請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22289
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳基旺(Ji-Wang Chern) | |
dc.contributor.author | Indah Primadona | en |
dc.contributor.author | 馬多娜 | zh_TW |
dc.date.accessioned | 2021-06-08T04:14:58Z | - |
dc.date.copyright | 2010-09-13 | |
dc.date.issued | 2010 | |
dc.date.submitted | 2010-08-10 | |
dc.identifier.citation | 1. Information retrieved from the internet homepages of the International Agency for Research on Cancer, World Health Organization (http://globocan.iarc.fr/).
2. Wilhelm, S.; Carter, C.; Lynch, M.; Lowinger, T.; Dumas, J.; Smith, R. A.; Schwartz, B.; Simantov, R.; Kelley, S. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat. Rev. Drug Discov. 2006, 5, 835-844. 3. Morphy, R. Selectively nonselective kinase inhibitions: Striking the right balance. J. Med. Chem. 2010, 53, 1413-1437. 4. Krause, D. S.; Van Etten, R. A. Tyrosine kinases as targets for cancer therapy. N. Engl. J. Med. 2005, 353, 172-187. 5. McKay, M. M.; Morrison, D. K. Integrating signal from RTKs to ERK/MAPK. Oncogene 2007, 26, 3113-3121. 6. Yancopoulos, G. D.; Davis, S.; Gale, N. W.; Rudge, J. S.; Wiegand, S. J.; Holash, J. Vascular-specific growth factors and blood vessel formation. Nature 2000, 407, 242-248. 7. Biladeau, M. T.; Fraley, M. E.; Hartman, G. D. Kinase insert domain-containing receptor kinase inhibitors as antiangiogenic agents. Expert Opin. Invest. Drugs 2002, 11, 737-745. 8. Board, R.; Jayson, G. C. Platelt-Derived Growth Factor Receptor (PDGFR): A target for anticancer therapeutics. Drug Resist.Updates 2005, 8, 75-83. 9. Ji, Z.; Ahmed, A. A.; Albert, D. H.; Bouska, J. J.; Bousquet, P. F.; Cunha, G. A.; Diaz, G.; Glaser, K. B.; Guo, J.; Harris, C. M.; Li, J.; Marcotte, P. A.; Moskey, M. D.; Oie, T.; Pease, L.; Soni, N. B.; Stewart, K. D.; Davidsen, S. K.; Michaelides, M. R. 3-Amino-benzo[d]isoxazoles as novel multitargeted inhibitors of receptor tyrosine kinases. J. Med. Chem. 2008, 51, 1231-1241. 10. Dhillon, A. S.; Hagan, S.; Rath, O.; Kolch, W. MAP kinase signaling pathways in cancer. Oncogene 2007, 26, 3279-3290. 11. Chang, F.; Steelman, L. S.; Lee, J. T.; Shelton, J. G.; Navolanic, P. M.; Blalock, P. L.; Franklin, R. A.; McCubrey, R.A. Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia 2003, 17, 1263-1293. 12. Zhang, Y.; Dong, C. Regulatory mechanisms of mitogen-activated kinase signaling. Cell. Mol. Life Sci. 2007, 64, 2771-2789. 13. Frey, R. R.; Curtin, M. L.; Albert, D. H.; Glaser, K. B.; Pease, L. J.; Soni, N. B.; Bouska, J. J.; Reuter, D.; Stewart, K. D.; Marcotte, P.; Bukofzer, G.; Li, J.; Davidsen, S. K.; Michaelides, M. R. 7-Aminopyrazolo[1,5-a]pyrimidines as potent multitargeted receptor tyrosine kinase inhibitors. J. Med. Chem. 2008, 51, 3777-3787. 14. Mandel, D. B.; Laird, A. D.; Xin, X.; Louie, S. G.; Christensen, J. G.; Li, G.; Schreck, R. E.; Abrams, T. J.; Ngai, T. J.; Lee, L. B.; Murray, L. J.; Carver, J.; Chan, E.; Moss, K. G.; Haznedar, J. O.; Sukbuntherng, J.; Blake, R. A.; Sun, L.; Tang, C.; Miller, T.; Shirazian, S.; McMahon, G.; Cherrington, J. M. In vivo antitumor activity of SU11248, A novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a phamarcokinetic/pharmacodynamic relationship. Clin. Cancer Res. 2003, 9, 327–337. 