白血病细胞,显示其可能具有杀死白血病干细胞的能力;测试了小檗胺衍生物对NF-κB的抑制活性,结果显示,化合物3.14,3.15,3.16和3.17可以显著的降低白血病细胞核内NF-κB p65的水平,NF-κB p65对于白血病干细胞的存活发挥重要作用。
Most of the signal transduction pathways are mediated by protein kinases regulating every aspect of cell function including cell growth,differentiation,migration, and apoptosis.Protein kinases were overexpressed or their function displayed aberrant activation or both result in many diseases such as cancers.There are two main subdivisions within the protein kinases superfamily:the protein tyrosine kinases(PTKs) and the protein serine/threonine kinases.One of the most exciting developments in cancer research in recent years has been the clinical validation of molecularly targeted drugs that inhibit the action of pathogenic tyrosine kinases.There are two classes of PTKs present in cells:the receptor protein tyrosine kinases and the nonreceptor protein tyrosine kinases.3-phosphoinositide-dependent protein kinase-1(PDK-1)and protein kinase B(PKB)are serine/threonine kinases,they play key roles in cell signal transduction pathways.In multiple human tumours,protein kinases(e.g.:EGFR,PDK-1 or PKB)are overexpressed and/or protein kinases signalling are upregulated,promoting tumour invasiveness,angiogenesis,and progression.Protein kinases are considered as significant anti-cancer drug targets.The partⅠof this thesis reviewed on several protein kinases and the current advance of the small molecular protein kinases inhibitors.
In this thesis,we chosed the protein tyrosine kinase inhibitor SU5416 as lead compound,three classes of novel indolin-2-ones were designed.Trisubsititued indolin-2-one derivatives were synthesized by using a traceless solid-phase approach with mercaptomethyl resin.109 Indolin-2-ones that designed based on SU5416 were synthesized in solution phase.Most of the synthesized compounds have been used for the biological evaluation in vitro.From the biological evaluation results,a series of indolin-2-ones were found to have moderate cytotoxic activity against the selected tumor cell lines.Compounds 2.94,2.96 and 2.171 were found to have more potent cytotoxicity against the K562 cell line compared to Sunitinib.Compound 2.94 exhibited the most potent inhibition activities against K562 and HepG2 cell lines with IC_(50)values of 0.089μM and 1.7μM.Compound 2.171 exhibited the most potent inhibition activities against PC-3 cell line with an IC_(50)value of 9.0μM.
Natural small molecules were considered as significant lead compounds in drug discoveries.Berbamine is a well-known bisbenzylisoquinoline alkaloid isolated from traditional Chinese herbal medicines such as berberis amurensis.Previous studies showed that berbamine was effective for inhibiting both Imatinib sensitive-and resistant-Ph~+ chronic myeloid leukemia(CML)cells.30 Berbamine derivatives were designed,synthesized and the anti-leukemia activity of them against imatinib-resistant K562 leukemia cell line was evaluated.From the biological evaluation results,most compounds displayed potent cytotoxic activity in vitro.14 derivatives were found have potent cytotoxic activity against K562-R cell line with IC_(50)values at 48 hours were in the submicromolar range.Compounds 3.6,3.8,3.19 and 3.29 showed the most potent inhibition activities against K562-R,whose IC_(50)values at 48 hours were 0.36μM,0.40μM,0.40μM and 0.46μM.The cell cycle analysis on K562-R cell line indicated that derivative 3.16 can reduce quiescent(G0/G1)phase cells,suggesting that berbamine derivatives may have potential to kill leukemia stem cells.In particular,compounds 3.14,3.15,3.16 and 3.17 also displayed potent inhibition of the cytoplasm-to-nucleus translocation of NF-κB p65 which is critical for survival of leukemia stem cells.
引文
[1]Hanks S.,Hunter T.,FASEB,1995,9,576-596.
[2]Baselga J.,Science 2006,312,1175-1178.
[3]Blume-Jensen P.,Hunter T.,Nature 2001,411,355.
[4]Schlessinger J,Ullrich A.,Neuron 1992,9,383-91.
[5]Hubbard S.R.,Till J.H.,Annu.Rev.Biochem.2000,69,373-98.
[6]Flanagan J.G.,Vanderhaeghen P.,Annu.Rev.Neurosci.1998,21,309-45.
[7]Holland S.J.,Peles E.,Pawson T.,Schlessinger J.,Curr.Opin.Neurobiol.1998,8,117-27.
[8]Yancopoulos G.D.,Klagsbrun M.,Folkman J.,Cell 1998,93,661-64.
[9]White M.F.,Mol.Cell.Biochem.1998,182,3-11.
[10]Cheatham B.,Vlahos C.J.,Cheatham L.,Wang L.,Blenis J.,et al.Mol.Cell.Biol.1994,14,4902-11.
[11]Okada T.,Kawano Y.,Sakakibara T.,et al.J.Biol.Chem.1994,269,3568-73.
[12]Kuriyan J.,Cowburn D.,Annu.Rev.Biophys.Biomol.Struct.1997,26,259-88.
[13]Ullrich A.,Schlessinger J.,Cell 1990,61,203-12.
[14]Heldin C.H.,Cell 1995,80,213-23.
[15]Hubbard S.R.,Wei L.,Ellis L.,Hendrickson W.A.,Nature 1994,372,746-54.
[16]Hubbard S.R.,EMBOJ.1997,16,5572-81.
[17]Neet K.,Hunter T.,Genes Cells 1996,1,147-69.
[18]Lemmon M.A.,Ferguson K.M.,Curr.Top.Microbiol.Immunol.1998,228,39-74.
[19]Darnell JE Jr.Science 1997,277,1630-35.
[20]Weiss A.,Littman D.R.,Cell 1994,76,263-74.
[21]Tonks N.K.,Neel B.G.,Cell 1996,87,365-68.
[22]Nada S.,Okada M.,MacAuley A.,Cooper J.A.,Nakagawa H.,Nature 1991,351,69-72.
[23]Cooper J.A.,Gould K.L.,Cartwright C.A.,Hunter T.,Science 1986,231,1431-34.
[24]Kmiecik T.E.,Shalloway D.,Cell 1987,49,65-73.
[25]Superti-Furga G.,Courtneidge S.A.,BioEssays 1995,17,321-30.
[26]Mayer B.J.,Baltimore D.,Mol.Cell.Biol.1994,14,2883-94.
[27]Van Etten R.A.,Debnath J.,Zhou H.,Casasnovas J.M.,Oncogene 1995,10, 1977-88.
[28]Wen S.T.,Van Etten R.A.,Genes Dev.1997,11,2456-67.
[29]Shiue L.,Zoller M.J.,Brugge J.S.,J.Biol.Chem.1995,270,10498-502.
[30]Chan A.C.,Dalton M.,Johnson R.,Kong G.H.,Wang T.,et al.EMBO J.1995,14,2499-508.
[31]Wilks A.F.,Harpur A.G.,Kurban R.R.,Ralph S.J.,Zurcher G.,et al.Mol.Cell.Biol.1991,11,2057-65.
[32]Velazquez L.,Mogensen K.E.,Barbieri G.,Fellous M.,Uze G.,et al.J.Biol.Chem.1995,270,3327-34
[33]Staal S.P.,Hartley J.W.,Rowe W.P.,Proc.Natl.Aca.Sci.USA.1977,74,3065-3067.
[34]Staal S.P.,Proc.Natl.Aca.Sci.USA.1987,84,5034-5037.
[35]Staal S.P.,Hartley J.,J.Exp.Med.1988,167,1259-1264.
[36]Nicholson K.M.;Anderson N.G.Cell.Signal.2002,14,381-395.
[37]Thomas C.C.,Deak M.,Alessi D.R.;et al.Curr.Biol.2002,12,1256-1262.
