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研究生:林振瑋
研究生(外文):Lin, Chen-Wei
論文名稱:以呋喃并嘧啶化合物為極光激酶抑制劑之研究
論文名稱(外文):Development of Furano[2,3-d]pyrimidine Compounds as Aurora Kinases Inhibitors
指導教授:廖俊臣謝興邦謝興邦引用關係
指導教授(外文):Liao, Chun-ChenHsieh, Hsing-Pang
學位類別:博士
校院名稱:國立清華大學
系所名稱:化學系
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:98
語文別:中文
論文頁數:443
中文關鍵詞:極光激酶呋喃并嘧啶
外文關鍵詞:Aurora kinasefurano[23-d]pyrimidine
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本論文主旨在設計並合成可抑制極光激酶(aurora kinases)之呋喃并嘧啶化合物,希望以此發展為抗癌標靶藥物。由知識基礎設計(knowledge-based design)所篩選出之潛力化合物1為改進對象,利用循理性設計及混成設計,分別發展出潛力化合物20及48,再從化合物與Aurora-A之共結晶結構中,發現這兩個潛力化合物之蛋白質結構屬於DFG-out及類DFG-out構型,並以共結晶結構分析來解釋蛋白質構型與生物活性之關係。同時以高通量平行合成(high-throughput parallel synthesis, HTPS)方法來加快合成衍生物之速度,挑選出適當化合物加以進行結構上之修飾,在加入脲基及末端苯環後,成功地發現先導化合物183,並從共結晶結構分析瞭解其結構與激酶之作用力,導致蛋白質結構改變為DFG-in構型,而展現極光激酶抑制劑之特性。接著利用各種合成方法進行先導化合物之最優化,確認最好之側鏈結構為乙基苯脲苯,並得到化合物252,成功降低化合物之分子量及親油性,並提昇其細胞活性。
This dissertation is concerned with the development of furano[2,3-d]pyrimidine compounds as Aurora kinases inhibitors. Start from compound 1, we utilize rational drug design to synthesize two particular hits, compound 20 and 48. We analyze the co-crystal structures of two hits with Aurora-A, and observe the protein structures belong to DFG-out and DFG-out-like conformation. At the same time, we apply high-throughput parallel synthesis (HTPS) to accelerate the synthesis of analogues. Fortunately, we discover the lead compound 183 which was modified from compound 145 by forming the urea functionality and terminal phenyl group. We analyze the co-crystal structure of compound 183, and find the protein structure is DFG-in conformation. The variety does not only display in protein conformation but also improve the bioactivity. After lead optimization, we confirm the ethyl-phenyl-urea was the best side chain structure, and find compound 252 which successfully improve the cell bioactivity and reduce the molecular weight and lipophilicity.
目 錄

中文摘要 i
英文摘要 ii
謝誌 iii
目錄 iv


一、緒論 1
1.1 癌症簡介 1
1.2 癌症起因 3
1.3 癌症治療 6
1.3.1 癌症化療藥物之分類 10
1.3.1.1 烷化劑藥物 11
1.3.1.2 抗代謝藥物 11
1.3.1.3 天然物 13
1.3.1.4 抗血管增生藥物 19
1.3.1.5 激酶抑制劑 20
1.3.2 標靶治療 24
1.3.3 抗癌藥物的市場概況 26
1.4 極光激酶 27
1.4.1 極光激酶之作用機制 28
1.4.1.1 Aurora-A之作用機制 29
1.4.1.2 Aurora-B之作用機制 30
1.4.2 以極光激酶為抗癌標的 31
1.4.3 極光激酶抑制劑之發展 33
1.4.3.1 Hesperadin 33
1.4.3.2 MK0457 (VX-680) 34
1.4.3.3 AZD1152 35
1.4.3.4 PHA-680632及PHA-739358 36
1.4.3.5 MLN8054 37
1.4.3.6 CCT129202 38
1.4.3.7 MP529 38
1.4.3.8 SNS-314 39
1.4.3.9 AT9283 40

二、研究構思 41
2.1 研究動機 41
2.2 文獻回顧 44
2.2.1 呋喃并嘧啶之合成文獻回顧 44
