抗肿瘤药物索拉非尼衍生物的设计、合成、生物活性及构效关系研究
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摘要
近年来,基于化学生物学和生物信息学的研究成果,理性地设计作用于多个细胞调控靶点的配体已成为抗肿瘤药物的研究趋势。索拉非尼是首个上市的口服多靶点激酶抑制剂,可以同时抑制与肿瘤细胞增殖和新生血管生长相关的多种激酶,包括Raf、VEGFR、PDGFR和KIT等。由于其多靶点机理、广谱、耐受性好和易于联合用药等优势,众多学者致力于索拉非尼结构改造的研究,期望发现新的具有自主知识产权的靶向抗肿瘤药物。
本研究以索拉非尼为先导化合物,在近年来国内外相关研究工作的基础上,通过对其靶蛋白活性位点结构的解析和3-D构效关系总结,设计并合成了四个系列109个小分子化合物,初步对其进行了体外EGFR、ABL1激酶的抑制活性试验；部分化合物进行了抑制VEGFR磷酸化的评价和体外抑制大鼠动脉环微血管生成的实验研究；所有化合物均采用MTT法进行了体外抑制肿瘤细胞增殖活性评价,以期找到具有良好抗肿瘤活性的索拉非尼衍生物。
本论文基于合理药物设计,共合成了四个系列109个新型ω-羧基取代的二苯硫脲类化合物,所合成的目标化合物均采用1HNMR、13C NMR和HRMS等表征手段进行了结构确证。经查阅文献证实,所合成的目标化合物绝大多数未见文献报道,其中化合物B9n和C9b采用单晶X-射线衍射进行了结构表征。
抗肿瘤活性方而,针对人结肠癌细胞HCT116、人乳腺癌细胞MDA-MB-231、人肾癌细胞PC-3、非小细胞肺癌A549细胞、人肝癌细胞HepG2和小鼠黑色素瘤细胞B16BL6,采用MTT法对所得化合物(109个)进行了细胞毒活性测试,大多数化合物对HCT116和PC-3细胞具有抑制活性,化合物A9o、 A9p、B9p、B9q、B9r、B9s、B9x、B9aa、C9f、C9g、C9r、C9s、D9K、D9o、 D9p、D9q、D9r和D9ac的活性与阳性对照药物索拉非尼相当甚至优于索拉非尼。测试结果表明：大多数B和D系列化合物的体外抑瘤活性强于A和C系列的化合物。末端酰胺键上取代基的大小和形状影响其对体外肿瘤细胞增殖的抑制活性和选择性,A、B、C系列中,酰胺末端取代基R较小时(如甲基)活性较强,取代基R较大时(如苄基)抑制活性较差,R为环已基时,对HCT116和MDA-MB-231两种细胞的选择性较强,该类化合物对HCT1l6细胞的抑制活性要好于其它取代基,但大部分该类化合物对MDA-MB-231细胞无明显抑制活性。而D系列化合物中,R基团较大的化合物(如苄基)往往具有较好的细胞毒性。末端苯环上取代基对化合物的肿瘤细胞抑制活性影响较大,在所合成的四个系列目标化合物中,末端苯环上的吸电子基(如三氟甲基)能够增强化合物的细胞毒活性,而供电子取代基(如甲基)会降低相应化合物的肿瘤细胞抑制活性。
酶活测试结果显示,目标化合物对EGFR激酶无明显抑制作用,部分化合物对ABL激酶有一定的抑制作用。在抑制新生血管生成方面,采用western blot检测了部分A系列化合物对细胞水平VEGFR磷酸化的抑制作用,用动脉环实验检测了部分D系列化合物的抗新生血管生成作用。western blot检测结果显示：所测化合物中A9m、A9o和A9p对VEGFR的磷酸化有一定抑制作用。这三个化合物的末端酰胺基上是甲基取代,并且在末端苯环上的取代基均含有3-CF3。动脉环实验结果显示,所测化合物中,D9g和D9p可以很好的抑制大鼠动脉环微血管的生成,化合物D9r在0.1μM浓度时能部分抑制大鼠动脉环微血管的生成,而化合物D9q在0.1μM浓度时则对大鼠动脉环微血管的生成没有明显的抑制作用。
最后,对部分代表性化合物进行了以分子对接为主的构效关系研究：将化合物与B-Raf和VEGFR-2激酶分别进行了对接打分,并创建了作用模式图,探讨了化合物与激酶活性位点的作用模式。
综上所述,本论文共设计、合成了109个新型含硫脲结构的索拉非尼衍生物,通过初步的生物活性评价,我们发现了几个具有进一步研究开发价值的化合物,如：化合物B9q、B9r、B9s、B9x、C9r、C9s、D9p、D9q、D9r和D9ac等,并进一步对其进行了以分子对接为主的构效关系研究,探讨了其与B-Raf和VEGFR-2活性位点的结合模式,为今后新型索拉非尼衍生物的设计、合成奠定了基础。
Recent years, based on the achievement of chemical biology and bioinformatics the rational design of multitarget drugs is being the research direction ofanticancer drugs. Sorafenib, the first oral multikinase inhibitor, can inhibit several kinases involved in tumor proliferation and angiogenesis including Raf, VEGFR, PDGFR, KIT and so on. Due to the advantages of multi-mechanisms, broad-spectrum anticancer potency, and well-tolerated results in combination trials, more and more researchers have focused on the optimization of sorafenib in order to develop novel multi-targeted anticancer drugs.
Based on the international current research works, by studying the active sites of sorafenib and using the strategies of rational drug design, we designed and synthesized four series of109targeted sorafenib derivatives, and tested their inhibitory activity against kinase EGFR and ABL1. In vitro anti-phosphorylation of VEGFR and anti-angiogenesis assay of some compounds was also investigated preliminarily. All compounds were evaluated by MTT assay for their in vitro cell cytotoxicity.
In this dissertation, based on the strategies of rational drug design, four series of109new diaryl thiourea containing ω-carboxy group sorafenib derivatives, which have not been reported in the literature, were designed and synthesized, and all the structures were identified by ESI-MS, HRMS,1H NMR and13C NMR. The compounds B9n and C9b were characterized by single-crystal X-ray diffraction.
The antiproliferative activities of109compounds against human colorectal carcinoma cell line (HCT116), human breast cancer cell line (MDA-MB-231), human prostate cell (PC-3), non-small cell lung cancer (A549), human hepatocellular liver carcinoma cell line(HepG2) and murine melanoma (B16BL6) were evaluated. All compounds exhibited potent antiproliferative activity against HCT116and PC-3cells; some compounds (A9o, A9p, B9p, B9q, B9r, B9s, B9x, B9aa, C9f, C9g, C9r, C9s, D9k, D9o, D9p, D9q, D9r and D9ac) demonstrated competitive antiproliferative activities to sorafenib. The size and shape of the substitutes on the terminal amide may affect the activity and selectivity of these derivatives against cancer cells:In the series A, B and C, the larger substitutes might cause a decrease in cytotoxicity in general, while in D series, the large group may improve the cytotoxicity of the compounds. The effect of the substitutes on the terminal phenyl ring is important to the activity of the compounds, and in the four series:electron-withdrawing groups (such as-CF3) can enhance the cytotoxicity of compounds, while the electron-donating group may reduce the cytotoxicity of compounds.
Enzyme test shows that all the target compounds have no inhibitory activity against EGFR, while some compounds can inhibit tyrosine kinase ABL1. Anti-angiogenesis activity was investigated from two aspects:a. the inhibitory activities of some compounds against the phosphorylation of VEGFR were evaluated by western blot; b. the anti-angiogenesis activity of some compounds was investigated by aorta ring assay. Western blot assay showed that compounds A9m, A9o, and A9p could inhibit the phosphorylation of VEGFR-2significantly. All these compounds have the methyl substitute on the terminal amide, and their substitutes in phenyl ring are3-CF3. The results of aorta ring assay showed that compounds D9g and D9p can significantly inhibit blood vessel formation at the concentration of0.1μM; D9r can partly block the formation of blood vessel; while the inhibitory ability of D9q is unconspicuous.
Finally, the SAR study of some representative compounds was also investigated by molecular docking:scoring the docking of compounds with B-Raf and VEGFR-2; sketching the figure of interaction mode, and studying the force and connection of compounds with kinases.
In summary, we designed and synthesized109new diaryl thiourea sorafenib derivatives in this dissertation. By preliminary bioactivity assay, we found several potential compounds such as compounds B9q、B9r、B9s、B9x、C9r、C9s、D9p、 D9q、D9r和D9ac, which need to be further developed in the future. The binding models of these compounds with B-Raf and VEGFR-2were also studied by SYBYL, which would be beneficial for further design and development of novel sorafenib derivatives.
本研究以索拉非尼为先导化合物,在近年来国内外相关研究工作的基础上,通过对其靶蛋白活性位点结构的解析和3-D构效关系总结,设计并合成了四个系列109个小分子化合物,初步对其进行了体外EGFR、ABL1激酶的抑制活性试验；部分化合物进行了抑制VEGFR磷酸化的评价和体外抑制大鼠动脉环微血管生成的实验研究；所有化合物均采用MTT法进行了体外抑制肿瘤细胞增殖活性评价,以期找到具有良好抗肿瘤活性的索拉非尼衍生物。
本论文基于合理药物设计,共合成了四个系列109个新型ω-羧基取代的二苯硫脲类化合物,所合成的目标化合物均采用1HNMR、13C NMR和HRMS等表征手段进行了结构确证。经查阅文献证实,所合成的目标化合物绝大多数未见文献报道,其中化合物B9n和C9b采用单晶X-射线衍射进行了结构表征。
抗肿瘤活性方而,针对人结肠癌细胞HCT116、人乳腺癌细胞MDA-MB-231、人肾癌细胞PC-3、非小细胞肺癌A549细胞、人肝癌细胞HepG2和小鼠黑色素瘤细胞B16BL6,采用MTT法对所得化合物(109个)进行了细胞毒活性测试,大多数化合物对HCT116和PC-3细胞具有抑制活性,化合物A9o、 A9p、B9p、B9q、B9r、B9s、B9x、B9aa、C9f、C9g、C9r、C9s、D9K、D9o、 D9p、D9q、D9r和D9ac的活性与阳性对照药物索拉非尼相当甚至优于索拉非尼。测试结果表明：大多数B和D系列化合物的体外抑瘤活性强于A和C系列的化合物。末端酰胺键上取代基的大小和形状影响其对体外肿瘤细胞增殖的抑制活性和选择性,A、B、C系列中,酰胺末端取代基R较小时(如甲基)活性较强,取代基R较大时(如苄基)抑制活性较差,R为环已基时,对HCT116和MDA-MB-231两种细胞的选择性较强,该类化合物对HCT1l6细胞的抑制活性要好于其它取代基,但大部分该类化合物对MDA-MB-231细胞无明显抑制活性。而D系列化合物中,R基团较大的化合物(如苄基)往往具有较好的细胞毒性。末端苯环上取代基对化合物的肿瘤细胞抑制活性影响较大,在所合成的四个系列目标化合物中,末端苯环上的吸电子基(如三氟甲基)能够增强化合物的细胞毒活性,而供电子取代基(如甲基)会降低相应化合物的肿瘤细胞抑制活性。
酶活测试结果显示,目标化合物对EGFR激酶无明显抑制作用,部分化合物对ABL激酶有一定的抑制作用。在抑制新生血管生成方面,采用western blot检测了部分A系列化合物对细胞水平VEGFR磷酸化的抑制作用,用动脉环实验检测了部分D系列化合物的抗新生血管生成作用。western blot检测结果显示：所测化合物中A9m、A9o和A9p对VEGFR的磷酸化有一定抑制作用。这三个化合物的末端酰胺基上是甲基取代,并且在末端苯环上的取代基均含有3-CF3。动脉环实验结果显示,所测化合物中,D9g和D9p可以很好的抑制大鼠动脉环微血管的生成,化合物D9r在0.1μM浓度时能部分抑制大鼠动脉环微血管的生成,而化合物D9q在0.1μM浓度时则对大鼠动脉环微血管的生成没有明显的抑制作用。
最后,对部分代表性化合物进行了以分子对接为主的构效关系研究：将化合物与B-Raf和VEGFR-2激酶分别进行了对接打分,并创建了作用模式图,探讨了化合物与激酶活性位点的作用模式。
综上所述,本论文共设计、合成了109个新型含硫脲结构的索拉非尼衍生物,通过初步的生物活性评价,我们发现了几个具有进一步研究开发价值的化合物,如：化合物B9q、B9r、B9s、B9x、C9r、C9s、D9p、D9q、D9r和D9ac等,并进一步对其进行了以分子对接为主的构效关系研究,探讨了其与B-Raf和VEGFR-2活性位点的结合模式,为今后新型索拉非尼衍生物的设计、合成奠定了基础。
Recent years, based on the achievement of chemical biology and bioinformatics the rational design of multitarget drugs is being the research direction ofanticancer drugs. Sorafenib, the first oral multikinase inhibitor, can inhibit several kinases involved in tumor proliferation and angiogenesis including Raf, VEGFR, PDGFR, KIT and so on. Due to the advantages of multi-mechanisms, broad-spectrum anticancer potency, and well-tolerated results in combination trials, more and more researchers have focused on the optimization of sorafenib in order to develop novel multi-targeted anticancer drugs.