[38]Moon Z.,Wang Y.,Scheid M.P.,et al.Cell.Signal.2008,20,2038-2049.
[39]Jung H.S.,Kim D.W.,Joy S.,et al Mol.Endocrinol.2005,19,2748-2759.
[40]Shao Z.L.,Bhattacharya K.,Hsich E.,et al.Circ.Res.2006,98,111-118.
[41]Li D.M.,Sun H.,CancerRes.1997,57,2124-2129.
[42]Li J.,Yen C.,Liaw,D.,et al.Science 1997,275,1943-1947.
[43]Steck P.A.,Pershouse M.A.,Jasser S.A.,et al.Nat.Genet.1997,15,356-362.
[44]Cristofano A.,Pandolfi P.P.,Cell 2000,100,387-390.
[45]Leslie N.,Biondi R.M.,Alessi D.R.,Chem.Rev.2001,101,2365-2380.
[46]茆勇军,李海泓,李剑峰,沈敬山.药学学报,2008,43,323-334.
[47]Liebmann C.,Cell Signal.2001,13,777-85.
[48]Chan T.O.,Rittenhouse S.E.,Tsichlis P.N.,Trends.Pharmacol.Sci.2003,24,366-376.
[49]Filippa N.,Sable C.L.,Hemmings B.A.,et al.Mol.Cell.Biol.2000,20,5712-5721.
[50]Frame S.,Cohen P.,Biochem.J.2001,359,1-16.
[51]Sano H.,Kane S.,Sano E.,et al.J.Biol.Chem.2003,278,14599-14602.
[52]Asnaghi L.,Bruno P.,Priulla M.,et al.Pharmacol.Res.2004,50,545-549.
[53]Sundqvist A.,Bengoechea-Alonso M.T.,Ye X.,et al.Cell Metab.2005,1,379-391.
[54]Parcellier A.,Tintignac L.A.,Hemmings B.A.,et al.Cell.Signal.2008,20,21-30.
[55]Heron-Milhavet L.,Franckhauser C.,Rana V.,et al.Mol.Cell,Biol.2006,26,8267-8280.
[56]Wei W.,Jin J.,Schlisio S.,et al.Cancer Cell 2005,8,25-33.
[57]Murray P.J.,J.Immunol.2007,178,2623-29.
[58]Salomon D.S.,Brandt R.,Ciardiello F.,Normanno N.,Critical Reviews in Oncology/Hematology,1995,19,183-232.
[59]Glossmann H.,Presek P.,Eigenbrodt E.,Arch.Pharmacol.1981,317,100-102.
[60]Weisberg E.,Manley P.W.,Cowan-Jacob S.W.,et al.Nat.Rev.Cancer 2007,7,345-56.
[61]Druker B.J.,et al.Nat.Med.1996,2,561.
[62]Daub H.,Specht K.,Ullrich A.,Nat.Rev.Drug Discov.2004,3,1001.
[63]Shah N.P.,et al.Science 2004,305,399.
[64]Talpaz M.,et al.Blood 2005,106,40.
[65]Weisberg D.,Manley P.W.,Breitenstein W.,et al.Cancer Cell 2005,7,129-141.
[66]Kimura S.,Naito H.,Segawa H.,et al.Blood 2005,106,3948-3954.
[67]Golas J.M.,Arndt K.,Etienne D.,et al.Cancer Res.2003,63,375-381.
[68]Manetti F.,Brullo C.,Magnani M.,et al.J.Med.Chem.2008,51,1252-1259.
[69]Young M.A.,Shah N.P.,Chao L.H.,et al.Cancer Res.2006,66,1007-1014.
[70]Gumireddy K.,Baker S.J.,Cosenza S.C.,et al.Proc.Natl.Acad.Sci.USA 2005,102,1992-1997.
[71]Modugno M.,Casale E.,Soncini C.,et al.Cancer Res.2007,67,7987-7990.
[72]Gontarewicz A.,Balabanov S.,Keller G.,et al.Blood 2008,111,4355-4364.
[73]Adjei A.A.,J.Natl.Cancer Inst.2001,93,1062.
[74]Olayioye M.A.,Neve R.M.,Lane H.A.,EMBOJ.2000,19,3159-3167.
[75]Vema A.,Rambabu G.,Ranigrahi S.K.,Sarma J.A.R.P.,Desiraju G.R.,J.Chem.Inf Model 2005,45,725.
[76]Vema A.,Panigrahi S.K.,Rambabu G.,Gopalakrishnan B.,Sarma J.A.R.P.,Desiraju G.R.,Bioorg.Med.Chem.Lett.2003,11,4643.
[77]Ciardiello F.,Bianco R.,Caputo R.,et al.Clin.Cancer Res.2004,10,784-793.
[78]Jose B.L.,Hammond L.A.,Oncology 2002,63,6-16.
[79]Erlichman C.,Hidalgo M.,Boni J.P.,et al.J.Clin.Oncol.2006,24,2252-2260.
[80]Reid A.,Vidal L.,Shaw H.,et al.Eur.J.Cancer 2007,43,481-489.
[81]毛志强,项伟中,俞雁,李绍顺.中国药物化学杂志 2005,15,121-128.
[82]Rewcastle G.W.,Murray D.K.,Elliott W.L.,et al.J.Med.Chem.1998,41,742-751.
[83]Lydon N.B.,Mett H.,Mueller M.,et al.Int.J.Cancer 1998,76,154-163.
[84]Younes M.N.,Yazici Y.D.,Kim S.,et al.Clin.Cancer Res.2006,12,3425-34.
[85]Hubbard R.D.,et al.Bioorg.Med.Chem.Lett.2008,18,5738-5740.
[86]Rheault T.R.,et al.Bioorg.Med.Chem.Lett.2009,19,817-820.
[87]Wong K.K.,Clin.Cancer Res.2007,13,4593-4596.
[88]茆勇军,张佩璇,田广辉,王震,沈敬山.中国新药杂志2008,17,445
[89]钟毅,李志裕,尤启冬.中国新药杂志2006,15,181-185.
[90]Thomas A.L.,Morgan B.,Horsfield M,A.,et al.J.Clin.Oncol.2005,23,4162-4171
[91]Kiselyov A.S.,Semenov V.V.,Milligan D.,Chem.Biol.Drug Des.2006,68,308-313.
[92]Drevs J.,Siegert P.,Medinger M.,et al.J.Clin.Oncol.2007,25,3045-3054.
[93]Inai T.,Mancuso M.,Hashizume H.,et al.Am.J.Pathol.2004,165,35-52.
[94]Sonpavde G.,Hutson T.E.,Curr.Oncol.Rep.2007,9,115-119.
[95]Sorbera L.A.,Serradell N.,Bolos J.,et al.Drugs Future 2006,31,847-853.
[96]Nakamura K.,Taguchi E.,Miura T.,et al.Cancer Res.2006,66,9134-9142.
[97]Reuter C.W.,Morgan M.A.,Grunwald V.,et al.World J.Urol.2007,25,59-72.
[98]Lawlor M.A.,Mora A.,Ashby P.R.,et al.EMBO J.2002,21,3728-3738.
[99]Pullen N.,Dennis P.B.,Andjelkovic M.,et al.Science 1998,279,707-710.
[100]Mora A.,Komander D.,Van Aalten D.M.F.,et al.Cell Dev.Biol.2004,15,161-170.
[101]Jacinto E.,Lorberg A.,Biochem.J.2008,410,19-37.
[102]Stephens L.,Anderson K.,Stokoe D.,et al.Science 1998,279,710-714.
[103]Peifer C.,Alessi D.,R.,ChemMedChem 2008,3,1810-1838.
[104]Krymskaya V.P.,BioDrugs 2007,21,85-95.
[105]Hubbard R.E.,J.Synchrotron Radiat.2008,15,227-230.