2.2.2 呋喃并嘧啶之生物活性文獻回顧 46
2.3 研究構想 52
2.4 生物活性測試分析 57
2.4.1 酵素活性測試分析法 57
2.4.2 細胞活性測試分析法 58

三、結果與討論 61
3.1 合成策略 61
3.2 循理性藥物設計 63
3.2.1 芳香胺化合物之設計 64
3.2.2 芳香胺化合物之合成 65
3.2.3 芳香胺化合物之生物活性分析 70
3.2.4 芳香胺化合物之共結晶結構分析 73
3.2.5 混成設計 78
3.2.6 混成設計之合成 79
3.2.7 混成設計之生物活性分析 82
3.2.8 混成設計之共結晶結構分析 85
3.2.9 循理性藥物設計之結論 92
3.3 高通量平行合成設計 93
3.3.1 高通量平行合成之方法 93
3.3.2 高通量平行合成之生物活性分析 95
3.3.3高通量平行合成之結論 108
3.4 高通量平行合成化合物之結構修飾 110
3.4.1 高通量平行合成化合物結構修飾之合成 112
3.4.1.1 哌嗪化合物之合成 112
3.4.1.2 乙基苯化合物之合成 116
3.4.2 高通量平行合成化合物結構修飾之生物活性分析 118
3.4.2.1 哌嗪化合物之生物活性分析 118
3.4.2.2 乙基苯化合物之生物活性分析 123
3.4.3 先導化合物之功能性生物活性分析 124
3.4.4 先導化合物之共結晶結構分析 129
3.4.5 高通量平行合成化合物結構修飾之結論 138
3.5 先導化合物最優化. 139
3.5.1 先導化合物最優化之設計 140
3.5.2 先導化合物最優化之合成 140
3.5.2.1 改變脲基官能基化合物之合成 140
3.5.2.2 移動脲基位置化合物之合成 142
3.5.2.3 改變末端苯環化合物之合成 144
3.5.2.4 增加末端苯環取代基化合物之合成 147
3.5.2.5 移動中間苯環化合物之合成 148
3.5.2.6 延伸乙基鏈結化合物之合成 149
3.5.2.7 改變四號位置氮取代化合物之合成 151
3.5.2.8 改變五、六號位置苯環化合物之合成 152
3.5.2.9 改變中間苯環化合物之合成 155
3.5.3 先導化合物最優化之生物活性分析 157
3.5.4 先導化合物與SNS-314之比較 169
3.5.4.1 先導化合物與SNS-314於生物活性之比較 169
3.5.4.2 先導化合物與SNS-314於共結晶結構之比較 175
3.5.5 先導化合物最優化之結論 177

四、總結 179

五、實驗部份 186
5.1 一般實驗方法 186
5.2 化合物之實驗步驟及光譜資料 188

參考資料 275

附錄一 天然物Pelseneeriol之合成研究 284
附錄二 化合物之ligplot圖 311
附錄三 化合物之核磁共振光譜圖 320
附錄四 生物活性測試分析方法 433
附錄五 化合物編號對照表 436
參考資料

1. Lodish, Harvey F.; Arnold Berk; Kaiser, Chris A.; Monty Krieger; Scott, Matthew P.; Anthony Bretscher; Hidde Ploegh; Matsudaira, Paul T. Molecular Cell Biology 6th Ed. 2007, W. H. Freeman & Co Ltd, ISBN 1429203145.
2. Alberts, Bruce Molecular Biology of the Cell 5th Ed. 2008, New York: Garland Science, ISBN 0815332181.
3. 世界衛生組織網站 http://www.who.int/en/
4. 中華民國九十六年死因統計, 1997, 行政院衛生署, ISSN 1992-2450.
5. Weinberg, Robert A. The Biology of Bancer 2007, New York: Garland Science, ISBN 0815340761.
6. Ruddon, Raymond W. Cancer Biology 4th Ed. 2007, Oxford University Press USA, ISBN 0195175433.
7. Hartwell, L. H.; Culotti, J.; Reid, B. Genetic Control of the Cell-Division Cycle in Yeast, I. Detection of Mutants. Proc. Natl. Acad. Sci. 1970, 66, 352-359.
8. Rossi, A. G.; et al. Cyclin-dependent Kinase Inhibitors Enhance the Resolution of Inflammation by Promoting Inflammatory Cell Apoptosis. Nat. Med. 2006, 12, 1056-1064.
9. Matlashewski, G.; Lamb, P.; Pim, D.; Peacock, J.; Crawford, L,; Benchimol, S. Isolation and Characterization of a Human p53 cDNA Clone: Expression of the Human p53 Gene. Embo J. 1984, 3, 3257-3262.
10. Isobe, M.; Emanuel, B. S.; Givol, D.; Oren, M.; Croce, C. M. Localization of Gene for Human p53 Tumour Antigen to Band 17p13. Nature 1986, 320, 84-85.