Based on the international current research works, by studying the active sites of sorafenib and using the strategies of rational drug design, we designed and synthesized four series of109targeted sorafenib derivatives, and tested their inhibitory activity against kinase EGFR and ABL1. In vitro anti-phosphorylation of VEGFR and anti-angiogenesis assay of some compounds was also investigated preliminarily. All compounds were evaluated by MTT assay for their in vitro cell cytotoxicity.
In this dissertation, based on the strategies of rational drug design, four series of109new diaryl thiourea containing ω-carboxy group sorafenib derivatives, which have not been reported in the literature, were designed and synthesized, and all the structures were identified by ESI-MS, HRMS,1H NMR and13C NMR. The compounds B9n and C9b were characterized by single-crystal X-ray diffraction.
The antiproliferative activities of109compounds against human colorectal carcinoma cell line (HCT116), human breast cancer cell line (MDA-MB-231), human prostate cell (PC-3), non-small cell lung cancer (A549), human hepatocellular liver carcinoma cell line(HepG2) and murine melanoma (B16BL6) were evaluated. All compounds exhibited potent antiproliferative activity against HCT116and PC-3cells; some compounds (A9o, A9p, B9p, B9q, B9r, B9s, B9x, B9aa, C9f, C9g, C9r, C9s, D9k, D9o, D9p, D9q, D9r and D9ac) demonstrated competitive antiproliferative activities to sorafenib. The size and shape of the substitutes on the terminal amide may affect the activity and selectivity of these derivatives against cancer cells:In the series A, B and C, the larger substitutes might cause a decrease in cytotoxicity in general, while in D series, the large group may improve the cytotoxicity of the compounds. The effect of the substitutes on the terminal phenyl ring is important to the activity of the compounds, and in the four series:electron-withdrawing groups (such as-CF3) can enhance the cytotoxicity of compounds, while the electron-donating group may reduce the cytotoxicity of compounds.
Enzyme test shows that all the target compounds have no inhibitory activity against EGFR, while some compounds can inhibit tyrosine kinase ABL1. Anti-angiogenesis activity was investigated from two aspects:a. the inhibitory activities of some compounds against the phosphorylation of VEGFR were evaluated by western blot; b. the anti-angiogenesis activity of some compounds was investigated by aorta ring assay. Western blot assay showed that compounds A9m, A9o, and A9p could inhibit the phosphorylation of VEGFR-2significantly. All these compounds have the methyl substitute on the terminal amide, and their substitutes in phenyl ring are3-CF3. The results of aorta ring assay showed that compounds D9g and D9p can significantly inhibit blood vessel formation at the concentration of0.1μM; D9r can partly block the formation of blood vessel; while the inhibitory ability of D9q is unconspicuous.
Finally, the SAR study of some representative compounds was also investigated by molecular docking:scoring the docking of compounds with B-Raf and VEGFR-2; sketching the figure of interaction mode, and studying the force and connection of compounds with kinases.
In summary, we designed and synthesized109new diaryl thiourea sorafenib derivatives in this dissertation. By preliminary bioactivity assay, we found several potential compounds such as compounds B9q、B9r、B9s、B9x、C9r、C9s、D9p、 D9q、D9r和D9ac, which need to be further developed in the future. The binding models of these compounds with B-Raf and VEGFR-2were also studied by SYBYL, which would be beneficial for further design and development of novel sorafenib derivatives.
引文
[1]G. R. Zimmermann, J. Lehar,C. T. Keith, Multi-target therapeutics:when the whole is greater than the sum of the parts [J]. Drug Discov Today 2007,12, 34-42.
[2]T. Korcsmaros, M. S. Szalay, C. Bode, I. A. Kovacs,P. Csermely, How to design multi-target drugs:target search options in cellular networks [J]. Expert Opinion on Drug Discovery 2007,2,1-10.
[3]I. Kola,J. Landis, Can the pharmaceutical industry reduce attrition rates? [J]. Nature reviews. Drug discovery 2004,3,711-715.
[4]R. Morphy, C. Kay,Z. Rankovic, From magic bullets to designed multiple ligands [J]. Drug Discov Today 2004,9,641-651.
[5]Z. Guo,药物化学总论,3nd edn.,科学出版社,Beijing,2010.
[6]R. Morphy,Z. Rankovic, Designing multiple ligands-medicinal chemistry strategies and challenges [J]. Curr Pharm Des 2009,15,587-600.
[7]N. Vicker, L. Burgess, I. S. Chuckowree, R. Dodd, A. J. Folkes, D. J. Hardick, T. C. Hancox, W. Miller, J. Milton, S. Sohal, S. Wang, S. P. Wren, P. A. Charlton, W. Dangerfield, C. Liddle, P. Mistry, A. J. Stewart,W. A. Denny, Novel angular benzophenazines:dual topoisomerase I and topoisomerase Ⅱ inhibitors as potential anticancer agents [J]. JMed Chem 2002,45,721-739.
[8]J. F. Riou, P. Fosse, C. H. Nguyen, A. K. Larsen, M. C. Bissery, L. Grondard, J. M. Saucier, E. Bisagni,F. Lavelle, Intoplicine (RP 60475) and its derivatives, a new class of antitumor agents inhibiting both topoisomerase Ⅰ and Ⅱ activities [J]. Cancer research 1993,53,5987-5993.
[9]K. J. Du, J. Q. Wang, J. F. Kou, G. Y. Li, L. L. Wang, H. Chao,L. N. Ji, Synthesis, DNA-binding and topoisomerase inhibitory activity of ruthenium(II) polypyridyl complexes [J]. EurJMed Chem 2011,46,1056-1065.
[10]S. Salerno, F. Da Settimo, S. Taliani, F. Simorini, C. La Motta, G. Fornaciari,A. M. Marini, Recent advances in the development of dual topoisomerase Ⅰ and Ⅱ inhibitors as anticancer drugs [J]. Curr Med Chem 2010,17,4270-4290.
[11]L. W. Woo, C. Bubert, O. B. Sutcliffe, A. Smith, S. K. Chander, M. F. Mahon, A. Purohit, M. J. Rccd,B. V. Potter, Dual aromatase-steroid sulfatase inhibitors [J]. JMed Chem 2007,50,3540-3560.
[12]L. W. Woo, T. Jackson, A. Putey, G. Cozier, P. Leonard, K. R. Acharya, S. K. Chander, A. Purohit, M. J. Reed,B. V. Potter, Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template [J]. J Med Chem 2010,53,2155-2170.
[13]C. Bubert, L. W. Woo, O. B. Sutcliffe, M. F. Mahon, S. K. Chander, A. Purohit, M. J. Reed,B. V. Potter, Synthesis of aromatase inhibitors and dual aromatase steroid sulfatase inhibitors by linking an arylsulfamate motif to 4-(4H-1,2,4-triazol-4-ylamino)benzonitrile:SAR, crystal structures, in vitro and in vivo activities [J]. ChemMedChem 2008,3,1708-1730.
[14]A. Gangjee, W. Li, R. L. Kisliuk, V. Cody, J. Pace, J. Piraino,J. Makin, Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents [J]. JMed Chem 2009,52,4892-4902.
[15]X. Zhang, X. Zhou, R. L. Kisliuk, J. Piraino, V. Cody,A. Gangjee, Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors [J]. Bioorg Med Chem 2011, 19,3585-3594.
[16]L. Chen, D. Wilson, H. N. Jayaram,K. W. Pankiewicz, Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylases for cancer treatment [J]. JMed Chem 2007,50,6685-6691.
[17]S. M. Marques, E. Nuti, A. Rossello, C. T. Supuran, T. Tuccinardi, A. Martinelli,M. A. Santos, Dual inhibitors of matrix metalloproteinases and carbonic anhydrases:iminodiacetyl-based hydroxamate-benzenesulfonamide conjugates [J]. JMed Chem 2008,51,7968-7979.
[18]C. Tse, A. R. Shoemaker, J. Adickes, M. G. Anderson, J. Chen, S. Jin, E. F. Johnson, K. C. Marsh, M. J. Mitten, P. Nimmer, L. Roberts, S. K. Tahir, Y. Xiao, X. Yang, H. Zhang, S. Fesik, S. H. Rosenberg,S. W. Elmore, ABT-263:a potent and orally bioavailable Bcl-2 family inhibitor [J]. Cancer research 2008,65,3421-3428.
[19]I. S. Vizirianakis, M. Chatzopoulou, I. D. Bonovolias, I. Nicolaou, V. J. Demopoulos,A. S. Tsiftsoglou, Toward the development of innovative bifunctional agents to induce differentiation and to promote apoptosis in leukemia:clinical candidates and perspectives [J]. JMed Chem 2010,53, 6779-6810.
[20]A. J. Knox, T. Price, M. Pawlak, G. Golfis, C. T. Flood, D. Fayne, D. C. Williams, M. J. Meegan,D. G. Lloyd, Integration of ligand and structure-based virtual screening for the identification of the first dual targeting agent for heat shock protein 90 (Hsp90) and tubulin [J]. JMed Chem 2009,52,2177-2180.
[21]P. Goldhoff, N. M. Warrington, D. D. Limbrick, Jr., A. Hope, B. M. Woerner, E. Jackson, A. Perry, D. Piwnica-Worms,J. B. Rubin, Targeted inhibition of cyclic AMP phosphodiesterase-4 promotes brain tumor regression [J]. Clin Cancer Res 2008,14,7717-7725.