[106]Tamguney T.,Zhang C.,Fiedler D.,Shokat K.,Stokoe D.,Exp.Cell Res.2008,314,2299-2312.
[107]Daly K.,Heron N.,Hird A.,et al.WO 106326,2006.
[108]Feldman R.I.,J Wu.M.,Polokoff M.A.,et al.J.Biol.Chem.2005,280,19867-19874.
[109]Engelhardt H.,Bader G.,Boehmelt G.,et al.WO 003766,2008.
[110]Parratt M.,Bower J.F.,Williamson D.,et al.WO 087707,2004.
[111]Bower J.F.,Cansfield A.,Jordan A.,et al.WO 108136,2004.
[112]Schultz M.,Burgdorf L.T.,Finsinger D.,WO 079826,2007.
[113]Capraro H.-G.,Furet P.,Garcia-Echeveria C.,WO 054238,2005.
[114]Stauffer F.,Maira S.M.,Furet P.,Bioorg.Med.Chem.Lett.2008,18,1027-1030.
[115]Maira S.M.,Stauffer F.,Brueggen J.,Mol.Cancer Ther.2008,7,1851-1863.
[116]Arnold W.,Bounaud P.,Gosberg A.,WO 015124,2006.
[117]Zhou T.,Parillon L.,Li F.,Chem.Biol.DrugDes.2007,70,171-181.
[118]Walmsley D.L.,Drysdale M.J.,Northfield C.J.,WO 134318,2006.
[119]Gopalsamy A.,Shi M.,Boschelli D.H.,J.Med.Chem.2007,50,5547-5549.
[120]Lind K.E.,Cao K.,Lin Y.-S.,WO 005457,2008.
[122]LoPiccolo J.,Granville C.A.,Gills J.J.,et al.Anti-Cancer Drugs,2007,18,861.
[123]Testa J.R.,Tsichlis P.N.,Oncogene 2005,24,7391-7393.
[124]Ruegg U.T.,Burgess G.M.,Trends Pharmacol.Sci.1989,10,218-220.
[125]Turek T.C.,Small E.C.,Bryant R.W.,et al.Anal.Biochem.2001,299,45-53.
[126]Chijiwa T.,MishimaA.,Hagiwara M.,et al.J.Biol.Chem.1990,265,5267-5272.
[127]Livnah N.,Levitzki A.,Reuveni H.,WO 0191754,2001.
[128]Reuveni H.,Livnah N.,Geiger T.,et al.Biochemistry 2002,41,10304-10314.
[129]Collins I.,Caldwell J.,Fonseca T.,et al.Bioorg.Med.Chem.2006,14,1255-1273.
[130]Li Q.,Li T.,Zhu G.D.,et al.Bioorg.Med.Chem.Lett.2006,16,1679-1685.
[131]Li Q.,Woods K.,Thomas S.,et al.Bioorg.Med.Chem.Lett.2006,16,2000-2007.
[132]Zhu G.D.,Gong J.,Claibone A.,et al.Bioorg.Med.Chem.Lett.2006,16,3150-3155.
[133]Woods K.,Fischer J.,Claiborne A.,et al.Bioorg.Med.Chem.2006,14, 6832-6846.
[134]Zhu G.D.,Gandhi V.,Gong J.,et al.Bioorg.Med.Chem.Lett.2006,16,3424-3429.
[135]Zhu G.D.,Gong J.,Gandhi V.,et al.Bioorg.Med.Chem.2007,15,2441-2452.
[136]Thomas S.,Li T.,Woods K.,et al.Bioorg.Med.Chem.Lett.2006,16,3740-3744.
[137]Zhu G.D.,Gandhi V.B.,Gong J.,et al.J.Med.Chem.2007,50,2990-3003.
[138]Donald A.,McHardy T.,Collins,I.,et al.J.Med.Chem.2007,50,2289-2292.
[139]Caldwell J.J.,Davies T.G.,Collins I.,et al.J.Med.Chem.2008,51,2147-2157.
[140]Lippa B.,Pan G.,Corbett M.,et al.Bioorg.Med.Chem.Lett.2008,18,3359-3363.
[141]Breitenlechner C.B.,Friebe W.G.,Brunet E.,et al.J.Med.Chem.2005,48,163-170.
[142]Ko J.H.,Yeon S.W.,Ryu C.K.,et al.Bioorg.Med.Chem.Lett.2006,16,6001-6005.
[143]Alessi D.R.,Caudwell F.B.,Andjelkovic M.,et al.FEBS Lett.1996,399,333-338.
[144]Obata T.,Yaffe M.B.,Leparc G.G.,et al.J.Biol.Chem.2000,275,36108-36115.
[145]Luo Y.,Smith R.A.,Guan R.,et al.Biochemistry 2004,43,1254-1263.
[146]Litman P.,Ohne O.,Livnah N.,et al.Biochemistry 2007,46,4716-4724.
[147]Barnett S.F.,Defeo-Jones D.,Fu S.,et al.Biochem.J.2005,385,399-408.
[148]Davidson W.,Frego L.,Peet G.W.,et al.Biochemistry 2004,43,11658-11671.
[149]Zhao Z.,Wisnoski D.D.,Wolkenberg S.E.,et al.Tetrahderon Lett.2004,45,4873.
[150]Lindsley C.W.,Zhao Z.,Leister W.H.,et al.Bioorg.Med.Chem.Lett.2005,15,761-764.
[151]Zhao Z.,Robinson R.G.,Barnett S.F.,et al.Bioorg.Med.Chem.Lett.2008,18,49-53.
[152]Hartnett J.C.,Barnett S.F.,Bilodeau M.T.,et al.Bioorg.Med.Chem.Lett.2008,18,2194-2197.
[153]Bilodeau M.T.,Balitza A.E.,Hoffman J.M.,et al.Bioorg.Med.Chem.Lett. 2008,18,3178-3182.
[1]Mohammadi M.,McMahon G.,Sun L.,et al.Science 1997,276,955-960.
[2]Sun L.,Tran N.,Tang F.,et al.J.Med.Chem.1998,41,2588-2603.
[3]Sun L.,Tran N.,Liang C.,et al.J.Med.Chem.1999,42,5120-5130.
[4]Tang P.C.,Miller T.,Li X.,et al.WO 2001060814,2001.
[5]Mendel D.B.,Laird A.D.,Xin X.,et al.Clin.Cancer Res.2003,9,327-337.
[6]Sun L.,Tran N.,Liang C.,et al.J.Med.Chem.2000,43,2655-2663.
[7]Guan H.,Laird A.D.,Blake R.A.,et al.Bioorg.Med.Chem.Lett.2004,14,187-190.
[8]Li X.,Huang P.,Cui J.J.,et al.Bioorg.Med.Chem.Lett.2003,13,1939-1942.
[9]Bramson H.N.,Corona J.,Davis S.T.et al.J.Med.Chem.2001,44,4339-4358.
[10]Wood E.R.,Kuyper L.,Petrov K.G,et al.Bioorg.Med.Chem.Lett.2004,14,953-957.
[11]Dermatakis A.,Luk K-C.,DePinto W.,Bioorg.Med.Chem.2003,11,1873-1881.
[12]Luk K-C.,Simcox M.E.,Schutt A.,et al.Bioorg.Med.Chem.Lett.2004,14,913-917.
[13]Zhu G.D.,Gandhi V.,Gong,J.,et al.Bioorg.Med.Chem.Lett.2006,16,3424-3429.
[14]Islam I.,Bryant J.,Chou,Y.L.,et al.Bioorg.Med.Chem.Lett.2007,17,3814-3818.
[15]Islam I.,Brown G.,Bryant J.,et al.Bioorg.Med.Chem.Lett.2007,17,3819-3825.
[16]Lawrence H.R.,Pireddu R.,Chen L.,et al.J.Med.Chem.2008,51,4948-4956.