11. Current Cancer Therapeutics 3rd Ed. 1998, Philadelphia, PA : Current Medicine, ISBN 0443065276.
12. Pecorino L. Molecular Biology of Cancer: Mechanisms, Targets, and Therapeutics 2nd Ed. 2008, Oxford New York: Oxford University Press, ISBN 0199211485.
13. Beverly A. T. Cancer Therapeutics: Experimental and Clinical Agents 2nd Ed. 1997, Totowa, N. J. : Humana, ISBN 0896034607.
14. Beverly A. T. Antiangiogenic Agents in Cancer Therapy 1999, Totowa, New Jersey : Humana Press, ISBN 0896036413.
15. Vasella D. Magic Cancer Bullet: How a Tiny Orange Pill is Rewriting Medical History 2003, New York :Harper Business, ISBN 0066610304.
16. Stephen N. Cancer Drug Design and Discovery 2008, Boston: Academic Press, ISBN 0123694485.
17. Scott, S. D. Rituximab: a New Therapeutic Monoclonal Antibody for Non-Hodgkin's Lymphoma. Cancer Pract. 1998, 6, 195-197.
18. Vera, E.; Ashley J. J. et al. VEGF Inhibition and Renal Thrombotic Microangiopathy. N. Engl. J. Med. 2008, 358, 1129.
19. Bokemeyer, C.; Bondarenko, I.; Makhson, A.; Hartmann, J. T.; Aparicio, J. et al. Fluorouracil, Leucovorin, and Oxaliplatin with and without Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer. J. Clin. Oncol. 2009, 27, 663-671.
20. Bange, J.; Zwick, E.; Ullrich, A. Molecular Targets for Breast Cancer Therapy and Prevention. Nat. Med. 2001, 7, 548-552.
21. Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L, Roy S, Sridhara, R.; Rahman, A.; Williams, G.; Pazdur, R. Approval Summary: Gemtuzumab Ozogamicin in Relapsed Acute Myeloid Leukemia. Clin. Cancer Res. 2001, 7, 1490-1496.
22. Jordan, V. C. Fourteenth Gaddum Memorial Lecture. A Current View of Tamoxifen for the Treatment and Prevention of Breast Cancer. Br. J. Pharmacol 1993, 110, 507-517.
23. Coombes, R. C.; et al. Survival and Safety of Exemestane Versus Tamoxifen after 2–3 Years' Tamoxifen Treatment: a Randomised Controlled Trial. Lancet 2007, 369, 559-570.
24. Howell, A.; Cuzick, J.; Baum, M. et al. Results of the ATAC Trial after Completion of 5 Years' Adjuvant Treatment for Breast Cancer. Lancet 2005, 365, 60-62.
25. Goodman, L. S.; Wintrobe, M. M.; Dameshek, W.; Goodman, M. J.; Gilman, A. Z,; McLennan, M. T. Nitrogen Mustard Therapy. Use of Methyl Bis(B-chloroethyl)- emine Hydrochloride and Tris(B-chloroethy)amine Hydrochloride for Hodgkin's Disease Lymphosarcoma, Leukemia, Certain Allied and Miscellaneous Disorders. J. Am. Med. Ass. 1946, 132, 126-132.
26. Rosenberg, B.; Van Camp, L.; Krigas, T. Inhibition of Cell Division in Escherichia Coli by Electrolysis Products from a Platinum Electrode. Nature 1965, 205, 698-699.
27. Rebecca, A.; Alderden, Matthew, D. H.; Trevor, W. H. The Discovery and Development of Cisplatin. J. Chem. Ed. 2006, 83, 728-724.
28. McLeod, H. L.; et al. Pharmacokinetic and Pharmacodynamic Evaluation of the Glycinamide Ribonucleotide Formyltransferase Inhibitor AG2034. Clin. Cancer Res. 2000, 62, 677-2684.
29. Vora, A.; Mitchell, C. D.; Lennard, L.; et al. Toxicity and Efficacy of 6-Thioguanine Versus 6-Mercaptopurine in Childhood Lymphoblastic Leukaemia: a Randomised Trial. Lancet 2006, 368, 1339-1348.
30. Tan, C.; Tasaka, H.; Kou-Ping, Y.; et al. Daunomycin, an Antitumor Antibiotic, In the Treatment of Neoplastic Disease. Clinical Evaluation with Special Reference to Childhood Leukemia. Cancer 1967, 20, 333-353.