15. Wilhelm, S. M.; Carter, C.; Tang, L.; Wilkie, D.; McNabola, A.; Rong, H.; Chen, C.; Zhang, X.; Vincent, P.; McHugh, M.; Cao, Y.; Shujath, J.; Gawlak, S.; Eveleigh, D.; Rowley, B.; Liu, L.; Adnane, L.; Lynch, M.; Auclair, D.; Taylor, I.; Gedrich, R.; Voznesensky, A.; Riedl, B.; Post, L. E.; Bollag, G.; Trail, P. A. 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. Cancer Res. 2004, 64, 7099–7109. 16. Albert, D. H.; Tapang, P.; Magoc, T. J.; Pease, L. J.; Reuter, D. R.; Wei, R.-Q.; Li, J.; Guo, J.; Bousquet, P. F.; Ghoreishi-Haack, N. S.; Wang, B.; Bukofzer, G. T.; Wang, Y.-C.; Stavropoulos, J. A.; Hartandi, K.; Niquette, A. L.; Soni, N.; Johnson, E. F.; McCall, J. O.; Bouska, J. J.; Luo, Y.; Donawho, C. K.; Dai, Y.; Marcotte, P. A.; Glaser, K. B.; Michaelides, M. R.; Davidsen, S. K. Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol. Cancer Ther. 2006, 5, 995–1006. 17. George, D. J. Phase 2 studies of sunitinib and AG013736 in patients with cytokine-refractory renal cell carcinoma. Clin. Cancer Res. 2007, 13, 753s–757s. 18. Heath, V. L.; Bicknell, R. Anticancer strategies involving the vasculature. Nat. Rev. Clin. Oncol. 2009, 6, 395-404. 19. Liu, L.; Cao, Y.; Chen, C.; Zhang, X.; McNabola, A.; Wilkie, D.; Wilhelm, S.; Lynch, M.; Carter, C. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006, 66, 11851-11858. 20. Zielinska, A.; Skulski, L. Eco-friendly oxidative iodination of various arenas with sodium percarbonate as the oxidant. Molecules 2005, 10, 1307-1317. 21. Takezawa, K.; Okamoto, I.; Yonesaka, K.; Hatashita, E.; Yamada, Y.; Fukuoka, M.; Nakagawa, K. Sorafenib inhibits non–small cell lung cancer cell growth by targeting B-RAF in KRAS wild-type cells and C-RAF in KRAS mutant cells. Cancer Res. 2009, 69, 6515-6521. 22. Ramurthy, S.; Subramanian, S.; Aikawa, M.; Amiri, P.; Costales, A.; Dove, J.; Fong, S.; Jansen, J. M.; Levine, B.; Ma, S.; McBride, C. M.; Michaelian, J.; Pick, T.; Poon, D. J.; Girish, S.; Shafer, C. M.; Stuart, D.; Sung, L.; Renhowe, P. A. Design and synthesis of orally bioavailable benzimidazoles as Raf kinase inhibitors. J. Med. Chem. 2008, 51, 7049-7052. 23. Anchori, R. K.; Kortenhorst, M. S.; Hidalgo, M.; Sarkar, S.; Hallur, G.; Bai, R.; Van Diest, P. J.; Hamel E.; Khan, S. R. Novel microtubule-interacting phenoxy pyridine and phenyl sulfanyl pyridine analogues for cancer therapy. J. Med. Chem. 2008, 51, 5953-5957. 24. Duvaz, D. N.; Gaulon, C.; Dijkstra, H. P.; Duvaz, I. N.; Zambon, A.; Me’nard, D.; Suijkerbuijk, B. M. J. M.; Nourry, A.; Davies, L.; Manne, H. A.; Friedlos, F.; Ogilvie, L.; Hedley, D.; Whittaker, S.; Kirk, R.; Gill, A.; Taylor, R. D.; Raynaud, F. I.; Farre, J. M.; Marais, R.; Springer, C. J. Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF). J. Med. Chem. 2009, 52, 2255-2264. 25. Me’nard, D.; Duvaz, I. N.; Dijkstra, H. P.; Duvaz, D. N.; Suijkerbuijk, B. M. J. M.; Zambon, A.; Nourry, A.; Roman, E.; Davies, L.; Manne, H. A.; Friedlos, F.; Kirk, R.; Whittaker, S.; Adrian, G.; Taylor, R. D.; Marais, R.; Springer, C. J. Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring. J. Med. Chem. 2009, 52, 3881-3891. 26. Nourry, A.; Zambon, A.; Davies, L.; Duvaz, I. N.; Dijkstra, H. P.; Menard, D.; Gaulon, C.; Duvaz, D. N.; Suijkerbuijk, B. M. J. M.; Friedlos, F.; Manne, H. A.; Kirk, R.; Whittaker, S.; Marais, R.; Springer, C. J. BRAF inhibitors based on an Imidazo [4,5]pyridin-2-one scaffold and a meta substituted middle ring. J. Med. Chem. 2010, 53, 1964-1978. 