[22]A. Brancale,R. Silvestri, Indole, a core nucleus for potent inhibitors of tubulin polymerization [J]. Med Res Rev 2007,27,209-238.
[23]R. G. Fu, Q. D. You, L. Yang, W. T. Wu, C. Jiang,X. L. Xu, Design, synthesis and bioevaluation of dihydropyrazolo[3,4-b]pyridine and benzo[4,5]imidazo[1,2-a]pyrimidine compounds as dual KSP and Aurora-A kinase inhibitors for anti-cancer agents [J]. Bioorg Med Chem 2010,18, 8035-8043.
[24]A. G. Waterson, K. G. Petrov, K. R. Hornberger, R. D. Hubbard, D. M. Sammond, S. C. Smith, H. D. Dickson, T. R. Caferro, K. W. Hinkle, K. L. Stevens, S. H. Dickerson, D. W. Rusnak, G. M. Spehar, E. R. Wood, R. J. Griffin,D. E. Uehling, Synthesis and evaluation of aniline headgroups for alkynyl thienopyrimidine dual EGFR/ErbB-2 kinase inhibitors [J]. Bioorg Med Chem Lett 2009,19,1332-1336.
[25]T. R. Rheault, T. R. Caferro, S. H. Dickerson, K. H. Donaldson, M. D. Gaul, A. S. Goetz, R. J. Mullin, O. B. McDonald, K. G. Petrov, D. W. Rusnak, L. M. Shewchuk, G. M. Spehar, A. T. Truesdale, D. E. Vanderwall, E. R. Wood,D. E. Uehling, Thienopyrimidine-based dual EGFR/ErbB-2 inhibitors [J]. Bioorg Med Chem Lett 2009,19,817-820.
[26]G. Xu, M. C. Abad, P. J. Connolly, M. P. Neeper, G. T. Struble, B. A. Springer, S. L. Emanuel, N. Pandey, R. H. Gruninger, M. Adams, S. Moreno-Mazza, A. R. Fuentes-Pesquera,S. A. Middleton, 4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as potent ErbB-2/EGFR dual kinase inhibitors [J]. Bioorg Med Chem Lett 2008,18, 4615-4619.
[27]G. Xu, L. L. Searle, T. V. Hughes, A. K. Beck, P. J. Connolly, M. C. Abad, M. P. Neeper, G. T. Struble, B. A. Springer, S. L. Emanuel, R. H. Gruninger, N. Pandey, M. Adams, S. Moreno-Mazza, A. R. Fuentes-Pesquera, S. A. Middleton,L. M. Greenberger, Discovery of novel 4-arnino-6-arylarninopyrimidine-5-carbaldehyde oximes as dual inhibitors of EGFR and ErbB-2 protein tyrosine kinases [J]. Bioorg Med Chem Lett 2008, 18,3495-3499.
[28]M. M. Stec, K. L. Andrews, S. K. Booker, S. Caenepeel, D. J. Freeman, J. Jiang, H. Liao, J. McCarter, E. L. Mullady, T. San Miguel, R. Subramanian, N. Tamayo, L. Wang, K. Yang, L. P. Zalameda, N. Zhang, P. E. Hughes,M. H. Norman, Structure-activity relationships of phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors: investigations of various 6,5-heterocycles to improve metabolic stability [J]. J Med Chem 2011,54,5174-5184.
[29]R. Morphy, Selectively nonselective kinase inhibition:striking the right balance [J]. J Med Chem 2010,53,1413-1437.
[30]L. Gossage,T. Eisen, Targeting multiple kinase pathways:a change in paradigm [J]. Clin Cancer Res 2010,16,1973-1978.
[31]唐海涛,陈国广,方正,王玮,韦萍,多靶点受体酪氨酸激酶抑制剂的研究进展[J].中国新药杂志2009,18,502-506.
[32]刘靖,王林,杨晓明,多靶点蛋白酪氨酸激酶抑制剂的研究进展[J].国际药学研究杂志2009,36,161-171.
[33]董静,黄文姝,多靶点抗肿瘤酪氨酸激酶抑制剂的研究开发[J].世界临床药物2009,30,306-311.
[34]A. Petrelli,S. Giordano, From single-to multi-target drugs in cancer therapy: when a specificity becomes an advantage [J]. Curr Med Chem 2008,15, 422-432.
[35]吴文,卢骋,陈思宇,余聂芳,已上市和部分正在Ⅲ期临床开发中的多靶点激酶抑制剂抑酶谱及信号传导通路分析[J].药学学报2009,242-257.
[36]S. M. Wilhelm, L. Adnane, P. Newell, A. Villanueva, J. M. Llovet,M. Lynch, Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling [J]. Molecular cancer therapeutics 2008,7,3129-3140.
[37]Y. Dai, K. Hartandi, Z. Ji, A. A. Ahmed, D. H. Albert, J. L. Bauch, J. J. Bouska, P. F. Bousquet, G. A. Cunha, K. B. Glaser, C. M. Harris, D. Hickman, J. Guo, J. Li, P. A. Marcotte, K. C. Marsh, M. D. Moskey, R. L. Martin, A. M. Olson, D. J. Osterling, L. J. Pease, N. B. Soni, K. D. Stewart, V. S. Stoll, P. Tapang, D. R. Reuter, S. K. Davidsen,M. R. Michaelides, Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor [J]. J Med Chem 2007,50,1584-1597.
[38]M. H. Potashman, J. Bready, A. Coxon, T. M. DeMelfi, Jr., L. DiPietro, N. Doerr, D. Elbaum, J. Estrada, P. Gallant, J. Germain, Y. Gu, J.-C. Harmange, S. A. Kaufman, R. Kendall, J. L. Kim, G. N. Kumar, A. M. Long, S. Neervannan, V. F. Patel, A. Polverino, P. Rose, S. Van der Plas, D. Whittington, R. Zanon,H. Zhao, Design, Synthesis, and Evaluation of Orally Active Benzimidazoles and Benzoxazoles as Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase Inhibitors [J]. Journal of Medicinal Chemistry 2007,50,4351-4373.
[39]S. Ramurthy, S. Subramanian, M. Aikawa, P. Amiri, A. Costales, J. Dove, S. Fong, J. M. Jansen, B. Levine, S. Ma, C. M. McBride, J. Michaelian, T. Pick, D. J. Poon, S. Girish, C. M. Shafer, D. Stuart, L. Sung,P. A. Renhowe, Design and synthesis of orally bioavailable benzimidazoles as Raf kinase inhibitors [J]. J Med Chem 2008,51,7049-7052.
[40]D. Menard, I. Niculescu-Duvaz, H. P. Dijkstra, D. Niculescu-Duvaz, B. M. Suijkerbuijk, A. Zambon, A. Nourry, E. Roman, L. Davies, H. A. Manne, F. Friedlos, R. Kirk, S. Whittaker, A. Gill, R. D. Taylor, R. Marais,C. J. Springer, Novel potent BRAF inhibitors:toward 1 nM compounds through optimization of the central phenyl ring [J]. J Med Chem 2009,52,3881-3891.
[41]M. Sun, X. Wu, J. Chen, J. Cai, M. Cao,M. Ji, Design, synthesis, and in vitro antitumor evaluation of novel diaryl ureas derivatives [J]. Eur J Med Chem 2010,45,2299-2306.
[42]S. M. Wilhelm, C. Carter, L. Tang, D. Wilkie, A. McNabola, H. Rong, C. Chen, X. Zhang, P. Vincent, M. McHugh, Y. Cao, J. Shujath, S. Gawlak, D. Eveleigh, B. Rowley, L. Liu, L. Adnane, M. Lynch, D. Auclair, I. Taylor, R. Gedrich, A. Voznesensky, B. Riedl, L. E. Post, G. Bollag,P. A. Trail, BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis [J]. Cancer research 2004,64,7099-7109.
[43]F. Carlomagno, S. Anaganti, T. Guida, G. Salvatore, G. Troncone, S. M. Wilhelm,M. Santoro, BAY 43-9006 inhibition of oncogenic RET mutants [J]. JNatl Cancer Inst 2006,98,326-334.
[44]G. Salvatore, V. De Falco, P. Salerno, T. C. Nappi, S. Pepe, G. Troncone, F. Carlomagno, R. M. Melillo, S. M. Wilhelm,M. Santoro, BRAF is a therapeutic target in aggressive thyroid carcinoma [J]. Clin Cancer Res 2006,12, 1623-1629.
[45]S. Wilhelm, C. Carter, M. Lynch, T. Lowinger, J. Dumas, R. A. Smith, B. Schwartz, R. Simantov,S. Kelley, Discovery and development of sorafenib:a multikinase inhibitor for treating cancer [J]. Nature reviews. Drug discovery 2006,5,835-844.
[46]L. Liu, Y. Cao, C. Chen, X. Zhang, A. McNabola, D. Wilkie, S. Wilhelm, M. Lynch,C. Carter, Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5 [J]. Cancer research 2006,66,11851-11858.
[47]T. Guida, S. Anaganti, L. Provitera, R. Gedrich, E. Sullivan, S. M. Wilhelm, M. Santoro,F. Carlomagno, Sorafenib inhibits imatinib-resistant KIT and platelet-derived growth factor receptor beta gatekeeper mutants [J]. Clin Cancer Res 2007,13,3363-3369.
[48]L. Adnane, P. A. Trail, I. Taylor,S. M. Wilhelm, Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature [J]. Methods in enzymology 2006,407,597-612.
[49]N. Dumaz,R. Marais, Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras [J]. JBiol Chem 2003, 278,29819-29823.
[50]颜彩虹,唐伟方,陈亚东,刘海春,陆涛,新型B-Raf激酶抑制剂研究进展[J].海峡药学2011,1-4.
[51]S. T. Yuen, H. Davies, T. L. Chan, J. W. Ho, G. R. Bignell, C. Cox, P. Stephens, S. Edkins, W. W. Tsui, A. S. Chan, P. A. Futreal, M. R. Stratton, R. Wooster,S. Y. Leung, Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia [J]. Cancer research 2002,62, 6451-6455.
[52]C. K. Weber, J. R. Slupsky, C. Herrmann, M. Schuler, U. R. Rapp.C. Block, Mitogenic signaling of Ras is regulated by differential interaction with Raf isozymes [J]. Oncogene 2000,19,169-176.
[53]T. Minamoto, M. Mai,Z. Ronai, K-ras mutation:early detection in molecular diagnosis and risk assessment of colorectal, pancreas, and lung cancers--a review [J]. Cancer Detect Prev 2000,24,1-12.
[54]C. A. Pritchard, M. L. Samuels, E. Bosch,M. McMahon, Conditionally oncogenic forms of the A-Raf and B-Raf protein kinases display different biological and biochemical properties in NIH 3T3 cells [J]. Mol Cell Biol 1995, 75,6430-6442.
[55]J. M. Zhang, P. L. Yang,N. S. Gray, Targeting cancer with small molecule kinase inhibitors [J]. Nat Rev Cancer 2009,9,28-39.
[56]王勇,龙业秋,蛋白酪氨酸激酶小分子抑制剂的研究新进展[J].有机化学2011,1595-1606.
[57]S. R. Hubbard, L. Wei, L. Ellis, W. A. Hendrickson, Crystal structure of the tyrosine kinase domain of the human insulin receptor [J]. Nature 1994,372, 746-754.