31. Fox, E. Management of Worsening Multiple Sclerosis with Mitoxantrone: a Review. Clin. Ther. 2006, 28, 461-474.
32. Mao, Y.; Varoglu, M.; Sherman, D. H. Molecular Characterization and Analysis of the Biosynthetic Gene Cluster for The Antitumor Antibiotic Mitomycin C from Streptomyces Iavendulae NRRL 2564. Chem. Biol. 1999, 6, 251-263.
33. Finlay, A. C.; Hochstein, F. A.; Sobin, B. A.; Murphy, F. X. Netropsin, a New Antibiotic Produced by a Streptomyces J. Am. Chem. Soc. 1951, 73, 341-343.
34. Kopka, M. L.; Yoon, C.; Goodsell, D.; Pjura, P.; Dickerson, R. E. The Molecular origin of DNA-drug Specificity in Netropsin and Distamycin. Proc. Natl. Acad. Sci. 1985, 82, 1376-1380.
35. Hiraku, Y.; Oikawa, S.; Kawanishi, S. Distamycin A, a Minor Groove Binder, Changes Enediyne-induced DNA Cleavage Site and Enhances Apoptosis. Nucleic Acids Res. Suppl. 2002, 2, 95-96.
36. Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail, A. I.; Sim, G. A. Plant antitumor agents. I. The Isolation and Structure of Camptothecin, a Novel Alkaloidal Leukemia and Tumor Inhibitor from Camptotheca Acuminate. J. Am. Chem. Soc. 1966, 88, 3888-3890.
37. Ulukan, H.; Swaan, P. W. Camptothecins, a Review of Their Chemotherapeutical Potential. Drugs 2002, 62, 2039-2057.
38. Hartwell, J. L.; Schrecker, A. W. Components of Podophyllin. V. The Constitution of Podophyllotoxin. J. Am. Chem. Soc. 1951, 73, 2909-2916.
39. Sugiura, Y.; Kikuchi, T. Formation of Superoxide and Hydroxyl Radicals in Iron(II)-bleomycin-oxygen System: Electron Spin Resonance Detection by Spin Trapping. J. Antibiotics 1978, 31, 1310-1312.
40. Mujagic, H.; Conger, B. M.; Smith, C. A.; Occhipinti, S. J.; Schuette, W. H.; Shackney, S. E. Schedule Dependence of Vincristine Lethality in Sarcoma 180 Cells Following Partial Synchronization with Hydroxyurea. Cancer Res. 1983, 43, 3598-3603.
41. Jordan, A.; Hadfield, J. A.; Lawrence, N. J.; McGown, A. T. Tubulin as A Target for Anticancer Drugs: Agents Which Interact with the Mitotic Spindle. Med. Res. Rev. 1998, 18, 259-296.
42. Manfriedi, J. J.; Horwitz, S. B. Taxol: an Antimitotic Agent with a New Mechanism of Action. Pharmacol. Ther. 1984, 25, 83.
43. Thoret, S.; Gueritte, F.; Guenard, D.; Dubois, J. Semisynthesis and Biological Evaluation of a Novel D-seco Docetaxel Analogue. Org. Lett. 2006, 8, 2301-2304.
44. Pettit, G. R.; Singh, S. B.; Niven, M. L.; Hamel, E.; Schmidt, J. M. Isolation, Structure, and Synthesis of Combretastatins A-1 and B-1, Potent New Inhibitors of Microtubule Assembly, Derived from Combretum caffrum. J. Nat. Prod. 1987, 50, 119-131.
45. Hsieh, H. P.; Liou, J. P.; Mahindroo, N. Pharmaceutical Design of Antimitotic Agents Based on Combretastatins. Curr. Pharm. Des. 2005, 11, 1655-1677.
46. Mahindroo, N.; Liou, J. P.; Chang, J. Y.; Hsieh, H. P. Antitubulin Agents for the Treatment of Cancer – a Medicinal Chemistry Update. Expert Opin. Ther. Patents 2006, 16, 647-691.
47. Folkman, J. Tumor Angiogenesis Factor. Cancer Research 1974, 34, 2109-2113.
48. Folkman, J. Angiogenesis in Cancer, Vascular, Rheumatoid and Other Disease. Nature Medicine 1995, 1, 27-30.
49. Xin, X.; Yang, S.; Kowalski, J.; Gerritsen, M. E. Peroxisome Proliferators-activated Receptor γ Ligands are Potent Inhibitors of Angiogenesis in Vitro and in Vivo. J. Bio. Chem. 1999, 274, 9116-9121.