27. Chao, Q.; Sprankle, K. G.; Grotzfeld, R. M.; Lai, A. G.; Carter, T. A.; Velasco, A. M.; Gunawardane, R. N.; Cramer, M. D.; Gardner, M. F.; James, J.; Zarrinkar, P. P.; Patel, H. K.; Bhagwat, S. S. Identification of N-(5-tert-Butyl-isoxazol-3-yl)-N0-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo- [2,1-b][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-Like tyrosine kinase-3 (FLT3) inhibitor. J. Med. Chem. 2009, 52, 7808-7816. 28. Wan, P. T.; Garnett, M. J.; Roe, S. M.; Lee, S.; Niculescu-Duvaz, D.; Good, V. M.; Jones, C. M.; Marshall, C. J.; Springer, C. J.; Barford, D.; Marais, R. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 2004, 116, 855–867. 29. Adimurthy, S.; Ramachandraiah, G.; Ghosh, P. K.; Bedekar, A. V. A new environment friendly protocol for iodination of electron-rich aromatic compounds. Tetrahedron Lett. 2003, 44, 5099-5101. 30. Kunz, K. R.; Iyengar, B. S.; Dorr, R. T.; Alberts, D. S.; Remers, W. A. Structure-Activity relationship for mitomycin C and mitomycin A analogues. J. Med. Chem. 1991, 34, 2281-2286. 31. Beer, H. F.; Haeberli, M.; Ametamey, S.; Schubiger, P. A. Comparison of two synthetic methods to obtain [18F] N-(2-aminoethyl)-5-fluoropyridine-2-carboxamide, a potential MAO-B imaging tracer for PET. J. Lab. Compd. Radiopharm. 1995, 36, 934-945. 32. Sammakia, T.; Stangeland, E. L.; Whitcomb, M. C. Total synthesis of caerulomycin C via the halogen dance reaction. Org. Lett. 2002, 4, 2385-2388. 33. Yue, S. W.; Li, J. J. A concise synthesis of all four possible benzo[4,5]furopyridines via palladium-mediated reactions. Org. Lett. 2002, 4, 2201-2203. 34. Zhang, Y. M.; Razler, T.; Jackson, P. F. Synthesis of pyrimido[4,5-b]indoles and benzo[4,5]furo[2,3-d]pyrimidines via palladium-catalyzed intramolecular arylation. Tetrahedron Lett. 2002, 43, 8235-8239. 35. Kiran, Y. B.; Konakahara, T.; Sakai, N. A green reagent for the iodination of phenols. Synthesis 2008, 15, 2327-2332. 36. Talekar, S. R. Design, synthesis and biological evaluation of quinoline analogues. Doctoral Dissertation National Taiwan University 2006. 37. Oberhauser, T. A new bromination method for phenols and anisols: NBS/HBF4.Et2O in CH3CN. J. Org. Chenm. 1997, 62, 4504-4506. 38. Lulinski, P.; Skulski, L. Iodination of both deactivated and activated arenas with sodium periodate or sodium iodate as the oxidants. Bull. Chem. Soc. Jpn. 2000, 73, 951-956. 39. Bankston, D.; Dumas, J.; Natero, R.; Riedl, B.; Monahan, M. K.; Sibley, R. A scaleable synthesis of BAY 43-9006: A potent Raf kinase inhibitor for the treatment of cancer. Org. Proc. Res. Develop. 2002, 6, 777-781. 40. Le, V. D.; Wong, C. H. Synthesis of 2-substituted polyhydroxytetrahydropyrimidines (N-Hydroxy Cyclic Guanidino-Sugars): Transition-state mimics of enzymatic glycosidic cleavage. J. Org. Chem. 2000, 65, 2399-2409. 41. Webb, R. L.; Labaw, C. S. Diphenyl cyanocarbonimidate. A versatile synthon for the construction of heterocyclic systems. J. Heterocyclic Chem. 1982, 19, 1205-1206. 