[17]Angenot,L.Plant Med.Phytother 1978,12,123-129.
[18]Lerchner A.,Carreira E.M.,J.Am.Chem.Soc.2002,124,14826-14827.
[19]Cui C.B.,Kakeya H.,Osada H.,Tetrahedron 1996,52,12651-12666.
[20]Marti C.,Carreira E.M.,J.Am.Chem.Soc.2005,127,1489-1501.
[21]Hayler J.D.,Howie S.L.B.,Giles,R.G,et al.Org.Proeess Res.Dev.1998,2,3-9.
[22]Jost W.H.,Angersbach D.,CNS Drug Rev.2005,11,253-272.
[23]Kelleher J.P.,Centorrino F.,Albert M.J.,et al.CNSDrugs 2002,16,249-261.
[24]Tokunaga T.,Hume W.E.,Umezome T.,et al.J.Med.Chem.2001,44,4641-4649.
[25]Tokunaga T.,Hume W.E.,Nagamine J.,et al.Bioorg.Med.Chem.Lett.2005,15,1789-1792.
[26]Jiang T.,Kuhen K.L.,Wolff K.,et al.Bioorg.Med.Chem.Lett.2006,16,2105-2108.
[27]Jiang T.,Kuhen K.L.,Wolff K.,et al.Bioorg.Med.Chem.Lett.2006,16,2109-2112.
[28]Chiba T.,Kinoshita Y.,Sawada M.,et al.Yale J.Biol.Med.1998,71,247.
[29]Ernura T.,Esaki T.,Tachibana K.,J.Org.Chem.,2006,71,8559-8564.
[30]Fensome A.,Adams W.R.,Adams A.L.,et al.J.Med.Chem.2008,51,1861-1873.
[31]Turiso F.G-L.,Curran D.P.,Org.Lett.2005,7,151-154.
[32]Volk B.,Bark(?)czy J.,Hegedus E.,et al.J.Med.Chem.2008,51,2522-2532.
[33]Stratmann,K.;Moore,R.E.;Bonjouklian,R.;et al.J.Am.Chem.Soc.1994,116,9935-9942.
[34]Reisman S.E.,Ready J.M.,Hasuoka A.,et al.J.Am.Chem.Soc.2006,128,1448-1449.
[35]Tron G.C.,Pirali T.,Sorba G.,et al.J.Med.Chem.2006,49,3033-3044.
[36]Hamdouchi C.,Zhong B.,Mendoza J.,et al.Bioorg.Med.Chem.Lett.2005,15,1943-1947.
[37]Merrifield R.B.J.Am.Chem.Soc.1963,85,2149.
[38]Geysen H.M.,Meloen R.H.,Barteling S.J.Proc.Natl.Acad.USA,1984,81,3998.
[39]Houghten R.A.Proc.Natl.Acad.USA,1985,82,5131.
[40]Furka,A.,Sebestyen M.,Dibo G.in Abstract 14th Congr.Biochem.,Prague,1988,47.
[41]Bunin B.A.,Ellman,J.A.J.Am.Chem.Soc.1992,114,10997.
[42]Sundberg R.J.Indoles;Academic Press:London,1996;pp 17,152-154.
[43]Beckett A.H.,Daisley R.W.,Walker J.Tetrahedron 1968,24,6093.
[44]Cabri W.,Candiani I.,Colombo M.,Franzoi L.,Bedeschi A.Tetrahedron Lett.1995,36,949.
[45]Jones K.,Wilkinson J.,Ewin R.Tetrahedron Lett.1994,35,7673.
[46]Hennessy E.J.,Buchwald S.L.J.Am.Chem.Soc.2003,125,12084.
[47]Arumugam V.,Routledge A.,Abell C.,Balasubramanian S.Tetrahedron Lett.1997,38,6473.
[48]Padwa A.,Kuethe J.T.J.Org.Chem.1998,63,4256.
[49]Kuethe J.T.,Cochran J.E.,Padwa A.J.Org.Chem.1995,60,7082.
[50]Gassman P.G.,Gruetzmacher G.,van Bergen T.J.J.Am.Chem.Soc.1974,96,5512.
[51]Gassman P.G.,van Bergen T.J.J.Am.Chem.Soc.1974,96,5508.
[52]Gassman P.G.,Gruetzmacher G.,van Bergen T.J.J.Am.Chem.Soc.1973,95,6508.
[53]McAllister L.A.,Turner K.L.,Brand S.,Stefaniak M.,Procter D.J.J.Org.Chem.2006,71,6497.
[54]McAllister L.A.,McCormick R.A.,Brand S.,Procter D.J.Angew.Chem.,Int.Ed.2005,44,452.
[55]McAllister L.A.,Brand S.,de Gentile R.,Procter D.J.Chem.Commun.2003,2380.
[56]Gassman P.G.,Gilbert D.P.,Luh T.-Y.J.Org.Chem.1977,42,1340.
[57]Andreani A.,Burnelli S.,Granaiola M.,et al.J.Med.Chem.2006,49,6922-6924.
[58]Gueiffier A.,Lhassani M.,Elhakmaoui A.et al.J.Med.Chem.1996,39,2856.
[59]Gudmundsson K.S.,Johns B.A.Org.Lett.2003,5,1369-1372.
[1]刘国声.植物学报 1987,9,36.
[2]Means A.R.,VanBerkum M.F.,Bagchi I.,et al.Pharmacol.Ther.1991,50,255.
[3]Wei J.W.,Morris H.P.,Hickie R.A.,Cancer Res.1982,42,2571.
[4]Hu Z.,Chen S.,Hao Z.,et al.Cell.Signal.1989,1,181.
[5]Xu Y.,Zhang S.,Biochem.Biophys.Res.Comm.1986,140,461.
[6]张金红,耿朝晖.南开大学学报 自然版 1996,29,89.
[7]张金红,段江燕,耿朝晖,等.中草药 1997,28,483.
[8]徐小华.中华神经外科杂志 1993,6,364.
[9]张金红,毛启龙,徐乃寒,等.中草药 1998,29,243.
[10]朱希伟,隋文作,印晓光,等.中西医结合杂志 1986,6,611.
[11]华国勋.中国医学科学院学报 1991,5,322.
[12]Liu J.,Qi S.,Zhu H.,et al.Chin.Med.J.2002,115,759.
[13]潘兵,周圆,齐静,等.中国医学科学院学报 2005.27,311.
[14]段江燕,袁丽环,刘胡燕,等.山西师范大学学报(自然科学版)2001,15,55.
[15]Dong Y.,Yang M.M.,Kwan C.Y.,Life Sci.1997,60,135.
[16]Ji Z.N.,Ye W.C.,Liu G Q.,et al.Planta Med.2002,68,596.
[17]徐磊,赵小英,徐荣臻,等.中华血液学杂志2003,24,261.
[18]吴东,林茂芳,蔡真,等.中华血液学杂志 2004,25,754.
[19]吴东,林茂芳,赵小英,中国实验血液学杂志 2005,13,373.
[20]何智文,赵小英,徐荣臻,等.浙江大学学报(医学版)2006,35,209.
[21]Zhao X.,He Z.,Wu D.,Xu.R.,Chin.Med.J.2007,120,802.
[22]孙建荣,张晓红,何智文,等.中华医学杂志 2006,86,2246.
[23]Xu R.,Dong Q.,Yu Y,et al.Leuk.Res.2006,30.17.
[24]Zhu H.,Wang J.,Guo Q.,et al.Biol.Pharm.Bull.2005,28,1974.
[25]林传荣,黄秀清.中成药 1996,16,29.
[26]田晖,潘启超.药学学报 1997,32,245.
[27]齐淑玲,刘杰文,付津,等.实验血液学考志 1996,4,294.