50. Kim, K. Y.; Cheon, H. G. Antiangiogenic Effect of Rosiglitazone is Mediated via Peroxisome Proliferators-activated Receptor γ-Activated Maxi-K Channel Opening in Human Umbilical Vein Endothelial Cells. J. Bio. Chem. 2006, 281, 13508-13512.
51. Yabu, T.; Tomimoto, H.; Taguchi, Y.; Yamaoka, S.; Igarashi, Y.; Okazaki, T. Thalidomide-induced Anti-angiogenic Action is Mediated by Ceramide Through Depletion of VEGF Receptors, and Antagonized by Sphingosine-1-phosphate. Blood 2005, 106, 125-134.
52. Manning, G.; Whyte, D. B.; Martinez, R.; Hunter, T.; Sudarsanam, S. The Protein Kinase Complement of the Human Genome Science 2002, 298, 1912-1934.
53. Liu, Y.; Gray, N. S. Rational Design of Inhibitors That Bind to Inactive Kinase Conformation. Nat. Chem. Bio. 2006, 2, 358-364.
54. Liao, J, J. L. Molecular Recognition of Protein Kinase Binding Pockets for Design of Potent and Selective Kinase Inhibitors. J. Med. Chem. 2007, 50, 1-16.
55. Zhukov, N. V.; Tjulandin, S. A. Targeted Therapy in the Treatment of Solid Tumors: Practice Contradicts Theory. Biochemistry Mosc. 2008, 73, 605-618.
56. Adams, J.; Kauffman, M. Development of the Proteasome Inhibitor Velcade (Bortezomib). Cancer Invest. 2004, 22, 304-311.
57. IMS Health網站 http://www.imshealth.com/
58. Francisco, L.; Wang, W.; Chan, C. S. Type 1 Protein Phosphatase Acts in Opposition to IpL1 Protein Kinase in Regulating Yeast Chromosome Segregation. Mol. Cell Biol. 1994, 14, 4731-4740
59. Glover, D. M.; Leibowitz, M. H.; McLean, D. A.; Parry, H. Mutations in Aurora Prevent Centrosome Separation Leading to the Formation of Monopolar Spindles. Cell 1995, 81, 95-105.
60. Keen, N.; Taylor, S. Aurora-kinase Inhibitors as Anticancer Agents. Nat. Rev. Cancer 2004, 4, 927-936.
61. Bischoff, J. R.; Plowman, G. D. The Aurora/Ipl1p Kinase Family: Regulators of Chromosome Segregation and Cytokinesis. Trends Cell Biol. 1999, 9, 454-459.
62. Giel, R.; Prigent, C. Aurora/Ipl1p-related Kinases, a New Oncogenic Family of Mitotic Serine-threonine Kinases. J. Cell Sci. 1999, 112, 3591-3601.
63. Bolanos-Garcia, V. M. Aurora Kinases. Int. J. Biochem. Cell Biol. 2005, 37, 1572-1577.
64. Ducat, D.; Zheng, Y. Aurora Kinases in Spindle Assembly and Chromosome Segregation. Exp. Cell Res. 2004, 301, 60-67.
65. Delaval, B.; Ferrand, A.; Conte, N.; Larroque, C.; Hernandez-Verdun, D.; Prigent, C.; Birnbaum, D. Aurora B -TACC1 Protein Complex in Cytokinesis. Oncogene 2004, 23, 4516-4522.
66. Ke, Y. W.; Dou, Z.; Zhang, J.; Yao, X. B. Function and Regulation of Aurora/Ipl1p Kinase Family in Cell Division. Cell Res. 2003, 13, 69-81.
67. Pollard, J. R.; Mortimore, M. Discovery and Development of Aurora Kinase Inhibitors as Anticancer Agents. J. Med. Chem. 2009, 52, 2629-2651.
68. Takayuki, I. Aurora Kinases as an Anti-cancer Target. Cancer Lett. 2008, 262, 1-9.
69. Jackson, J. R.; Patrick, D. R.; Dar, M. M.; Huang, P. S. Targeted Anti-mitotic Therapies: Can We Improve on Tubulin Agents? Nat. Rev. Cancer 2007, 7, 107-117.
70. Montembault, E.; Prigent, C. Aurora Kinases: Therapeutic Potential. Drugs Fut. 2005, 30, 29-37.
71. Gautschi, O.; Heighway, J.; Mack, P. C.; Purnell, P. R.; Lara, P. N., Jr.; Gandara, D. R. Aurora Kinases as Anticancer Drug Targets. Clin. Cancer Res. 2008, 14, 1639-1648.