42. Tagmose, T. M.; Schou, S. C.; Mogensen, J. P.; Nielsen, F. E.; Arkhammar, P. O. G.; Wahl, P.; Hansen, B. S.; Worsaae, A.; Boonen, H. C. M.; Antoine, M. H.; Lebrun, P.; Hansen, J. B. Arylcyanoguanidines as activators of Kir6.2/SUR1KATP channels and inhibitors of insulin release. J. Med. Chem. 2004, 47, 3202-3211. 43. Atwal, K. S.; Ferrara, F. N.; Ahmed, S. Z. Trimethylaluminum promoted synthesis of cyanoguanidines. Tetrahedron Lett. 1994, 35, 8085-8088. 44. Butera, J. A.; Antane, M. M.; Antane, S. A.; Argentieri, T. M.; Freeden, C.; Graceffa, R. F.; Hirth, B. H.; Jenkins, D.; Lennox, J. R.; Matelan, E.; Norton, N. W.; Quagliato, D.; Sheldon, J. H.; Spinelli, W.; Warga, D.; Wojdan, A.; Woods, M. Design and SAR of novel potassium channel openers targeted for urge urinary incontinence. 1. N-cyanoguanidine bioisosteres possessing in vivo bladder selectivity. J. Med. Chem. 2000, 43, 1187-1202. 45. Ducry, L.; Reinelt, S.; Seiler, P.; Diederich, F.; Bolin, D. R.; Campbell, R. M.; Olson, G. L. Synthesis of 1,2,5-thiadiazolidin-3-one 1,1-dioxide derivatives and evaluation of their affinity for MHC class-II proteins. Helv. Chim. Acta 1999, 82, 2432-2447. 46. Dale, E.; Jagarlapudi, A. R. P.; Duvvuri; Sucha; Francine. Modulators of multiple kinases. WO 2008/042867 A2. 47. Heiskanen, J. P.; Omar, W. A. E.; Ylikunnari, M. K.; Haavisto, K. M.; Juan, M. J.; Hormi, O. E. O. Synthesis of 4-Alkoxy-8-hydroxyquinolines. J. Org. Chem. 2007, 72, 920-922. 48. Omar, W. A. E.; Heiskanen, J. P.; Hormi, O. E. O. Synthesis of 8-hydoxyquinolines with amino and thioalkyl funtionalities at position 4. J. Heterocyclic Chem. 2008, 45, 593-595. 49. Chankeshwara, S. V.; Chakraborti, A. K. Catalyst-free chemoselective N-tert-butyloxycarbonylation of amines in water. Org. Lett. 2006, 8, 3259-3262. 50. Shimizu, T.; Fujiwara, Y.; Osawa, T.; Sakai, T.; Kubo, K.; Nishitoba, T.; Kimura, K.; Senga, T.; Murooka, H.; Iwai, A.; Fukushima, K.; Yoshino, T.; Miwa, A. Orally active anti-proliferation agents: novel diphenylamine derivatives as FGF-R2 autophosphorylation inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 875-879. 51. Ramadas, K.; Srinivasan, N. Iron-ammonium chloride – A convenient and inexpensive reductant. Synth. Commn. 1992, 22, 3189-3195. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22289 | - |
dc.description.abstract | 蕾莎瓦(Sorafenib)作為多種激酶的抑制劑(multikinase inhibitors),可以抑制Raf 激酶及多種酪胺酸激酶接受體,包含VEGFR、PDGFR、Flt3、Ret及c-Kit。蕾莎瓦目前在臨床上用於晚期腎細胞癌及肝癌之治療。為了改善其物化性質及發展新型具抗癌潛力的藥物,我們運用了構形限制、生物等配物及電腦模擬等三種理論方法,設計了一些蕾莎瓦的衍生物。
經由取代反應,一系列的尿素官能基生物等配物例如:氮羥基胍、氮甲氧基胍、氮苯氧基胍、氮氰基胍、二胺硝乙基、磺酰胺取代基可以接到蕾莎瓦上,而產生化合物37、38、39、54、56、58。這些化合物經由細胞毒性及酵素抑制活性測試,其中最具生物活性的為化合物56,其具有對Raf 1(IC50 27 nM)及 Flt3 (IC50 227 nM)的抑制活性。而喹啉衍生物 (17) 根據電腦模擬設計而來,在1 μM對於Flt3在48%的抑制效果,但對於Raf1卻只有26%的抑制效果。在C環上也合成了一系列的氮羥基胍衍生物,其生物活性結果顯示了第三位置的疏水性取代基對於Raf1的抑制活性是必需的,所以化合物45在1 μM對於Raf1有45%的抑制效果。 | zh_TW |
dc.description.abstract | Sorafenib is a multikinase inhibitor with activity against Raf kinase and several receptor tyrosine kinases, including VEGFR, PDGFR, Flt3, Ret, and c-Kit. This drug is currently used in clinic for the treatment of advance renal cell carcinoma and hepatocellular carcinoma. In order to improve physicochemical properties of sorafenib and to develop a novel potent anticancer agent, we proposed to design several sorafenib analogues by using three different rational approaches, including conformational restriction, bioisosterism, and computer modeling.