[28]王晨光,葛曰萍,陈尊器,等.中国病理生理杂志 1995,11,496.
[29]程燕红,齐静,熊冬生,等.中国医学科学院学报 2006,28,164.
[30]刘新,周正任.中国医科大学学报 1996,25,229.
[31]葛明珠,刘昕,张勇.免疫学杂志 1998,14,238.
[32]Luo C.,Liu X.,Li W.,et al.Phytother.Res.1997,11,585.
[33]朱灿阳.中国热带医学2005,5,109.
[34]Samanta A.K.,Lin H.,Sun T.,Kantarjian H.,Arlinghaus R.B.,Cancer Res.2006,66,6468.
[35]Mukhopadhyay A.,Shishodia S.,Suttles J.,Brittingham K.,Lamothe B.,Nimmanapalli R.,Bhalla K.N.,Aggarwal B.B.,J.Biol.Chem.2002,277,30622.
[36]Kirchner D.,Duyster J.,Ottmann O.,Schmid R.M.,Bergmann L.,Munzert G.,Exp.Hematol.2003,31,504.
[37]Braun T.,Carvalho G.,Coquelle A.,Vozenin M.C.,Lepelley P.,Hirsch F.,Kiladjian J.J.,Ribrag V.,Fenaux P.,Kroemer G.,Blood2006,107,1156.
[38]Vilimas T.,Mascarenhas J.,Palomero T.,Mandal M.,Buonamici S.,Meng F.,Thompson B.,Spaulding C.,Macaroun S.,Alegre M.L.,Kee B.L.,Ferrando A.,Miele L.,Aifantis I.,Nat.Med.2007,13,70.
[39]Guzman M.L.,Neering S.J.,Upchurch D.,Grimes B.,Howard D.S.,Rizzieri D.A.,Luger S.M.,Jordan C.T.,Blood2001,98,2301.
[40]Holtz M.S.,Forman S.J.,Bhatia R.,Leukemia 2005,19,103.
[2]Baselga J.,Science 2006,312,1175-1178.
[3]Blume-Jensen P.,Hunter T.,Nature 2001,411,355.
[4]Schlessinger J,Ullrich A.,Neuron 1992,9,383-91.
[5]Hubbard S.R.,Till J.H.,Annu.Rev.Biochem.2000,69,373-98.
[6]Flanagan J.G.,Vanderhaeghen P.,Annu.Rev.Neurosci.1998,21,309-45.
[7]Holland S.J.,Peles E.,Pawson T.,Schlessinger J.,Curr.Opin.Neurobiol.1998,8,117-27.
[8]Yancopoulos G.D.,Klagsbrun M.,Folkman J.,Cell 1998,93,661-64.
[9]White M.F.,Mol.Cell.Biochem.1998,182,3-11.
[10]Cheatham B.,Vlahos C.J.,Cheatham L.,Wang L.,Blenis J.,et al.Mol.Cell.Biol.1994,14,4902-11.
[11]Okada T.,Kawano Y.,Sakakibara T.,et al.J.Biol.Chem.1994,269,3568-73.
[12]Kuriyan J.,Cowburn D.,Annu.Rev.Biophys.Biomol.Struct.1997,26,259-88.
[13]Ullrich A.,Schlessinger J.,Cell 1990,61,203-12.
[14]Heldin C.H.,Cell 1995,80,213-23.
[15]Hubbard S.R.,Wei L.,Ellis L.,Hendrickson W.A.,Nature 1994,372,746-54.
[16]Hubbard S.R.,EMBOJ.1997,16,5572-81.
[17]Neet K.,Hunter T.,Genes Cells 1996,1,147-69.
[18]Lemmon M.A.,Ferguson K.M.,Curr.Top.Microbiol.Immunol.1998,228,39-74.
[19]Darnell JE Jr.Science 1997,277,1630-35.
[20]Weiss A.,Littman D.R.,Cell 1994,76,263-74.
[21]Tonks N.K.,Neel B.G.,Cell 1996,87,365-68.
[22]Nada S.,Okada M.,MacAuley A.,Cooper J.A.,Nakagawa H.,Nature 1991,351,69-72.
[23]Cooper J.A.,Gould K.L.,Cartwright C.A.,Hunter T.,Science 1986,231,1431-34.
[24]Kmiecik T.E.,Shalloway D.,Cell 1987,49,65-73.
[25]Superti-Furga G.,Courtneidge S.A.,BioEssays 1995,17,321-30.
[26]Mayer B.J.,Baltimore D.,Mol.Cell.Biol.1994,14,2883-94.
[27]Van Etten R.A.,Debnath J.,Zhou H.,Casasnovas J.M.,Oncogene 1995,10, 1977-88.
[28]Wen S.T.,Van Etten R.A.,Genes Dev.1997,11,2456-67.
[29]Shiue L.,Zoller M.J.,Brugge J.S.,J.Biol.Chem.1995,270,10498-502.
[30]Chan A.C.,Dalton M.,Johnson R.,Kong G.H.,Wang T.,et al.EMBO J.1995,14,2499-508.
[31]Wilks A.F.,Harpur A.G.,Kurban R.R.,Ralph S.J.,Zurcher G.,et al.Mol.Cell.Biol.1991,11,2057-65.
[32]Velazquez L.,Mogensen K.E.,Barbieri G.,Fellous M.,Uze G.,et al.J.Biol.Chem.1995,270,3327-34
[33]Staal S.P.,Hartley J.W.,Rowe W.P.,Proc.Natl.Aca.Sci.USA.1977,74,3065-3067.
[34]Staal S.P.,Proc.Natl.Aca.Sci.USA.1987,84,5034-5037.
[35]Staal S.P.,Hartley J.,J.Exp.Med.1988,167,1259-1264.
[36]Nicholson K.M.;Anderson N.G.Cell.Signal.2002,14,381-395.
[37]Thomas C.C.,Deak M.,Alessi D.R.;et al.Curr.Biol.2002,12,1256-1262.
[38]Moon Z.,Wang Y.,Scheid M.P.,et al.Cell.Signal.2008,20,2038-2049.
[39]Jung H.S.,Kim D.W.,Joy S.,et al Mol.Endocrinol.2005,19,2748-2759.
[40]Shao Z.L.,Bhattacharya K.,Hsich E.,et al.Circ.Res.2006,98,111-118.
[41]Li D.M.,Sun H.,CancerRes.1997,57,2124-2129.
[42]Li J.,Yen C.,Liaw,D.,et al.Science 1997,275,1943-1947.
[43]Steck P.A.,Pershouse M.A.,Jasser S.A.,et al.Nat.Genet.1997,15,356-362.
[44]Cristofano A.,Pandolfi P.P.,Cell 2000,100,387-390.
[45]Leslie N.,Biondi R.M.,Alessi D.R.,Chem.Rev.2001,101,2365-2380.
[46]茆勇军,李海泓,李剑峰,沈敬山.药学学报,2008,43,323-334.
[47]Liebmann C.,Cell Signal.2001,13,777-85.
[48]Chan T.O.,Rittenhouse S.E.,Tsichlis P.N.,Trends.Pharmacol.Sci.2003,24,366-376.
[49]Filippa N.,Sable C.L.,Hemmings B.A.,et al.Mol.Cell.Biol.2000,20,5712-5721.
[50]Frame S.,Cohen P.,Biochem.J.2001,359,1-16.
[51]Sano H.,Kane S.,Sano E.,et al.J.Biol.Chem.2003,278,14599-14602.
[52]Asnaghi L.,Bruno P.,Priulla M.,et al.Pharmacol.Res.2004,50,545-549.
[53]Sundqvist A.,Bengoechea-Alonso M.T.,Ye X.,et al.Cell Metab.2005,1,379-391.
[54]Parcellier A.,Tintignac L.A.,Hemmings B.A.,et al.Cell.Signal.2008,20,21-30.