72. Giannis, M.; Evangelos, T.; Meletios-Athanassios, D. Aurora Kinases as Targets for Cancer Therapy. Cancer Treat. Rev. 2008, 34, 175-182.
73. Giet, R.; Glover, D. M. Drosophila Aurora B Kinase Is Required for Histone H3 Phosphorylation and Condensin Recruitment during Chromosome Condensation and to Organize the Central Spindle during Cytokinesis. J. Cell Biol. 2001, 152, 669-682.
74. Giet, R.; McLean, D.; Descamps, S.; Lee, M. J.; Raff, J. W.; Prigent, C.; Glover, D. M. Drosophila Aurora A Kinase is Required to Localize D-TACC to Centrosomes and to Regulate Astral Microtubules. J. Cell Biol. 2002, 156, 437-451.
75. Hauf, S.; Cole, R. W.; LaTerra, S.; Zimmer, C.; Schnapp, G.; Walter, R.; Heckel, A.; van Meel, J.; Rieder, C. L.; Peters, J.-M. The Small Molecule Hesperadin Reveals a Role for Aurora B in Correcting Kinetochore-microtubule Attachment and in Maintaining the Spindle Assembly Checkpoint. J. Cell Biol. 2003, 161, 281-294.
76. Sessa, F.; Mapelli, M.; Ciferri, C.; Tarricone, C.; Areces, L. B.; Schneider, T. R.; Stukenberg, P. T.; Musacchio, A. Mechanism of Aurora B Activation by INCENP and Inhibition by Hesperadin. Molecular Cell 2005, 18, 379-391.
77. Harrington, E. A.; Bebbington, D.; Moore, J.; Rasmussen, R. K. et al. VX-680, a Potent and Selective Small-molecule Inhibitor of the Aurora Kinases, Suppresses Tumor Growth in Vivo. Nat. Med. 2004, 10, 262-267.
78. Young, M. A.; Shah, N. P.; Chao, L. H.; Milanov, Z. V. et al. Structure of the Kinase Domain of an Imatinib-resistant Abl Mutant in Complex with the Aurora Kinase in Hibitor VX-680. Cancer Res. 2005, 66, 1007-1014.
79. Cheetham, G. M. T.; Charlton, P. A.; Goiec, J. M. C.; Pollard, J. R. Structure Basis for Potent Inhibition of the Aurora Linases a T315I Multi-drug Resistant Mutant form of Abl Kinase by VX-680. Cancer Lett. 2007, 251, 323-329.
80. Ditchfield, C.; Johnson, V. L.; Tighe, A.; Ellston, R.; Haworth, C.; Johnson, T.; Mortlock, A.; Keen, N.; Taylor, S. S. Aurora B Couples Chromosome Alignment with Anaphase by Targeting BubR1, Mad2, and Cenp-E to kinetochores. J. Cell Biol. 2003, 161, 267-280
81. Heron, N. M.; Anderson, M.; Blowers, D. P.; Breed, J. et al. SAR and Inhibitor Complex Structure Determination of a Novel Class of Potent and Specific Aurora Kinase Inhibitors. Bioorg. Med. Chem. Lett. 2006, 16, 1320-1323.
82. Jung, F. H.; Pasquet, G.; Brempt, C. L.; Lohmann, J. J. M.; Warin, N. et al. Discovery of Novel and Potent Thiazoloquinazolines as Selective Aurora A and B Kinase Inhibitors. J. Med. Chem. 2006, 49, 955-970.
83. Mortlock, A. A.; Foote, K. M.; Heron, N. M.; Jung, F. H.; Pasquet, G. et al. Discovery, Synthesis, and in Vivo Activity of a New Class of Pyrazoloquinazolines as Selective Inhibitors of Aurora B Kinase. J. Med. Chem. 2007, 50, 2213-2224.
84. Wilkinson, R. W.; Odedra, R.; Heaton, S. P.; Wedge, S. R.; Keen, N. J. et al. AZD1152, a Selective Inhibitor of Aurora B Kinases, Inhibits Human Tumor Xenograft Growth by Inducing Apoptosis. Clin. Cancer Res. 2007, 13, 3682-3688.
85. Fancelli, D.; Berta, D.; Bindi, S.; Cameron, A.; Cappella, P.; Carpinelli, P. et al. Potent and Selective Aurora Inhibitors Identified by the Expansion of a Novel Scaffold for Protein Kinase Inhibition. J. Med. Chem. 2005, 48, 3083-3084.