[58]N. Ortega, H. Hutchings,J. Plouet, Signal relays in the VEGF system [J]. Front Biosci 1999,4, D141-152.
[59]C. de Vries, J. A. Escobedo, H. Ueno, K. Houck, N. Ferrara,L. T. Williams, The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor [J]. Science 1992,255,989-991.
[60]P. A. Harris, A. Boloor, M. Cheung, R. Kumar, R. M. Crosby, R. G. Davis-Ward, A. H. Epperly, K. W. Hinkle, R. N. Hunter,3rd, J. H. Johnson, V. B. Knick, C. P. Laudeman, D. K. Luttrell, R. A. Mook, R. T. Nolte, S. K. Rudolph, J. R. Szewczyk, A. T. Truesdale, J. M. Veal, L. Wang,J. A. Stafford, Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methyl amino]-2-pyrirnidinyl]arnino]-2-methyl-b enzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor [J]. J Med Chem 2008,51,4632-4640.
[61]Y. Liu,N. S. Gray, Rational design of inhibitors that bind to inactive kinase conformations [J]. Nat Chem Biol 2006,2,358-364.
[62]C. D. Mol, D. Fabbro,D. J. Hosfield, Structural insights into the conformational selectivity of STI-571 and related kinase inhibitors [J]. Curr Opin Drug Discov Devel 2004,7,639-648.
[63]M. Carroll, S. Ohno-Jones, S. Tamura, E. Buchdunger, J. Zimmermann, N. B. Lydon, D. G. Gilliland,B. J. Druker, CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins [J]. Blood 1997,90,4947-4952.
[64]M. C. Heinrich, D. J. Griffith, B. J. Druker, C. L. Wait, K. A. Ott,A. J. Zigler, Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor [J]. Blood 2000,96,925-932.
[65]唐克,李燕,陈晓光,多靶点抗肿瘤药物索拉非尼的研究进展[J].中国新约杂志2011.20,2434-2441.
[66]M. Rahmani, E. M. Davis, C. Bauer, P. Dent,S. Grant, Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation [J]. J Biol Chem 2005,250,35217-35227.
[67]C. Yu, L. M. Bruzek, X. W. Meng, G. J. Gores, C. A. Carter, S. H. Kaufmann,A. A. Adjei, The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006 [J]. Oncogene 2005,24, 6861-6869.
[68]K.-F. Chen, W.-T. Tai, J.-W. Huang, C.-Y. Hsu, W.-L. Chen, A.-L. Cheng, P.-J. Chen,C.-W. Shiau, Sorafenib derivatives induce apoptosis through inhibition of STAT3 independent of Raf [J]. European Journal of Medicinal Chemistry 2011,46,2845-2851.
[69]S. Huang,F. A. Sinicrope, Sorafenib inhibits STAT3 activation to enhance TRAIL-mediated apoptosis in human pancreatic cancer cells [J]. Molecular cancer therapeutics 2010,9,742-750.
[70]F. Yang, T. E. Van Meter, R. Buettner, M. Hedvat, W. Liang, C. M. Kowolik, N. Mepani, J. Mirosevich, S. Nam, M. Y. Chen, G. Tye, M. Kirschbaum,R. Jove, Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas [J]. Molecular cancer therapeutics 2008,7,3519-3526.
[71]D. J. Panka, W. Wang, M. B. Atkins,J.W. Mier, The Raf inhibitor BAY 43-9006 (Sorafenib) induces caspase-independent apoptosis in melanoma cells [J]. Cancer research 2006,66,1611-1619.
[72]J. Hasskarl, Sorafenib [J]. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 2010,184,61-70.
[73]Y. S. Chang, J. Adnane, P. A. Trail, J. Levy, A. Henderson, D. Xue, E. Bortolon, M. Ichetovkin, C. Chen, A. McNabola, D. Wilkie, C. A. Carter, I. C. A. Taylor, M. Lynch,S. Wilhelm, Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models [J]. Cancer chemotherapy and pharmacology 2007,59, 561-574.
[74]D. Strumberg, Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment [J]. Drugs Today (Barc) 2005,41, 773-784.
[75]Y. S. Chang, A. Henderson, D. Xue, C. Chen, A. McNabola, D. Wilkie, B. Rowley, C. A. Carter, B. Riedl, P. A. Trail,S. Wilhelm, BAY 43-9006 (Sorafenib) inhibits ectopic (s.c.) and orthotopic growth of a murine model of renal adenocarcinoma (Renca) predominantly through inhibition of tumor angiogenesis [J]. Proceedings of the American Association for Cancer Research Annual Meeting 2005,46,1372.
[76]V. Ramakrishnan, M. Timm, J. L. Haug, T. K. Kimlinger, L. E. Wellik, T. E. Witzig, S. V. Rajkumar, A. A. Adjei,S. Kumar, Sorafenib, a dual Raf kinase/vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common anti-myeloma drugs [J]. Oncogene 2010,29,1190-1202.
[77]C. H. Takimoto,A. Awada, Safety and anti-tumor activity of sorafenib (Nexavar) in combination with other anti-cancer agents:a review of clinical trials [J]. Cancer chemotherapy and pharmacology 2008,61,535-548.
[78]Z. Hu, Y. Su, Z. Wang, X. Zeng, S. Liu, Q. Zhang, W. Yang, J. Liu,Z. Ye, Safety and Management of Sorafenib in Treatment of 31 Patients with Metastatic Renal Cell Carcinoma [J]. Cancer Research on Prevention and Treatment (肿瘤防治研究) 2010,37,589-591.
[79]J. W. Clark, J. P. Eder, D. Ryan, C. Lathia,H. J. Lenz, Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors [J]. Clin Cancer Res 2005,77,5472-5480.
[80]M. Iijima, K. Fukino, M. Adachi, T. Tsukamoto, M. Murai, S. Naito, H. Minami, J. Furuse,H. Akaza, Sorafenib-associated hand-foot syndrome in Japanese patients [J]. The Journal of dermatology 2011,38,261-266.
[81]D. Niculescu-Duvaz, C. Gaulon, H. P. Dijkstra, I. Niculescu-Duvaz, A. Zambon, D. Menard, B. M. Suijkerbuijk, A. Nourry, L. Davies, H. Manne, F. Friedlos, L. Ogilvie, D. Hedley, S. Whittaker, R. Kirk, A. Gill, R. D. Taylor, F. I. Raynaud, J. Moreno-Farre, R. Marais,C. J. Springer, Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1(BRAF) [J]. JMed Chem 2009,52,2255-2264.
[82]B. M. Suijkerbuijk, I. Niculescu-Duvaz, C. Gaulon, H. P. Dijkstra, D. Niculescu-Duvaz, D. Menard, A. Zambon, A. Nourry, L. Davies, H. A. Manne, F. Friedlos, L. M. Ogilvie, D. Hedley, F. Lopes, N. P. Preece, J. Moreno-Farre, F. I. Raynaud, R. Kirk, S. Whittaker, R. Marais,C. J. Springer, Development of novel, highly potent inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF):increasing cellular potency through optimization of a distal heteroaromatic group [J]. JMed Chem 2010,53,2741-2756.
[83]B. S. Nam, H. Kim, C.-H. Oh, S. H. Lee, S. J. Cho, T. B. Sim, J.-M. Hah, D. J. Kim, J. H. Choi,K. H. Yoo, Aminoquinoline derivatives with antiproliferative activity against melanoma cell line [J]. Bioorganic& Medicinal Chemistry Letters 2009,19,3517-3520.
[84]M.-H. Jung, H. Kim, W.-K. Choi, M. I. E1-Gamal, J.-H. Park, K. H. Yoo, T. B. Sim, S. H. Lee, D. Baek, J.-M. Hah, J.-H. Cho,C.-H. Oh, Synthesis of pyrrolo[2,3-d]pyrimidine derivatives and their antiproliferative activity against melanoma cell line [J]. Bioorganic & Medicinal Chemistry Letters 2009,19, 6538-6543.
[85]H. J. Kim, M.-H. Jung, H. Kim, M. I. El-Gamal, T. B. Sim, S. H. Lee, J. H. Hong, J.-M. Hah, J.-H. Cho, J. H. Choi, K. H. Yoo,C.-H. Oh, Synthesis and antiproliferative activity of pyrrolo[3,2-b]pyridine derivatives against melanoma [J]. Bioorganic & Medicinal Chemistry Letters 2010,20,413-417.
[86]M. I. El-Gamal, M.-H. Jung, W. S. Lee, T. Sim, K. H. Yoo,C.-H. Oh, Design, synthesis, and antiproliferative activity of new 1H-pyrrolo[3,2-c]pyridine derivatives against melanoma cell lines [J]. European Journal of Medicinal Chemistry 2011,46,3218-3226.
[87]杨照,方正,王志祥,韦萍,Sorafenib硫脲衍生物的合成及活性研究[J].药学学报2011,1093-1097.
[88]W. Li, X. Zhai, Z. Zhong, G. Li, Y. Pu,P. Gong, Design, synthesis and evaluation of novel rhodanine-containing sorafenib analogs as potential antitumor agents [J]. Archiv der Pharmazie 2011,344,349-357.
[1]S. M. Wilhelm, L. Adnane, P. Newell, A. Villanueva, J. M. Llovet,M. Lynch, Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling [J]. Molecular cancer therapeutics 2008,7,3129-3140.
[2]ZHOU A P, SUN Y. Recent advances in sorafenib:A multiple targeted anti-tumor agent [J].Oncol Prog(癌症进展杂志)2006,529-533.
[3]Y. Dai, K. Hartandi, Z. Ji, A. A. Ahmed, D. H. Albert, J. L. Bauch, J. J. Bouska, P. F. Bousquet, G. A. Cunha, K. B. Glaser, C. M. Harris, D. Hickman, J. Guo, J. Li, P. A. Marcotte, K. C. Marsh, M. D. Moskey, R. L. Martin, A. M. Olson, D. J. Osterling, L. J. Pease, N. B. Soni, K. D. Stewart, V. S. Stoll, P. Tapang, D. R. Reuter, S. K. Davidsen,M. R. Michaelides, Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor [J]. JMed Chem 2007,50.1584-1597.
[4]M. H. Potashman, J. Bready, A. Coxon, T. M. DeMelfi, Jr., L. DiPietro, N. Doerr, D. Elbaum, J. Estrada, P. Gallant, J. Germain, Y. Gu, J.-C. Harmange, S. A. Kaufman, R. Kendall, J. L. Kim, G. N. Kumar, A. M. Long, S. Neervannan, V. F. Patel, A. Polverino, P. Rose, S. Van der Plas, D. Whittington, R. Zanon,H. Zhao, Design, Synthesis, and Evaluation of Orally Active Benzimidazoles and Benzoxazoles as Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase Inhibitors [J]. Journal of Medicinal Chemistry 2007,50,4351-4373.
[5]S. Ramurthy, S. Subramanian, M. Aikawa, P. Amiri, A. Costales, J. Dove, S. Fong, J. M. Jansen, B. Levine, S. Ma, C. M. McBride, J. Michaelian, T. Pick, D. J. Poon, S. Girish, C. M. Shafer, D. Stuart, L. Sung,P. A. Renhowe, Design and synthesis of orally bioavailable benzimidazoles as Raf kinase inhibitors [J]. J Med Chem 2008,57,7049-7052.