A series of urea bioisosteres, such as N-hydroxyguanidine, N-methoxyguanidine, N-benzoxyguanidine, N-cyanoguanidine, diaminonitroethylene, and sulfamide, were introduced on sorafenib through substitution reactions to provide compound 37, 38, 39, 54, 56, and 58. Those were then evaluated for cellular cytotoxicity and enzymatic kinase activity (Raf1, Flt3, VEGFR). The most active compound in this series, 4-{4-[1-(4-chloro-3-trifluoromethyl-phenylamino)-2-nitro-vinylamino]-phenoxy}-pyridine-2-carboxylic acid methylamide (56), showed an excellent inhibitory activity against Raf1 (IC50 27 nM) and Flt3 (IC50 227 nM). A quinoline derivative (17), derived from docking model study on Raf1 active site, demonstrated less activity against Raf1 (26% inhibition) but moderate activity against Flt3 (48% inhibition) at 1 μM. Different substituents on ring C of N-hydroxyguanidine derivative were synthesized. The result indicates that presence of hydrophobic group at 3-position is necessary for inhibitory activity against Raf1, it was presented by compound 45 which inhibit 45% Raf1 activity at 1 μM. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T04:14:58Z (GMT). No. of bitstreams: 1 ntu-99-R97423025-1.pdf: 2519690 bytes, checksum: 53a98b81664e5ea64055e48fcdeb0f93 (MD5) Previous issue date: 2010 | en |
dc.description.tableofcontents | Acknowledgements i
中文摘要 ii Abstract iii Table of Contents iv List of Schemes v List of Tables vi List of Figures vii List of Abbreviation viii 1. Introduction 1 1.1 Receptor tyrosine kinases and the Ras/Raf/MEK/ERK signaling pathway 2 1.2 Multitargeted kinase inhibitors 4 1.3 Review of sorafenib analogues 6 2. Rationale design of sorafenib analogues 10 3. Result and discussion 13 3.1 Synthesis of target compounds 13 3.1.1 Sorafenib analogue by using conformational restriction strategy 13 3.1.2 Sorafenib analogues by using urea bioisosteres 19 3.1.3 Sorafenib analogue by using quinoline scaffold 27 3.2 Biological evaluation 31 3.2.1 In vitro cytotoxicity studies 32 3.2.2 Kinases inhibition activities study 34 4. Summary 35 5. Experimental section 36 6. References 63 7. Appendix I | |
dc.language.iso | en | |
dc.title | 設計與合成Sorafenib類似物為多靶點酪胺酸激酶抑制劑 | zh_TW |
dc.title | Design and Synthesis of Sorafenib Analogues as Multitargeted Tyrosine Kinase Inhibitors | en |
dc.type | Thesis | |
dc.date.schoolyear | 98-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 王光昭(Kwang-Chao Wang),忻凌偉(Ling-Wei Hsin),陳香惠(Grace Shiahuy Chen),顧記華(Jih-Hwa Guh),孔繁璐(Fan-Lu Kung) | |
dc.subject.keyword | sorafenib,protein tyrosine kinase,multikinase inhibitor,Raf1,Flt3,VEGFR, | en |
dc.relation.page | 69 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2010-08-10 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-99-1.pdf 目前未授權公開取用 | 2.46 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。