86. Fancelli, D.; Moll, J.; Varasi, M.; Bravo, R.; Artico, R.; Berta, D.; Bindi, S. et al. 1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazoles: Identification of a Potent Aurora Kinase Inhibitor with a Favorable Antitumor Kinase Inhibition Profile. J. Med. Chem. 2006, 49, 7247-7251.
87. Carpinelli, R.; Ceruti, R; Gianellini, L.; Carpinelli, P. et al. PHA-739358, a Potent Inhibitor of Aurora Kinases with a Selective Target Inhibition Profile Relevant to Cancer. Mol. Cancer Ther. 2007, 6, 3158-3168.
88. Soncini, C.; Carpinelli, P.; Gianellini, L.; Fancelli, D.; Vianello, P. et al. PHA-680632, a Novel Aurora Kinase Inhibitor with Potent Antitumoral Activity. Clin. Cancer Res. 2006, 12, 4080-4089.
89. Manfredi, M. G.; Ecsedy, J. A.; Meetze, K. A.; Balani, S. K.; Burenkova, O. et al. Antitumor Activity of MLN8054, an Orally Active Small-molecule Inhibitor of Aurora A Kinase. Proc. Natl. Acad. Sci. 2007, 104, 4106-4111.
90. Hoar, K.; Chakravarty, A.; Rabino, C.; Wysong, D.; Bownman, D.; Roy, N.; Ecsedy, J. A. MLN8054, a Small-molecule Inhibitor of Aurora A, Causes Spindle Pole and Chromosome Congression Defects Leads Leading to Aneuploidy. Mol. Cell. Biol. 2007, 27, 4513-4525.
91. Fancelli, D. Compounds and Methods for Inhibiting Mitotic Progression. Expert. Opin. Ther. Patents 2006, 16, 1179-1182.
92. Chan, F.; Sun, C.; Perumal, M.; Nguyen, Q. D.; Bavetsias, V. et al. Mechanism of Action of the Aurora Kinase Inhibitor CCT129202 and in Vivo Quantification of Biological Activity. Mol. Cancer Ther. 2007, 6, 3147-3157.
93. Warner, S. L.; Bashyam, Sridevi.; Vankayalapati, H.; Bearss, D.; Han, H.; Hoff, D. D. V.; Hurley, L. H. Identification of a Lead Small-molecule Inhibitor of the Aurora Kinases Using a Structure-assisted, Fragment-based Approach. Mol. Cancer Ther. 2006, 5, 1764-1773.
94. Oslob, J. D.; Romanowski, M. J.; Allen, D. A.; Baskaran, S.; Bui, M.; Elling, R. A. et al. Discovery of a Potent and Selective Aurora Kinase Inhibitor. Bioorg. Med.Chem. Lett. 2008, 18, 4880-4884.
95. Zhong, M.; Bui, M.; Shen, W.; Baskaran, S.; Allen, D. A.; Elling, R. A. et al. 2-Aminobenzimidazole as Potent Aurora Kinase Inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 5158-5161.
96. Howard, S.; Berdini, V.; Boulstridge, J. A.; Carr, M. G.; Cross, D. M.; Curry, J.; Devine, L. A. et al. Fragment-based Discovery of the Pyrazol-4-yl Urea (AT9283), a Multitargeted Kinase Inhibitor with Potent Aurora Kinase Activity. J. Med. Chem. 2009, 52, 379-388.
97. Gewald, K. Heterocyclen aus CH-aciden Nitrilen, IX. Über die Reaktion von α-Hydroxy-ketonen mit Malodinitril. Chemische Berichte 1966, 99, 1002-1007.
98. Temnikova, T. I.; Sharanin, Y. A. Zh. Org. Khim. 1966, 2, 2018.
99. Hassan, N. Syntheses of Furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines and Furo[2`,3`:5,6]-pyrimido[3,4-b][2,3-e]indolo[1,2,4]triazine as a New Ring System. Molecules 2000, 5, 826-834.
100. Pyo J. I.; Lee, S. H.; Cheong, C. S. A Facile Synthesis of Some Substituted Furopyrimidine Derivatives. J. Heter. Chem. 2006, 43, 1129-1133.
101. ISidor, J. L.; Brookhart, M. S.; McKee, R. L. A Novel Furan Dimer. J. Org. Chem. 1973, 38, 612-613.
102. Shishoo, C. J.; Devani, M. B.; Bhadti, V. S.; Jain, K. S.; Ananthan, S. Reaction of Nitriles under Acidic Conditions. Part VI. Synthesis of Condensed 4-Chloro- and 4-Aminopyrimidines from ortho-Aminonitriles. J. Heter. Chem. 1990, 27, 119-126.