[55]Heron-Milhavet L.,Franckhauser C.,Rana V.,et al.Mol.Cell,Biol.2006,26,8267-8280.
[56]Wei W.,Jin J.,Schlisio S.,et al.Cancer Cell 2005,8,25-33.
[57]Murray P.J.,J.Immunol.2007,178,2623-29.
[58]Salomon D.S.,Brandt R.,Ciardiello F.,Normanno N.,Critical Reviews in Oncology/Hematology,1995,19,183-232.
[59]Glossmann H.,Presek P.,Eigenbrodt E.,Arch.Pharmacol.1981,317,100-102.
[60]Weisberg E.,Manley P.W.,Cowan-Jacob S.W.,et al.Nat.Rev.Cancer 2007,7,345-56.
[61]Druker B.J.,et al.Nat.Med.1996,2,561.
[62]Daub H.,Specht K.,Ullrich A.,Nat.Rev.Drug Discov.2004,3,1001.
[63]Shah N.P.,et al.Science 2004,305,399.
[64]Talpaz M.,et al.Blood 2005,106,40.
[65]Weisberg D.,Manley P.W.,Breitenstein W.,et al.Cancer Cell 2005,7,129-141.
[66]Kimura S.,Naito H.,Segawa H.,et al.Blood 2005,106,3948-3954.
[67]Golas J.M.,Arndt K.,Etienne D.,et al.Cancer Res.2003,63,375-381.
[68]Manetti F.,Brullo C.,Magnani M.,et al.J.Med.Chem.2008,51,1252-1259.
[69]Young M.A.,Shah N.P.,Chao L.H.,et al.Cancer Res.2006,66,1007-1014.
[70]Gumireddy K.,Baker S.J.,Cosenza S.C.,et al.Proc.Natl.Acad.Sci.USA 2005,102,1992-1997.
[71]Modugno M.,Casale E.,Soncini C.,et al.Cancer Res.2007,67,7987-7990.
[72]Gontarewicz A.,Balabanov S.,Keller G.,et al.Blood 2008,111,4355-4364.
[73]Adjei A.A.,J.Natl.Cancer Inst.2001,93,1062.
[74]Olayioye M.A.,Neve R.M.,Lane H.A.,EMBOJ.2000,19,3159-3167.
[75]Vema A.,Rambabu G.,Ranigrahi S.K.,Sarma J.A.R.P.,Desiraju G.R.,J.Chem.Inf Model 2005,45,725.
[76]Vema A.,Panigrahi S.K.,Rambabu G.,Gopalakrishnan B.,Sarma J.A.R.P.,Desiraju G.R.,Bioorg.Med.Chem.Lett.2003,11,4643.
[77]Ciardiello F.,Bianco R.,Caputo R.,et al.Clin.Cancer Res.2004,10,784-793.
[78]Jose B.L.,Hammond L.A.,Oncology 2002,63,6-16.
[79]Erlichman C.,Hidalgo M.,Boni J.P.,et al.J.Clin.Oncol.2006,24,2252-2260.
[80]Reid A.,Vidal L.,Shaw H.,et al.Eur.J.Cancer 2007,43,481-489.
[81]毛志强,项伟中,俞雁,李绍顺.中国药物化学杂志 2005,15,121-128.
[82]Rewcastle G.W.,Murray D.K.,Elliott W.L.,et al.J.Med.Chem.1998,41,742-751.
[83]Lydon N.B.,Mett H.,Mueller M.,et al.Int.J.Cancer 1998,76,154-163.
[84]Younes M.N.,Yazici Y.D.,Kim S.,et al.Clin.Cancer Res.2006,12,3425-34.
[85]Hubbard R.D.,et al.Bioorg.Med.Chem.Lett.2008,18,5738-5740.
[86]Rheault T.R.,et al.Bioorg.Med.Chem.Lett.2009,19,817-820.
[87]Wong K.K.,Clin.Cancer Res.2007,13,4593-4596.
[88]茆勇军,张佩璇,田广辉,王震,沈敬山.中国新药杂志2008,17,445
[89]钟毅,李志裕,尤启冬.中国新药杂志2006,15,181-185.
[90]Thomas A.L.,Morgan B.,Horsfield M,A.,et al.J.Clin.Oncol.2005,23,4162-4171
[91]Kiselyov A.S.,Semenov V.V.,Milligan D.,Chem.Biol.Drug Des.2006,68,308-313.
[92]Drevs J.,Siegert P.,Medinger M.,et al.J.Clin.Oncol.2007,25,3045-3054.
[93]Inai T.,Mancuso M.,Hashizume H.,et al.Am.J.Pathol.2004,165,35-52.
[94]Sonpavde G.,Hutson T.E.,Curr.Oncol.Rep.2007,9,115-119.
[95]Sorbera L.A.,Serradell N.,Bolos J.,et al.Drugs Future 2006,31,847-853.
[96]Nakamura K.,Taguchi E.,Miura T.,et al.Cancer Res.2006,66,9134-9142.
[97]Reuter C.W.,Morgan M.A.,Grunwald V.,et al.World J.Urol.2007,25,59-72.
[98]Lawlor M.A.,Mora A.,Ashby P.R.,et al.EMBO J.2002,21,3728-3738.
[99]Pullen N.,Dennis P.B.,Andjelkovic M.,et al.Science 1998,279,707-710.
[100]Mora A.,Komander D.,Van Aalten D.M.F.,et al.Cell Dev.Biol.2004,15,161-170.
[101]Jacinto E.,Lorberg A.,Biochem.J.2008,410,19-37.
[102]Stephens L.,Anderson K.,Stokoe D.,et al.Science 1998,279,710-714.
[103]Peifer C.,Alessi D.,R.,ChemMedChem 2008,3,1810-1838.
[104]Krymskaya V.P.,BioDrugs 2007,21,85-95.
[105]Hubbard R.E.,J.Synchrotron Radiat.2008,15,227-230.
[106]Tamguney T.,Zhang C.,Fiedler D.,Shokat K.,Stokoe D.,Exp.Cell Res.2008,314,2299-2312.
[107]Daly K.,Heron N.,Hird A.,et al.WO 106326,2006.
[108]Feldman R.I.,J Wu.M.,Polokoff M.A.,et al.J.Biol.Chem.2005,280,19867-19874.
[109]Engelhardt H.,Bader G.,Boehmelt G.,et al.WO 003766,2008.
[110]Parratt M.,Bower J.F.,Williamson D.,et al.WO 087707,2004.
[111]Bower J.F.,Cansfield A.,Jordan A.,et al.WO 108136,2004.
[112]Schultz M.,Burgdorf L.T.,Finsinger D.,WO 079826,2007.
[113]Capraro H.-G.,Furet P.,Garcia-Echeveria C.,WO 054238,2005.
[114]Stauffer F.,Maira S.M.,Furet P.,Bioorg.Med.Chem.Lett.2008,18,1027-1030.
[115]Maira S.M.,Stauffer F.,Brueggen J.,Mol.Cancer Ther.2008,7,1851-1863.
[116]Arnold W.,Bounaud P.,Gosberg A.,WO 015124,2006.
[117]Zhou T.,Parillon L.,Li F.,Chem.Biol.DrugDes.2007,70,171-181.
[118]Walmsley D.L.,Drysdale M.J.,Northfield C.J.,WO 134318,2006.
[119]Gopalsamy A.,Shi M.,Boschelli D.H.,J.Med.Chem.2007,50,5547-5549.
[120]Lind K.E.,Cao K.,Lin Y.-S.,WO 005457,2008.
[122]LoPiccolo J.,Granville C.A.,Gills J.J.,et al.Anti-Cancer Drugs,2007,18,861.
[123]Testa J.R.,Tsichlis P.N.,Oncogene 2005,24,7391-7393.