[6]D. Menard, I. Niculescu-Duvaz, H. P. Dijkstra, D. Niculescu-Duvaz, B. M. Suijkerbuijk, A. Zambon, A. Nourry, E. Roman, L. Davies, H. A. Manne, F. Friedlos, R. Kirk, S. Whittaker, A. Gill, R. D. Taylor, R. Marais,C. J. Springer, Novel potent BRAF inhibitors:toward 1 nM compounds through optimization of the central phenyl ring [J]. J Med Chem 2009,52,3881-3891.
[7]M. Sun, X. Wu, J. Chen, J. Cai, M. Cao,M. Ji, Design, synthesis, and in vitro antitumor evaluation of novel diaryl ureas derivatives [J]. Eur J Med Chem 2010,45,2299-2306.
[8]P. T. Wan, M. J. Garnett, S. M. Roe, S. Lee, D. Niculescu-Duvaz, V. M. Good, C. M. Jones, C. J. Marshall, C. J. Springer, D. Barford,R. Marais, Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF [J]. Cell 2004,116,855-867.
[9]L. Adnane, P. A. Trail, I. Taylor,S. M. Wilhelm, Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature [J]. Methods in enzymology 2006,407,597-612.
[10]S. M. Wilhelm, C. Carter, L. Tang, D. Wilkie, A. McNabola, H. Rong, C. Chen, X. Zhang, P. Vincent, M. McHugh, Y. Cao, J. Shujath, S. Gawlak, D. Eveleigh, B. Rowley, L. Liu, L. Adnane, M. Lynch, D. Auclair, I. Taylor, R. Gedrich, A. Voznesensky, B. Riedl, L. E. Post, G. Bollag,P. A. Trail, BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis [J]. Cancer research 2004,64,7099-7109.
[11]D. Niculescu-Duvaz, C. Gaulon, H. P. Dijkstra, I. Niculescu-Duvaz, A. Zambon, D. Menard, B. M. Suijkerbuijk, A. Nourry, L. Davies, H. Manne, F. Friedlos, L. Ogilvie, D. Hedley, S. Whittaker, R. Kirk, A. Gill, R. D. Taylor, F. I. Raynaud, J. Moreno-Farre, R. Marais,C. J. Springer, Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue Bl (BRAF) [J]. JMed Chem 2009,52,2255-2264.
[12]杨照,方正,王志祥,韦萍,Sorafenib硫脲衍生物的合成及活性研究[J].药学学报2011,1093-1097.
[13]M. W. Holladay, B. T. Campbell, M. W. Rowbottom, Q. Chao, K. G. Sprankle, A. G. Lai, S. Abraham, E. Setti, R. Faraoni, L. Tran, R. C. Armstrong, R. N. Gunawardane, M. F. Gardner, M. D. Cramer, D. Gitnick, M. A. Ator, B. D. Dorsey, B. R. Ruggeri, M. Williams, S. S. Bhagwat,J. James, 4-Quinazolinyloxy-diaryl ureas as novel BRAFV600E inhibitors [J]. Bioorg Med Chem Lett 2011,21,5342-5346.
[1]Rossetto P, Macdonald L, Canavesi A, et al. Process for the preparation of sorafenib and salts thereof [P] WO.2009111061,2009-09-11
[2]张楠,钟荣,抗癌用化合物及制备方法[P].CN.101830847 A,2010-09-15
[3]赵乘有,陈林捷,等.对甲苯磺酸索拉非尼的合成[J].中国医药工业杂志,2007,38(9)：614-616
[4]杨照,方正,王志祥,韦萍,Sorafenib硫脲衍生物的合成及活性研究[J].药学学报2011,(46)9：1093-1097.
[5]PULLA REDDY, Muddasani, VENKAIAH CHOWDARY, Nannapaneni. Process for the preparation of sorafenib [P]. WO.2009054004,2009-04-30
[6]D. Bankston, J. Dumas, R. Natero, B. Riedl, M.-K. Monahan,R. Sibley, A Scaleable Synthesis of BAY 43-9006:A Potent Raf Kinase Inhibitor for the Treatment of Cancer [J]. Organic Process Research & Development 2002,6, 777-781.
[7]陈静,王程鹏,何作鹏,姚建文,抗肿瘤药物索拉非尼合成工艺的改进[J].烟台大学学报(自然科学与工程版)2012,25(2):146-149
[8]Lijuan Zhang, Wenpin Xia, Bo Wang, Yu Luo & Wei Lu, Convenient Synthesis of Sorafenib and Its Derivatives [J]. Synthetic Communications 2011,41,3140-3146
[9]Li W, Zhai X, Zhong Z, et al. Design, synthesis and evaluation of novel rhodanine-containing sorafenib analogs as potential antitumor agents [J]. Archiv der Pharmazie,2011,11:349-357
[10]杜晓华,许响生,等,非硫光气法合成一些难合成的芳基异硫氰酸酯[J].农药2004,43(2)：78-79
[11]Larsen C, Steliou K, Harpp DN. Organic sulfur chemistry.25. Thiocarbonyl transfer reagents [J]. J Org Chem,1978,43:337-339.
[1]Bruker, [J]. SAINT and SMART. Bruker AXSInc., Madison, Wisconsin, USA. 2002.
[21 G. M. Sheldrick, [J]. SHSLXL97, Program for Crystal Structure Refinement, University of Gottingen, Germany 1997.
[3]A. Altomare, G. Cascarano, C. Giacovazzo,A. Guagliardi, SIR92 [J]. J. Appl. Cryst.1993,26, SIR92.
[4]A. L. Spek, [J]. PLATON. Version 280301. University of Utreecht, The Netherlands 1980.
[5]L. J. Farrugia, [J]. J. Appl. Cryst.1999,32,837-838.
[6]L. J. Farrugia, [J]. J. Appl. Cryst.1997,30,565.
[7]D. M. Watkin, L. Pearce,C. K. Prout, [J]. CAMERON. Chemical Crystallography Laboratory, University of Oxford, England.1993.
[8]K. Ravikumar, B. Sridhar, A. K. Bhujanga Rao,M. Pulla Reddy, Sorafenib and its tosylate salt:a multikinase inhibitor for treating cancer [J]. Acta crystallographica. Section C, Crystal structure communications 2011,67, o29-32.
[9]L. Pauling,P. Pauling, Chemistry, Freeman, San Francisco,1975.
[10]S. Chang, L. Zhang, S. Xu, J. Luo, X. Lu, Z. Zhang, T. Xu, Y. Liu, Z. Tu, Y. Xu, X. Ren, M. Geng, J. Ding, D. Pei,K. Ding, Design, synthesis, and biological evaluation of novel conformationally constrained inhibitors targeting epidermal growth factor receptor threonine(7)(9)(0)--> methionine(7)(9)(0) mutant [J]. JMed Chem 2012,55,2711-2723.
[11]R. F. Nicosia,A. Ottinetti, Growth of micro vessels in serum-free matrix culture of rat aorta. A quantitative assay of angiogenesis in vitro [J]. Lab Invest 1990,63,115-122.
[12]B. J. Pyun, S. Choi, Y. Lee, T. W. Kim, J. K. Min, Y. Kim, B. D. Kim, J. H. Kim, T. Y. Kim, Y. M. Kim,Y. G. Kwon, Capsiate, a nonpungent capsaicin-like compound, inhibits angiogenesis and vascular permeability via a direct inhibition of Src kinase activity [J]. Cancer research 2008,68, 227-235.
[1]P. T. Wan, M. J. Garnett, S. M. Roe, S. Lee, D. Niculescu-Duvaz, V. M. Good, C. M. Jones, C. J. Marshall, C. J. Springer, D. Barford,R. Marais, Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF [J]. Cell 2004,116,855-867.
[2]FlexXTM is distributed by Tripos Inc.,1699, South Hanley Rd., St. Louis, Missouri, USA (http://www.tripos.com)
[3]Rarey, M.; Kramer, B.; Lengauer, T., et al. A Fast Flexible Docking Method using an Incremental Construction Algorithm [J]. J. Mol.Biol.,1996,261(3): 470-489.
[4]Harris PA, Boloor A, Cheung M, et al. Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]arnino]-2-methyl-b enzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor [J]. J Med Chem,2008,51(15): 4632-4640
[5]BiopolymerTM is distributed by Tripos Inc.,1699, South Hanley Rd., St. Louis, Missouri, USA (http://www.tripos.com)
[6]Kellenberger, E.; Rodrigo, J.; Muller. P., et al. Comparative evaluation of eight docking tools for docking and virtual screening accuracy [J]. Proteins.,2004, 57(2):225-242.
[2]T. Korcsmaros, M. S. Szalay, C. Bode, I. A. Kovacs,P. Csermely, How to design multi-target drugs:target search options in cellular networks [J]. Expert Opinion on Drug Discovery 2007,2,1-10.
[3]I. Kola,J. Landis, Can the pharmaceutical industry reduce attrition rates? [J]. Nature reviews. Drug discovery 2004,3,711-715.
[4]R. Morphy, C. Kay,Z. Rankovic, From magic bullets to designed multiple ligands [J]. Drug Discov Today 2004,9,641-651.
[5]Z. Guo,药物化学总论,3nd edn.,科学出版社,Beijing,2010.
[6]R. Morphy,Z. Rankovic, Designing multiple ligands-medicinal chemistry strategies and challenges [J]. Curr Pharm Des 2009,15,587-600.
[7]N. Vicker, L. Burgess, I. S. Chuckowree, R. Dodd, A. J. Folkes, D. J. Hardick, T. C. Hancox, W. Miller, J. Milton, S. Sohal, S. Wang, S. P. Wren, P. A. Charlton, W. Dangerfield, C. Liddle, P. Mistry, A. J. Stewart,W. A. Denny, Novel angular benzophenazines:dual topoisomerase I and topoisomerase Ⅱ inhibitors as potential anticancer agents [J]. JMed Chem 2002,45,721-739.
[8]J. F. Riou, P. Fosse, C. H. Nguyen, A. K. Larsen, M. C. Bissery, L. Grondard, J. M. Saucier, E. Bisagni,F. Lavelle, Intoplicine (RP 60475) and its derivatives, a new class of antitumor agents inhibiting both topoisomerase Ⅰ and Ⅱ activities [J]. Cancer research 1993,53,5987-5993.
[9]K. J. Du, J. Q. Wang, J. F. Kou, G. Y. Li, L. L. Wang, H. Chao,L. N. Ji, Synthesis, DNA-binding and topoisomerase inhibitory activity of ruthenium(II) polypyridyl complexes [J]. EurJMed Chem 2011,46,1056-1065.
[10]S. Salerno, F. Da Settimo, S. Taliani, F. Simorini, C. La Motta, G. Fornaciari,A. M. Marini, Recent advances in the development of dual topoisomerase Ⅰ and Ⅱ inhibitors as anticancer drugs [J]. Curr Med Chem 2010,17,4270-4290.
[11]L. W. Woo, C. Bubert, O. B. Sutcliffe, A. Smith, S. K. Chander, M. F. Mahon, A. Purohit, M. J. Rccd,B. V. Potter, Dual aromatase-steroid sulfatase inhibitors [J]. JMed Chem 2007,50,3540-3560.
[12]L. W. Woo, T. Jackson, A. Putey, G. Cozier, P. Leonard, K. R. Acharya, S. K. Chander, A. Purohit, M. J. Reed,B. V. Potter, Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template [J]. J Med Chem 2010,53,2155-2170.
