設計與合成Sorafenib類似物為多靶點酪胺酸激酶抑制劑

Design and Synthesis of Sorafenib Analogues as Multitargeted Tyrosine Kinase Inhibitors

馬多娜(Indah Primadona)

指導教授 ： 陳基旺

國立臺灣大學/醫學院/藥學研究所/碩士(2010年)

https://doi.org/10.6342/NTU.2010.10163

摘要

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。

關鍵字

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並列摘要

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.

並列關鍵字

sorafenib ； protein tyrosine kinase ； multikinase inhibitor ； Raf1 ； Flt3 ； VEGFR

參考文獻

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