[124]Ruegg U.T.,Burgess G.M.,Trends Pharmacol.Sci.1989,10,218-220.
[125]Turek T.C.,Small E.C.,Bryant R.W.,et al.Anal.Biochem.2001,299,45-53.
[126]Chijiwa T.,MishimaA.,Hagiwara M.,et al.J.Biol.Chem.1990,265,5267-5272.
[127]Livnah N.,Levitzki A.,Reuveni H.,WO 0191754,2001.
[128]Reuveni H.,Livnah N.,Geiger T.,et al.Biochemistry 2002,41,10304-10314.
[129]Collins I.,Caldwell J.,Fonseca T.,et al.Bioorg.Med.Chem.2006,14,1255-1273.
[130]Li Q.,Li T.,Zhu G.D.,et al.Bioorg.Med.Chem.Lett.2006,16,1679-1685.
[131]Li Q.,Woods K.,Thomas S.,et al.Bioorg.Med.Chem.Lett.2006,16,2000-2007.
[132]Zhu G.D.,Gong J.,Claibone A.,et al.Bioorg.Med.Chem.Lett.2006,16,3150-3155.
[133]Woods K.,Fischer J.,Claiborne A.,et al.Bioorg.Med.Chem.2006,14, 6832-6846.
[134]Zhu G.D.,Gandhi V.,Gong J.,et al.Bioorg.Med.Chem.Lett.2006,16,3424-3429.
[135]Zhu G.D.,Gong J.,Gandhi V.,et al.Bioorg.Med.Chem.2007,15,2441-2452.
[136]Thomas S.,Li T.,Woods K.,et al.Bioorg.Med.Chem.Lett.2006,16,3740-3744.
[137]Zhu G.D.,Gandhi V.B.,Gong J.,et al.J.Med.Chem.2007,50,2990-3003.
[138]Donald A.,McHardy T.,Collins,I.,et al.J.Med.Chem.2007,50,2289-2292.
[139]Caldwell J.J.,Davies T.G.,Collins I.,et al.J.Med.Chem.2008,51,2147-2157.
[140]Lippa B.,Pan G.,Corbett M.,et al.Bioorg.Med.Chem.Lett.2008,18,3359-3363.
[141]Breitenlechner C.B.,Friebe W.G.,Brunet E.,et al.J.Med.Chem.2005,48,163-170.
[142]Ko J.H.,Yeon S.W.,Ryu C.K.,et al.Bioorg.Med.Chem.Lett.2006,16,6001-6005.
[143]Alessi D.R.,Caudwell F.B.,Andjelkovic M.,et al.FEBS Lett.1996,399,333-338.
[144]Obata T.,Yaffe M.B.,Leparc G.G.,et al.J.Biol.Chem.2000,275,36108-36115.
[145]Luo Y.,Smith R.A.,Guan R.,et al.Biochemistry 2004,43,1254-1263.
[146]Litman P.,Ohne O.,Livnah N.,et al.Biochemistry 2007,46,4716-4724.
[147]Barnett S.F.,Defeo-Jones D.,Fu S.,et al.Biochem.J.2005,385,399-408.
[148]Davidson W.,Frego L.,Peet G.W.,et al.Biochemistry 2004,43,11658-11671.
[149]Zhao Z.,Wisnoski D.D.,Wolkenberg S.E.,et al.Tetrahderon Lett.2004,45,4873.
[150]Lindsley C.W.,Zhao Z.,Leister W.H.,et al.Bioorg.Med.Chem.Lett.2005,15,761-764.
[151]Zhao Z.,Robinson R.G.,Barnett S.F.,et al.Bioorg.Med.Chem.Lett.2008,18,49-53.
[152]Hartnett J.C.,Barnett S.F.,Bilodeau M.T.,et al.Bioorg.Med.Chem.Lett.2008,18,2194-2197.
[153]Bilodeau M.T.,Balitza A.E.,Hoffman J.M.,et al.Bioorg.Med.Chem.Lett. 2008,18,3178-3182.
[1]Mohammadi M.,McMahon G.,Sun L.,et al.Science 1997,276,955-960.
[2]Sun L.,Tran N.,Tang F.,et al.J.Med.Chem.1998,41,2588-2603.
[3]Sun L.,Tran N.,Liang C.,et al.J.Med.Chem.1999,42,5120-5130.
[4]Tang P.C.,Miller T.,Li X.,et al.WO 2001060814,2001.
[5]Mendel D.B.,Laird A.D.,Xin X.,et al.Clin.Cancer Res.2003,9,327-337.
[6]Sun L.,Tran N.,Liang C.,et al.J.Med.Chem.2000,43,2655-2663.
[7]Guan H.,Laird A.D.,Blake R.A.,et al.Bioorg.Med.Chem.Lett.2004,14,187-190.
[8]Li X.,Huang P.,Cui J.J.,et al.Bioorg.Med.Chem.Lett.2003,13,1939-1942.
[9]Bramson H.N.,Corona J.,Davis S.T.et al.J.Med.Chem.2001,44,4339-4358.
[10]Wood E.R.,Kuyper L.,Petrov K.G,et al.Bioorg.Med.Chem.Lett.2004,14,953-957.
[11]Dermatakis A.,Luk K-C.,DePinto W.,Bioorg.Med.Chem.2003,11,1873-1881.
[12]Luk K-C.,Simcox M.E.,Schutt A.,et al.Bioorg.Med.Chem.Lett.2004,14,913-917.
[13]Zhu G.D.,Gandhi V.,Gong,J.,et al.Bioorg.Med.Chem.Lett.2006,16,3424-3429.
[14]Islam I.,Bryant J.,Chou,Y.L.,et al.Bioorg.Med.Chem.Lett.2007,17,3814-3818.
[15]Islam I.,Brown G.,Bryant J.,et al.Bioorg.Med.Chem.Lett.2007,17,3819-3825.
[16]Lawrence H.R.,Pireddu R.,Chen L.,et al.J.Med.Chem.2008,51,4948-4956.
[17]Angenot,L.Plant Med.Phytother 1978,12,123-129.
[18]Lerchner A.,Carreira E.M.,J.Am.Chem.Soc.2002,124,14826-14827.
[19]Cui C.B.,Kakeya H.,Osada H.,Tetrahedron 1996,52,12651-12666.
[20]Marti C.,Carreira E.M.,J.Am.Chem.Soc.2005,127,1489-1501.
[21]Hayler J.D.,Howie S.L.B.,Giles,R.G,et al.Org.Proeess Res.Dev.1998,2,3-9.
[22]Jost W.H.,Angersbach D.,CNS Drug Rev.2005,11,253-272.
[23]Kelleher J.P.,Centorrino F.,Albert M.J.,et al.CNSDrugs 2002,16,249-261.
[24]Tokunaga T.,Hume W.E.,Umezome T.,et al.J.Med.Chem.2001,44,4641-4649.
[25]Tokunaga T.,Hume W.E.,Nagamine J.,et al.Bioorg.Med.Chem.Lett.2005,15,1789-1792.
[26]Jiang T.,Kuhen K.L.,Wolff K.,et al.Bioorg.Med.Chem.Lett.2006,16,2105-2108.
[27]Jiang T.,Kuhen K.L.,Wolff K.,et al.Bioorg.Med.Chem.Lett.2006,16,2109-2112.
[28]Chiba T.,Kinoshita Y.,Sawada M.,et al.Yale J.Biol.Med.1998,71,247.
[29]Ernura T.,Esaki T.,Tachibana K.,J.Org.Chem.,2006,71,8559-8564.
[30]Fensome A.,Adams W.R.,Adams A.L.,et al.J.Med.Chem.2008,51,1861-1873.
[31]Turiso F.G-L.,Curran D.P.,Org.Lett.2005,7,151-154.