[13]C. Bubert, L. W. Woo, O. B. Sutcliffe, M. F. Mahon, S. K. Chander, A. Purohit, M. J. Reed,B. V. Potter, Synthesis of aromatase inhibitors and dual aromatase steroid sulfatase inhibitors by linking an arylsulfamate motif to 4-(4H-1,2,4-triazol-4-ylamino)benzonitrile:SAR, crystal structures, in vitro and in vivo activities [J]. ChemMedChem 2008,3,1708-1730.
[14]A. Gangjee, W. Li, R. L. Kisliuk, V. Cody, J. Pace, J. Piraino,J. Makin, Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents [J]. JMed Chem 2009,52,4892-4902.
[15]X. Zhang, X. Zhou, R. L. Kisliuk, J. Piraino, V. Cody,A. Gangjee, Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors [J]. Bioorg Med Chem 2011, 19,3585-3594.
[16]L. Chen, D. Wilson, H. N. Jayaram,K. W. Pankiewicz, Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylases for cancer treatment [J]. JMed Chem 2007,50,6685-6691.
[17]S. M. Marques, E. Nuti, A. Rossello, C. T. Supuran, T. Tuccinardi, A. Martinelli,M. A. Santos, Dual inhibitors of matrix metalloproteinases and carbonic anhydrases:iminodiacetyl-based hydroxamate-benzenesulfonamide conjugates [J]. JMed Chem 2008,51,7968-7979.
[18]C. Tse, A. R. Shoemaker, J. Adickes, M. G. Anderson, J. Chen, S. Jin, E. F. Johnson, K. C. Marsh, M. J. Mitten, P. Nimmer, L. Roberts, S. K. Tahir, Y. Xiao, X. Yang, H. Zhang, S. Fesik, S. H. Rosenberg,S. W. Elmore, ABT-263:a potent and orally bioavailable Bcl-2 family inhibitor [J]. Cancer research 2008,65,3421-3428.
[19]I. S. Vizirianakis, M. Chatzopoulou, I. D. Bonovolias, I. Nicolaou, V. J. Demopoulos,A. S. Tsiftsoglou, Toward the development of innovative bifunctional agents to induce differentiation and to promote apoptosis in leukemia:clinical candidates and perspectives [J]. JMed Chem 2010,53, 6779-6810.
[20]A. J. Knox, T. Price, M. Pawlak, G. Golfis, C. T. Flood, D. Fayne, D. C. Williams, M. J. Meegan,D. G. Lloyd, Integration of ligand and structure-based virtual screening for the identification of the first dual targeting agent for heat shock protein 90 (Hsp90) and tubulin [J]. JMed Chem 2009,52,2177-2180.
[21]P. Goldhoff, N. M. Warrington, D. D. Limbrick, Jr., A. Hope, B. M. Woerner, E. Jackson, A. Perry, D. Piwnica-Worms,J. B. Rubin, Targeted inhibition of cyclic AMP phosphodiesterase-4 promotes brain tumor regression [J]. Clin Cancer Res 2008,14,7717-7725.
[22]A. Brancale,R. Silvestri, Indole, a core nucleus for potent inhibitors of tubulin polymerization [J]. Med Res Rev 2007,27,209-238.
[23]R. G. Fu, Q. D. You, L. Yang, W. T. Wu, C. Jiang,X. L. Xu, Design, synthesis and bioevaluation of dihydropyrazolo[3,4-b]pyridine and benzo[4,5]imidazo[1,2-a]pyrimidine compounds as dual KSP and Aurora-A kinase inhibitors for anti-cancer agents [J]. Bioorg Med Chem 2010,18, 8035-8043.
[24]A. G. Waterson, K. G. Petrov, K. R. Hornberger, R. D. Hubbard, D. M. Sammond, S. C. Smith, H. D. Dickson, T. R. Caferro, K. W. Hinkle, K. L. Stevens, S. H. Dickerson, D. W. Rusnak, G. M. Spehar, E. R. Wood, R. J. Griffin,D. E. Uehling, Synthesis and evaluation of aniline headgroups for alkynyl thienopyrimidine dual EGFR/ErbB-2 kinase inhibitors [J]. Bioorg Med Chem Lett 2009,19,1332-1336.
[25]T. R. Rheault, T. R. Caferro, S. H. Dickerson, K. H. Donaldson, M. D. Gaul, A. S. Goetz, R. J. Mullin, O. B. McDonald, K. G. Petrov, D. W. Rusnak, L. M. Shewchuk, G. M. Spehar, A. T. Truesdale, D. E. Vanderwall, E. R. Wood,D. E. Uehling, Thienopyrimidine-based dual EGFR/ErbB-2 inhibitors [J]. Bioorg Med Chem Lett 2009,19,817-820.
[26]G. Xu, M. C. Abad, P. J. Connolly, M. P. Neeper, G. T. Struble, B. A. Springer, S. L. Emanuel, N. Pandey, R. H. Gruninger, M. Adams, S. Moreno-Mazza, A. R. Fuentes-Pesquera,S. A. Middleton, 4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as potent ErbB-2/EGFR dual kinase inhibitors [J]. Bioorg Med Chem Lett 2008,18, 4615-4619.
[27]G. Xu, L. L. Searle, T. V. Hughes, A. K. Beck, P. J. Connolly, M. C. Abad, M. P. Neeper, G. T. Struble, B. A. Springer, S. L. Emanuel, R. H. Gruninger, N. Pandey, M. Adams, S. Moreno-Mazza, A. R. Fuentes-Pesquera, S. A. Middleton,L. M. Greenberger, Discovery of novel 4-arnino-6-arylarninopyrimidine-5-carbaldehyde oximes as dual inhibitors of EGFR and ErbB-2 protein tyrosine kinases [J]. Bioorg Med Chem Lett 2008, 18,3495-3499.
[28]M. M. Stec, K. L. Andrews, S. K. Booker, S. Caenepeel, D. J. Freeman, J. Jiang, H. Liao, J. McCarter, E. L. Mullady, T. San Miguel, R. Subramanian, N. Tamayo, L. Wang, K. Yang, L. P. Zalameda, N. Zhang, P. E. Hughes,M. H. Norman, Structure-activity relationships of phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors: investigations of various 6,5-heterocycles to improve metabolic stability [J]. J Med Chem 2011,54,5174-5184.
[29]R. Morphy, Selectively nonselective kinase inhibition:striking the right balance [J]. J Med Chem 2010,53,1413-1437.
[30]L. Gossage,T. Eisen, Targeting multiple kinase pathways:a change in paradigm [J]. Clin Cancer Res 2010,16,1973-1978.
[31]唐海涛,陈国广,方正,王玮,韦萍,多靶点受体酪氨酸激酶抑制剂的研究进展[J].中国新药杂志2009,18,502-506.
[32]刘靖,王林,杨晓明,多靶点蛋白酪氨酸激酶抑制剂的研究进展[J].国际药学研究杂志2009,36,161-171.
[33]董静,黄文姝,多靶点抗肿瘤酪氨酸激酶抑制剂的研究开发[J].世界临床药物2009,30,306-311.
[34]A. Petrelli,S. Giordano, From single-to multi-target drugs in cancer therapy: when a specificity becomes an advantage [J]. Curr Med Chem 2008,15, 422-432.
[35]吴文,卢骋,陈思宇,余聂芳,已上市和部分正在Ⅲ期临床开发中的多靶点激酶抑制剂抑酶谱及信号传导通路分析[J].药学学报2009,242-257.
[36]S. M. Wilhelm, L. Adnane, P. Newell, A. Villanueva, J. M. Llovet,M. Lynch, Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling [J]. Molecular cancer therapeutics 2008,7,3129-3140.
[37]Y. Dai, K. Hartandi, Z. Ji, A. A. Ahmed, D. H. Albert, J. L. Bauch, J. J. Bouska, P. F. Bousquet, G. A. Cunha, K. B. Glaser, C. M. Harris, D. Hickman, J. Guo, J. Li, P. A. Marcotte, K. C. Marsh, M. D. Moskey, R. L. Martin, A. M. Olson, D. J. Osterling, L. J. Pease, N. B. Soni, K. D. Stewart, V. S. Stoll, P. Tapang, D. R. Reuter, S. K. Davidsen,M. R. Michaelides, Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor [J]. J Med Chem 2007,50,1584-1597.
[38]M. H. Potashman, J. Bready, A. Coxon, T. M. DeMelfi, Jr., L. DiPietro, N. Doerr, D. Elbaum, J. Estrada, P. Gallant, J. Germain, Y. Gu, J.-C. Harmange, S. A. Kaufman, R. Kendall, J. L. Kim, G. N. Kumar, A. M. Long, S. Neervannan, V. F. Patel, A. Polverino, P. Rose, S. Van der Plas, D. Whittington, R. Zanon,H. Zhao, Design, Synthesis, and Evaluation of Orally Active Benzimidazoles and Benzoxazoles as Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase Inhibitors [J]. Journal of Medicinal Chemistry 2007,50,4351-4373.
[39]S. Ramurthy, S. Subramanian, M. Aikawa, P. Amiri, A. Costales, J. Dove, S. Fong, J. M. Jansen, B. Levine, S. Ma, C. M. McBride, J. Michaelian, T. Pick, D. J. Poon, S. Girish, C. M. Shafer, D. Stuart, L. Sung,P. A. Renhowe, Design and synthesis of orally bioavailable benzimidazoles as Raf kinase inhibitors [J]. J Med Chem 2008,51,7049-7052.
[40]D. Menard, I. Niculescu-Duvaz, H. P. Dijkstra, D. Niculescu-Duvaz, B. M. Suijkerbuijk, A. Zambon, A. Nourry, E. Roman, L. Davies, H. A. Manne, F. Friedlos, R. Kirk, S. Whittaker, A. Gill, R. D. Taylor, R. Marais,C. J. Springer, Novel potent BRAF inhibitors:toward 1 nM compounds through optimization of the central phenyl ring [J]. J Med Chem 2009,52,3881-3891.
[41]M. Sun, X. Wu, J. Chen, J. Cai, M. Cao,M. Ji, Design, synthesis, and in vitro antitumor evaluation of novel diaryl ureas derivatives [J]. Eur J Med Chem 2010,45,2299-2306.
[42]S. M. Wilhelm, C. Carter, L. Tang, D. Wilkie, A. McNabola, H. Rong, C. Chen, X. Zhang, P. Vincent, M. McHugh, Y. Cao, J. Shujath, S. Gawlak, D. Eveleigh, B. Rowley, L. Liu, L. Adnane, M. Lynch, D. Auclair, I. Taylor, R. Gedrich, A. Voznesensky, B. Riedl, L. E. Post, G. Bollag,P. A. Trail, BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis [J]. Cancer research 2004,64,7099-7109.
[43]F. Carlomagno, S. Anaganti, T. Guida, G. Salvatore, G. Troncone, S. M. Wilhelm,M. Santoro, BAY 43-9006 inhibition of oncogenic RET mutants [J]. JNatl Cancer Inst 2006,98,326-334.
[44]G. Salvatore, V. De Falco, P. Salerno, T. C. Nappi, S. Pepe, G. Troncone, F. Carlomagno, R. M. Melillo, S. M. Wilhelm,M. Santoro, BRAF is a therapeutic target in aggressive thyroid carcinoma [J]. Clin Cancer Res 2006,12, 1623-1629.