103. Kidwai, M.; Rastogi, S.; Venkataramanan, R. A Novel Approach to Furo- pyrimidinones Using Dry Media. Bull. Chem. Soc. Jpn. 2003, 76, 203-204.
104. Aii, M. M.; Zahran, M. A.; Ammar, Y. A.; Mohamed, Y. A.; Seleim, A. T. Synthesis of Furo[2,3-d]pyrimidines and Furo[2,3-b]pyrimidines. Indian J. Heterocyclic Chem. 1995, 4, 191-194.
105. Seleim, A. T. Synthesis of Certain Furopyrimidines as Potential Antitumor Agents. Indian J. Heterocyclic Chem. 1998, 8, 147-150.
106. El Ashry E. S. H. et al. Adv. Heterocycl. Chem. 1999, 75, 79-167.
107. Dauzonne, D.; Adam-Launay, A. A Convenient Procedure for the Preparation of 5,6-Dihydro-6-nitro-5-phenylfuro[2,3-d]pyrimidin-4(3H)-ones and 5-Phenylfuro- [2,3,d]pyrimidin-4(3H)-ones. Tetrahedron 1992, 48, 3069-3080.
108. DiMauro, E. F.; Newcomb, J.; Nunes, J. J.; Bemis, J. E.; Boucher, C.; Buchanan, J. L.; Buckner, W. H.; Cheng, A.; Faust, T.; Hsieh, F.; Huang, X.; Lee, J. H.; Marshall, T. L.; Martin, M. W.; McGowan, D. C.; Schneider, S.; Turci, S. M.; White, R. D.; Zhu, X. Discovery of 4-Amino-5,6-biaryl-furo[2,3-d]pyrimidines as Inhibitors of Lck: Development of an Expedient and Divergent Synthetic Route and Preliminary SAR. Bioorg. Med. Chem. Lett. 2007, 17, 2305-2309.
109. Foloppe, N.; Fisher, L. M.; Howes, R.; Kierstan, P.; Potter, A.; Robertson, A. G. S.; Surgenor, A. E. Structure-based Design of Novel Chk1 Inhibitors: Insights into Hydrogen Bonding and Protein-ligand Affinity. J. Med. Chem. 2005, 48, 4332-4345.
110. Park, J.; Vaidyanathan, G.; Singh, B.; Gupta, R. Identification and Biochemical Studies on Novel Non-nucleoside Inhibitors of the Enzyme Adenosine Kinase. The Protein Journal 2007, 26, 203-212.
111. Andreas M. K.; Jorg W.; Guido B.; Thomas M.; Urs S.; Peter T. Furo[2,3-d]pyrimidines and Oxazolo[5,4-d]pyrimidines as Inhibitors of Receptor Tyrosine Kinases (RTK). Helv. Chim. Acta 2004, 87, 956-975.
112. Maeda, Y.; Nakano, M.; Sato, H.; Miyazaki, Y.; Schweiker, S. L.; Smith, J. L.; Truesdale, A. T. 4-Acylamino-6-arylfuro[2,3-d]pyrimidines: Potent and Selective Glycogen Synthase Kinase-3 Inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 3907-3911.
113. Miyazaki, Y.; Matsunaga, S.; Tang, J.; Maeda, Y.; Nakano, M.; Philippe, R. J.; Shibahara, M.; Liu, W.; Sato, H.; Wang, L.; Nolte, R. T. Novel 4-Amino-furo[2,3-d]pyrimidines as Tie-2 and VEGFR2 Dual Inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 2203-2207.
114. Miyazaki, Y.; Maeda, Y.; Sato, H.; Nakano, M.; Mellor, G. W. Rational Design of 4-Amino-5,6-diaryl-furo[2,3-d]pyrimidines as Potent Glycogen Synthase Kinase-3 Inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 1967-1971.
115. Guner, Osman F. Pharmacophore Perception, Development, and use in Drug Design. 2000, La Jolla, Calif: International University Line. ISBN 0963681761.
116. Wang, R.; Gao, Y.; Lai, L. LigBuilder: a Multi-Purpose Program for Structure- Based Drug Design. J. Mol. Model. 2000, 6, 498-516.
117. R. B. Merrifield Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide. J. Am. Chem. Soc. 1963, 85, 2149-2154.
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