[32]Volk B.,Bark(?)czy J.,Hegedus E.,et al.J.Med.Chem.2008,51,2522-2532.
[33]Stratmann,K.;Moore,R.E.;Bonjouklian,R.;et al.J.Am.Chem.Soc.1994,116,9935-9942.
[34]Reisman S.E.,Ready J.M.,Hasuoka A.,et al.J.Am.Chem.Soc.2006,128,1448-1449.
[35]Tron G.C.,Pirali T.,Sorba G.,et al.J.Med.Chem.2006,49,3033-3044.
[36]Hamdouchi C.,Zhong B.,Mendoza J.,et al.Bioorg.Med.Chem.Lett.2005,15,1943-1947.
[37]Merrifield R.B.J.Am.Chem.Soc.1963,85,2149.
[38]Geysen H.M.,Meloen R.H.,Barteling S.J.Proc.Natl.Acad.USA,1984,81,3998.
[39]Houghten R.A.Proc.Natl.Acad.USA,1985,82,5131.
[40]Furka,A.,Sebestyen M.,Dibo G.in Abstract 14th Congr.Biochem.,Prague,1988,47.
[41]Bunin B.A.,Ellman,J.A.J.Am.Chem.Soc.1992,114,10997.
[42]Sundberg R.J.Indoles;Academic Press:London,1996;pp 17,152-154.
[43]Beckett A.H.,Daisley R.W.,Walker J.Tetrahedron 1968,24,6093.
[44]Cabri W.,Candiani I.,Colombo M.,Franzoi L.,Bedeschi A.Tetrahedron Lett.1995,36,949.
[45]Jones K.,Wilkinson J.,Ewin R.Tetrahedron Lett.1994,35,7673.
[46]Hennessy E.J.,Buchwald S.L.J.Am.Chem.Soc.2003,125,12084.
[47]Arumugam V.,Routledge A.,Abell C.,Balasubramanian S.Tetrahedron Lett.1997,38,6473.
[48]Padwa A.,Kuethe J.T.J.Org.Chem.1998,63,4256.
[49]Kuethe J.T.,Cochran J.E.,Padwa A.J.Org.Chem.1995,60,7082.
[50]Gassman P.G.,Gruetzmacher G.,van Bergen T.J.J.Am.Chem.Soc.1974,96,5512.
[51]Gassman P.G.,van Bergen T.J.J.Am.Chem.Soc.1974,96,5508.
[52]Gassman P.G.,Gruetzmacher G.,van Bergen T.J.J.Am.Chem.Soc.1973,95,6508.
[53]McAllister L.A.,Turner K.L.,Brand S.,Stefaniak M.,Procter D.J.J.Org.Chem.2006,71,6497.
[54]McAllister L.A.,McCormick R.A.,Brand S.,Procter D.J.Angew.Chem.,Int.Ed.2005,44,452.
[55]McAllister L.A.,Brand S.,de Gentile R.,Procter D.J.Chem.Commun.2003,2380.
[56]Gassman P.G.,Gilbert D.P.,Luh T.-Y.J.Org.Chem.1977,42,1340.
[57]Andreani A.,Burnelli S.,Granaiola M.,et al.J.Med.Chem.2006,49,6922-6924.
[58]Gueiffier A.,Lhassani M.,Elhakmaoui A.et al.J.Med.Chem.1996,39,2856.
[59]Gudmundsson K.S.,Johns B.A.Org.Lett.2003,5,1369-1372.
[1]刘国声.植物学报 1987,9,36.
[2]Means A.R.,VanBerkum M.F.,Bagchi I.,et al.Pharmacol.Ther.1991,50,255.
[3]Wei J.W.,Morris H.P.,Hickie R.A.,Cancer Res.1982,42,2571.
[4]Hu Z.,Chen S.,Hao Z.,et al.Cell.Signal.1989,1,181.
[5]Xu Y.,Zhang S.,Biochem.Biophys.Res.Comm.1986,140,461.
[6]张金红,耿朝晖.南开大学学报 自然版 1996,29,89.
[7]张金红,段江燕,耿朝晖,等.中草药 1997,28,483.
[8]徐小华.中华神经外科杂志 1993,6,364.
[9]张金红,毛启龙,徐乃寒,等.中草药 1998,29,243.
[10]朱希伟,隋文作,印晓光,等.中西医结合杂志 1986,6,611.
[11]华国勋.中国医学科学院学报 1991,5,322.
[12]Liu J.,Qi S.,Zhu H.,et al.Chin.Med.J.2002,115,759.
[13]潘兵,周圆,齐静,等.中国医学科学院学报 2005.27,311.
[14]段江燕,袁丽环,刘胡燕,等.山西师范大学学报(自然科学版)2001,15,55.
[15]Dong Y.,Yang M.M.,Kwan C.Y.,Life Sci.1997,60,135.
[16]Ji Z.N.,Ye W.C.,Liu G Q.,et al.Planta Med.2002,68,596.
[17]徐磊,赵小英,徐荣臻,等.中华血液学杂志2003,24,261.
[18]吴东,林茂芳,蔡真,等.中华血液学杂志 2004,25,754.
[19]吴东,林茂芳,赵小英,中国实验血液学杂志 2005,13,373.
[20]何智文,赵小英,徐荣臻,等.浙江大学学报(医学版)2006,35,209.
[21]Zhao X.,He Z.,Wu D.,Xu.R.,Chin.Med.J.2007,120,802.
[22]孙建荣,张晓红,何智文,等.中华医学杂志 2006,86,2246.
[23]Xu R.,Dong Q.,Yu Y,et al.Leuk.Res.2006,30.17.
[24]Zhu H.,Wang J.,Guo Q.,et al.Biol.Pharm.Bull.2005,28,1974.
[25]林传荣,黄秀清.中成药 1996,16,29.
[26]田晖,潘启超.药学学报 1997,32,245.
[27]齐淑玲,刘杰文,付津,等.实验血液学考志 1996,4,294.
[28]王晨光,葛曰萍,陈尊器,等.中国病理生理杂志 1995,11,496.
[29]程燕红,齐静,熊冬生,等.中国医学科学院学报 2006,28,164.
[30]刘新,周正任.中国医科大学学报 1996,25,229.
[31]葛明珠,刘昕,张勇.免疫学杂志 1998,14,238.
[32]Luo C.,Liu X.,Li W.,et al.Phytother.Res.1997,11,585.
[33]朱灿阳.中国热带医学2005,5,109.
[34]Samanta A.K.,Lin H.,Sun T.,Kantarjian H.,Arlinghaus R.B.,Cancer Res.2006,66,6468.
[35]Mukhopadhyay A.,Shishodia S.,Suttles J.,Brittingham K.,Lamothe B.,Nimmanapalli R.,Bhalla K.N.,Aggarwal B.B.,J.Biol.Chem.2002,277,30622.
[36]Kirchner D.,Duyster J.,Ottmann O.,Schmid R.M.,Bergmann L.,Munzert G.,Exp.Hematol.2003,31,504.
[37]Braun T.,Carvalho G.,Coquelle A.,Vozenin M.C.,Lepelley P.,Hirsch F.,Kiladjian J.J.,Ribrag V.,Fenaux P.,Kroemer G.,Blood2006,107,1156.
[38]Vilimas T.,Mascarenhas J.,Palomero T.,Mandal M.,Buonamici S.,Meng F.,Thompson B.,Spaulding C.,Macaroun S.,Alegre M.L.,Kee B.L.,Ferrando A.,Miele L.,Aifantis I.,Nat.Med.2007,13,70.
[39]Guzman M.L.,Neering S.J.,Upchurch D.,Grimes B.,Howard D.S.,Rizzieri D.A.,Luger S.M.,Jordan C.T.,Blood2001,98,2301.
[40]Holtz M.S.,Forman S.J.,Bhatia R.,Leukemia 2005,19,103.