[45]S. Wilhelm, C. Carter, M. Lynch, T. Lowinger, J. Dumas, R. A. Smith, B. Schwartz, R. Simantov,S. Kelley, Discovery and development of sorafenib:a multikinase inhibitor for treating cancer [J]. Nature reviews. Drug discovery 2006,5,835-844.
[46]L. Liu, Y. Cao, C. Chen, X. Zhang, A. McNabola, D. Wilkie, S. Wilhelm, M. Lynch,C. Carter, Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5 [J]. Cancer research 2006,66,11851-11858.
[47]T. Guida, S. Anaganti, L. Provitera, R. Gedrich, E. Sullivan, S. M. Wilhelm, M. Santoro,F. Carlomagno, Sorafenib inhibits imatinib-resistant KIT and platelet-derived growth factor receptor beta gatekeeper mutants [J]. Clin Cancer Res 2007,13,3363-3369.
[48]L. Adnane, P. A. Trail, I. Taylor,S. M. Wilhelm, Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature [J]. Methods in enzymology 2006,407,597-612.
[49]N. Dumaz,R. Marais, Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras [J]. JBiol Chem 2003, 278,29819-29823.
[50]颜彩虹,唐伟方,陈亚东,刘海春,陆涛,新型B-Raf激酶抑制剂研究进展[J].海峡药学2011,1-4.
[51]S. T. Yuen, H. Davies, T. L. Chan, J. W. Ho, G. R. Bignell, C. Cox, P. Stephens, S. Edkins, W. W. Tsui, A. S. Chan, P. A. Futreal, M. R. Stratton, R. Wooster,S. Y. Leung, Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia [J]. Cancer research 2002,62, 6451-6455.
[52]C. K. Weber, J. R. Slupsky, C. Herrmann, M. Schuler, U. R. Rapp.C. Block, Mitogenic signaling of Ras is regulated by differential interaction with Raf isozymes [J]. Oncogene 2000,19,169-176.
[53]T. Minamoto, M. Mai,Z. Ronai, K-ras mutation:early detection in molecular diagnosis and risk assessment of colorectal, pancreas, and lung cancers--a review [J]. Cancer Detect Prev 2000,24,1-12.
[54]C. A. Pritchard, M. L. Samuels, E. Bosch,M. McMahon, Conditionally oncogenic forms of the A-Raf and B-Raf protein kinases display different biological and biochemical properties in NIH 3T3 cells [J]. Mol Cell Biol 1995, 75,6430-6442.
[55]J. M. Zhang, P. L. Yang,N. S. Gray, Targeting cancer with small molecule kinase inhibitors [J]. Nat Rev Cancer 2009,9,28-39.
[56]王勇,龙业秋,蛋白酪氨酸激酶小分子抑制剂的研究新进展[J].有机化学2011,1595-1606.
[57]S. R. Hubbard, L. Wei, L. Ellis, W. A. Hendrickson, Crystal structure of the tyrosine kinase domain of the human insulin receptor [J]. Nature 1994,372, 746-754.
[58]N. Ortega, H. Hutchings,J. Plouet, Signal relays in the VEGF system [J]. Front Biosci 1999,4, D141-152.
[59]C. de Vries, J. A. Escobedo, H. Ueno, K. Houck, N. Ferrara,L. T. Williams, The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor [J]. Science 1992,255,989-991.
[60]P. A. Harris, A. Boloor, M. Cheung, R. Kumar, R. M. Crosby, R. G. Davis-Ward, A. H. Epperly, K. W. Hinkle, R. N. Hunter,3rd, J. H. Johnson, V. B. Knick, C. P. Laudeman, D. K. Luttrell, R. A. Mook, R. T. Nolte, S. K. Rudolph, J. R. Szewczyk, A. T. Truesdale, J. M. Veal, L. Wang,J. A. Stafford, Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methyl amino]-2-pyrirnidinyl]arnino]-2-methyl-b enzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor [J]. J Med Chem 2008,51,4632-4640.
[61]Y. Liu,N. S. Gray, Rational design of inhibitors that bind to inactive kinase conformations [J]. Nat Chem Biol 2006,2,358-364.
[62]C. D. Mol, D. Fabbro,D. J. Hosfield, Structural insights into the conformational selectivity of STI-571 and related kinase inhibitors [J]. Curr Opin Drug Discov Devel 2004,7,639-648.
[63]M. Carroll, S. Ohno-Jones, S. Tamura, E. Buchdunger, J. Zimmermann, N. B. Lydon, D. G. Gilliland,B. J. Druker, CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins [J]. Blood 1997,90,4947-4952.
[64]M. C. Heinrich, D. J. Griffith, B. J. Druker, C. L. Wait, K. A. Ott,A. J. Zigler, Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor [J]. Blood 2000,96,925-932.
[65]唐克,李燕,陈晓光,多靶点抗肿瘤药物索拉非尼的研究进展[J].中国新约杂志2011.20,2434-2441.
[66]M. Rahmani, E. M. Davis, C. Bauer, P. Dent,S. Grant, Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation [J]. J Biol Chem 2005,250,35217-35227.
[67]C. Yu, L. M. Bruzek, X. W. Meng, G. J. Gores, C. A. Carter, S. H. Kaufmann,A. A. Adjei, The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006 [J]. Oncogene 2005,24, 6861-6869.
[68]K.-F. Chen, W.-T. Tai, J.-W. Huang, C.-Y. Hsu, W.-L. Chen, A.-L. Cheng, P.-J. Chen,C.-W. Shiau, Sorafenib derivatives induce apoptosis through inhibition of STAT3 independent of Raf [J]. European Journal of Medicinal Chemistry 2011,46,2845-2851.
[69]S. Huang,F. A. Sinicrope, Sorafenib inhibits STAT3 activation to enhance TRAIL-mediated apoptosis in human pancreatic cancer cells [J]. Molecular cancer therapeutics 2010,9,742-750.
[70]F. Yang, T. E. Van Meter, R. Buettner, M. Hedvat, W. Liang, C. M. Kowolik, N. Mepani, J. Mirosevich, S. Nam, M. Y. Chen, G. Tye, M. Kirschbaum,R. Jove, Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas [J]. Molecular cancer therapeutics 2008,7,3519-3526.
[71]D. J. Panka, W. Wang, M. B. Atkins,J.W. Mier, The Raf inhibitor BAY 43-9006 (Sorafenib) induces caspase-independent apoptosis in melanoma cells [J]. Cancer research 2006,66,1611-1619.
[72]J. Hasskarl, Sorafenib [J]. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 2010,184,61-70.
[73]Y. S. Chang, J. Adnane, P. A. Trail, J. Levy, A. Henderson, D. Xue, E. Bortolon, M. Ichetovkin, C. Chen, A. McNabola, D. Wilkie, C. A. Carter, I. C. A. Taylor, M. Lynch,S. Wilhelm, Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models [J]. Cancer chemotherapy and pharmacology 2007,59, 561-574.
[74]D. Strumberg, Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment [J]. Drugs Today (Barc) 2005,41, 773-784.
[75]Y. S. Chang, A. Henderson, D. Xue, C. Chen, A. McNabola, D. Wilkie, B. Rowley, C. A. Carter, B. Riedl, P. A. Trail,S. Wilhelm, BAY 43-9006 (Sorafenib) inhibits ectopic (s.c.) and orthotopic growth of a murine model of renal adenocarcinoma (Renca) predominantly through inhibition of tumor angiogenesis [J]. Proceedings of the American Association for Cancer Research Annual Meeting 2005,46,1372.
[76]V. Ramakrishnan, M. Timm, J. L. Haug, T. K. Kimlinger, L. E. Wellik, T. E. Witzig, S. V. Rajkumar, A. A. Adjei,S. Kumar, Sorafenib, a dual Raf kinase/vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common anti-myeloma drugs [J]. Oncogene 2010,29,1190-1202.
[77]C. H. Takimoto,A. Awada, Safety and anti-tumor activity of sorafenib (Nexavar) in combination with other anti-cancer agents:a review of clinical trials [J]. Cancer chemotherapy and pharmacology 2008,61,535-548.
[78]Z. Hu, Y. Su, Z. Wang, X. Zeng, S. Liu, Q. Zhang, W. Yang, J. Liu,Z. Ye, Safety and Management of Sorafenib in Treatment of 31 Patients with Metastatic Renal Cell Carcinoma [J]. Cancer Research on Prevention and Treatment (肿瘤防治研究) 2010,37,589-591.
[79]J. W. Clark, J. P. Eder, D. Ryan, C. Lathia,H. J. Lenz, Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors [J]. Clin Cancer Res 2005,77,5472-5480.
[80]M. Iijima, K. Fukino, M. Adachi, T. Tsukamoto, M. Murai, S. Naito, H. Minami, J. Furuse,H. Akaza, Sorafenib-associated hand-foot syndrome in Japanese patients [J]. The Journal of dermatology 2011,38,261-266.
[81]D. Niculescu-Duvaz, C. Gaulon, H. P. Dijkstra, I. Niculescu-Duvaz, A. Zambon, D. Menard, B. M. Suijkerbuijk, A. Nourry, L. Davies, H. Manne, F. Friedlos, L. Ogilvie, D. Hedley, S. Whittaker, R. Kirk, A. Gill, R. D. Taylor, F. I. Raynaud, J. Moreno-Farre, R. Marais,C. J. Springer, Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1(BRAF) [J]. JMed Chem 2009,52,2255-2264.
[82]B. M. Suijkerbuijk, I. Niculescu-Duvaz, C. Gaulon, H. P. Dijkstra, D. Niculescu-Duvaz, D. Menard, A. Zambon, A. Nourry, L. Davies, H. A. Manne, F. Friedlos, L. M. Ogilvie, D. Hedley, F. Lopes, N. P. Preece, J. Moreno-Farre, F. I. Raynaud, R. Kirk, S. Whittaker, R. Marais,C. J. Springer, Development of novel, highly potent inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF):increasing cellular potency through optimization of a distal heteroaromatic group [J]. JMed Chem 2010,53,2741-2756.
[83]B. S. Nam, H. Kim, C.-H. Oh, S. H. Lee, S. J. Cho, T. B. Sim, J.-M. Hah, D. J. Kim, J. H. Choi,K. H. Yoo, Aminoquinoline derivatives with antiproliferative activity against melanoma cell line [J]. Bioorganic& Medicinal Chemistry Letters 2009,19,3517-3520.
[84]M.-H. Jung, H. Kim, W.-K. Choi, M. I. E1-Gamal, J.-H. Park, K. H. Yoo, T. B. Sim, S. H. Lee, D. Baek, J.-M. Hah, J.-H. Cho,C.-H. Oh, Synthesis of pyrrolo[2,3-d]pyrimidine derivatives and their antiproliferative activity against melanoma cell line [J]. Bioorganic & Medicinal Chemistry Letters 2009,19, 6538-6543.
[85]H. J. Kim, M.-H. Jung, H. Kim, M. I. El-Gamal, T. B. Sim, S. H. Lee, J. H. Hong, J.-M. Hah, J.-H. Cho, J. H. Choi, K. H. Yoo,C.-H. Oh, Synthesis and antiproliferative activity of pyrrolo[3,2-b]pyridine derivatives against melanoma [J]. Bioorganic & Medicinal Chemistry Letters 2010,20,413-417.
[86]M. I. El-Gamal, M.-H. Jung, W. S. Lee, T. Sim, K. H. Yoo,C.-H. Oh, Design, synthesis, and antiproliferative activity of new 1H-pyrrolo[3,2-c]pyridine derivatives against melanoma cell lines [J]. European Journal of Medicinal Chemistry 2011,46,3218-3226.
[87]杨照,方正,王志祥,韦萍,Sorafenib硫脲衍生物的合成及活性研究[J].药学学报2011,1093-1097.
[88]W. Li, X. Zhai, Z. Zhong, G. Li, Y. Pu,P. Gong, Design, synthesis and evaluation of novel rhodanine-containing sorafenib analogs as potential antitumor agents [J]. Archiv der Pharmazie 2011,344,349-357.
[1]S. M. Wilhelm, L. Adnane, P. Newell, A. Villanueva, J. M. Llovet,M. Lynch, Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling [J]. Molecular cancer therapeutics 2008,7,3129-3140.
[2]ZHOU A P, SUN Y. Recent advances in sorafenib:A multiple targeted anti-tumor agent [J].Oncol Prog(癌症进展杂志)2006,529-533.
[3]Y. Dai, K. Hartandi, Z. Ji, A. A. Ahmed, D. H. Albert, J. L. Bauch, J. J. Bouska, P. F. Bousquet, G. A. Cunha, K. B. Glaser, C. M. Harris, D. Hickman, J. Guo, J. Li, P. A. Marcotte, K. C. Marsh, M. D. Moskey, R. L. Martin, A. M. Olson, D. J. Osterling, L. J. Pease, N. B. Soni, K. D. Stewart, V. S. Stoll, P. Tapang, D. R. Reuter, S. K. Davidsen,M. R. Michaelides, Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor [J]. JMed Chem 2007,50.1584-1597.
[4]M. H. Potashman, J. Bready, A. Coxon, T. M. DeMelfi, Jr., L. DiPietro, N. Doerr, D. Elbaum, J. Estrada, P. Gallant, J. Germain, Y. Gu, J.-C. Harmange, S. A. Kaufman, R. Kendall, J. L. Kim, G. N. Kumar, A. M. Long, S. Neervannan, V. F. Patel, A. Polverino, P. Rose, S. Van der Plas, D. Whittington, R. Zanon,H. Zhao, Design, Synthesis, and Evaluation of Orally Active Benzimidazoles and Benzoxazoles as Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase Inhibitors [J]. Journal of Medicinal Chemistry 2007,50,4351-4373.
[5]S. Ramurthy, S. Subramanian, M. Aikawa, P. Amiri, A. Costales, J. Dove, S. Fong, J. M. Jansen, B. Levine, S. Ma, C. M. McBride, J. Michaelian, T. Pick, D. J. Poon, S. Girish, C. M. Shafer, D. Stuart, L. Sung,P. A. Renhowe, Design and synthesis of orally bioavailable benzimidazoles as Raf kinase inhibitors [J]. J Med Chem 2008,57,7049-7052.
[6]D. Menard, I. Niculescu-Duvaz, H. P. Dijkstra, D. Niculescu-Duvaz, B. M. Suijkerbuijk, A. Zambon, A. Nourry, E. Roman, L. Davies, H. A. Manne, F. Friedlos, R. Kirk, S. Whittaker, A. Gill, R. D. Taylor, R. Marais,C. J. Springer, Novel potent BRAF inhibitors:toward 1 nM compounds through optimization of the central phenyl ring [J]. J Med Chem 2009,52,3881-3891.
[7]M. Sun, X. Wu, J. Chen, J. Cai, M. Cao,M. Ji, Design, synthesis, and in vitro antitumor evaluation of novel diaryl ureas derivatives [J]. Eur J Med Chem 2010,45,2299-2306.
[8]P. T. Wan, M. J. Garnett, S. M. Roe, S. Lee, D. Niculescu-Duvaz, V. M. Good, C. M. Jones, C. J. Marshall, C. J. Springer, D. Barford,R. Marais, Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF [J]. Cell 2004,116,855-867.
[9]L. Adnane, P. A. Trail, I. Taylor,S. M. Wilhelm, Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature [J]. Methods in enzymology 2006,407,597-612.
[10]S. M. Wilhelm, C. Carter, L. Tang, D. Wilkie, A. McNabola, H. Rong, C. Chen, X. Zhang, P. Vincent, M. McHugh, Y. Cao, J. Shujath, S. Gawlak, D. Eveleigh, B. Rowley, L. Liu, L. Adnane, M. Lynch, D. Auclair, I. Taylor, R. Gedrich, A. Voznesensky, B. Riedl, L. E. Post, G. Bollag,P. A. Trail, BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis [J]. Cancer research 2004,64,7099-7109.
[11]D. Niculescu-Duvaz, C. Gaulon, H. P. Dijkstra, I. Niculescu-Duvaz, A. Zambon, D. Menard, B. M. Suijkerbuijk, A. Nourry, L. Davies, H. Manne, F. Friedlos, L. Ogilvie, D. Hedley, S. Whittaker, R. Kirk, A. Gill, R. D. Taylor, F. I. Raynaud, J. Moreno-Farre, R. Marais,C. J. Springer, Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue Bl (BRAF) [J]. JMed Chem 2009,52,2255-2264.
[12]杨照,方正,王志祥,韦萍,Sorafenib硫脲衍生物的合成及活性研究[J].药学学报2011,1093-1097.
[13]M. W. Holladay, B. T. Campbell, M. W. Rowbottom, Q. Chao, K. G. Sprankle, A. G. Lai, S. Abraham, E. Setti, R. Faraoni, L. Tran, R. C. Armstrong, R. N. Gunawardane, M. F. Gardner, M. D. Cramer, D. Gitnick, M. A. Ator, B. D. Dorsey, B. R. Ruggeri, M. Williams, S. S. Bhagwat,J. James, 4-Quinazolinyloxy-diaryl ureas as novel BRAFV600E inhibitors [J]. Bioorg Med Chem Lett 2011,21,5342-5346.
[1]Rossetto P, Macdonald L, Canavesi A, et al. Process for the preparation of sorafenib and salts thereof [P] WO.2009111061,2009-09-11
[2]张楠,钟荣,抗癌用化合物及制备方法[P].CN.101830847 A,2010-09-15
[3]赵乘有,陈林捷,等.对甲苯磺酸索拉非尼的合成[J].中国医药工业杂志,2007,38(9)：614-616
[4]杨照,方正,王志祥,韦萍,Sorafenib硫脲衍生物的合成及活性研究[J].药学学报2011,(46)9：1093-1097.
[5]PULLA REDDY, Muddasani, VENKAIAH CHOWDARY, Nannapaneni. Process for the preparation of sorafenib [P]. WO.2009054004,2009-04-30
[6]D. Bankston, J. Dumas, R. Natero, B. Riedl, M.-K. Monahan,R. Sibley, A Scaleable Synthesis of BAY 43-9006:A Potent Raf Kinase Inhibitor for the Treatment of Cancer [J]. Organic Process Research & Development 2002,6, 777-781.
[7]陈静,王程鹏,何作鹏,姚建文,抗肿瘤药物索拉非尼合成工艺的改进[J].烟台大学学报(自然科学与工程版)2012,25(2):146-149
[8]Lijuan Zhang, Wenpin Xia, Bo Wang, Yu Luo & Wei Lu, Convenient Synthesis of Sorafenib and Its Derivatives [J]. Synthetic Communications 2011,41,3140-3146
[9]Li W, Zhai X, Zhong Z, et al. Design, synthesis and evaluation of novel rhodanine-containing sorafenib analogs as potential antitumor agents [J]. Archiv der Pharmazie,2011,11:349-357
[10]杜晓华,许响生,等,非硫光气法合成一些难合成的芳基异硫氰酸酯[J].农药2004,43(2)：78-79
[11]Larsen C, Steliou K, Harpp DN. Organic sulfur chemistry.25. Thiocarbonyl transfer reagents [J]. J Org Chem,1978,43:337-339.
[1]Bruker, [J]. SAINT and SMART. Bruker AXSInc., Madison, Wisconsin, USA. 2002.
[21 G. M. Sheldrick, [J]. SHSLXL97, Program for Crystal Structure Refinement, University of Gottingen, Germany 1997.
[3]A. Altomare, G. Cascarano, C. Giacovazzo,A. Guagliardi, SIR92 [J]. J. Appl. Cryst.1993,26, SIR92.
[4]A. L. Spek, [J]. PLATON. Version 280301. University of Utreecht, The Netherlands 1980.
[5]L. J. Farrugia, [J]. J. Appl. Cryst.1999,32,837-838.
[6]L. J. Farrugia, [J]. J. Appl. Cryst.1997,30,565.
[7]D. M. Watkin, L. Pearce,C. K. Prout, [J]. CAMERON. Chemical Crystallography Laboratory, University of Oxford, England.1993.
[8]K. Ravikumar, B. Sridhar, A. K. Bhujanga Rao,M. Pulla Reddy, Sorafenib and its tosylate salt:a multikinase inhibitor for treating cancer [J]. Acta crystallographica. Section C, Crystal structure communications 2011,67, o29-32.
[9]L. Pauling,P. Pauling, Chemistry, Freeman, San Francisco,1975.
[10]S. Chang, L. Zhang, S. Xu, J. Luo, X. Lu, Z. Zhang, T. Xu, Y. Liu, Z. Tu, Y. Xu, X. Ren, M. Geng, J. Ding, D. Pei,K. Ding, Design, synthesis, and biological evaluation of novel conformationally constrained inhibitors targeting epidermal growth factor receptor threonine(7)(9)(0)--> methionine(7)(9)(0) mutant [J]. JMed Chem 2012,55,2711-2723.
[11]R. F. Nicosia,A. Ottinetti, Growth of micro vessels in serum-free matrix culture of rat aorta. A quantitative assay of angiogenesis in vitro [J]. Lab Invest 1990,63,115-122.
[12]B. J. Pyun, S. Choi, Y. Lee, T. W. Kim, J. K. Min, Y. Kim, B. D. Kim, J. H. Kim, T. Y. Kim, Y. M. Kim,Y. G. Kwon, Capsiate, a nonpungent capsaicin-like compound, inhibits angiogenesis and vascular permeability via a direct inhibition of Src kinase activity [J]. Cancer research 2008,68, 227-235.
[1]P. T. Wan, M. J. Garnett, S. M. Roe, S. Lee, D. Niculescu-Duvaz, V. M. Good, C. M. Jones, C. J. Marshall, C. J. Springer, D. Barford,R. Marais, Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF [J]. Cell 2004,116,855-867.
[2]FlexXTM is distributed by Tripos Inc.,1699, South Hanley Rd., St. Louis, Missouri, USA (http://www.tripos.com)
[3]Rarey, M.; Kramer, B.; Lengauer, T., et al. A Fast Flexible Docking Method using an Incremental Construction Algorithm [J]. J. Mol.Biol.,1996,261(3): 470-489.
[4]Harris PA, Boloor A, Cheung M, et al. Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]arnino]-2-methyl-b enzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor [J]. J Med Chem,2008,51(15): 4632-4640
[5]BiopolymerTM is distributed by Tripos Inc.,1699, South Hanley Rd., St. Louis, Missouri, USA (http://www.tripos.com)
[6]Kellenberger, E.; Rodrigo, J.; Muller. P., et al. Comparative evaluation of eight docking tools for docking and virtual screening accuracy [J]. Proteins.,2004, 57(2):225-242.