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Design and Synthesis of 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine Derivatives as Mammalian Target of Rapamycin (mTOR) Inhibitors
mTOR,mammalian target of rapamycin,mTOR inhibitors,PI3K/AKT/mTOR signaling pathway,breast cancer,5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine derivatives,5,6,7,8-tetrahydro-1,6-naphthyridine derivatives,
|Publication Year :||2017|
本論文主旨為設計與合成Torin2 (12) 的類似物及四氫吡啶[4,3-d]嘧啶的衍生物作為具有潛能的mTOR蛋白質激酶抑制劑。第一部分以四氫吡啶[4,3-d]嘧啶作為核心結構。將該主結構依序透過氯化、親核性取代反應合成化合物26a-b, 46, 52，去芐基反應後與飽和及不飽和側鏈進行偶合得到化合物29a-b, 29f-h, 30a-e, 48和 54。根據酵素抑制實驗結果顯示，四氫吡啶[4,3-d]嘧啶衍生化合物26a-b, 29a, 29f-h, 30a-e和54對mTOR蛋白質激酶皆失去抑制活性，透過細胞毒性的測試發現，對於不同的癌症細胞株(A549、MCF7、K562)，化合物 29f, 29h及 54對於乳癌細胞可以達到µM的毒殺效果。第二部分選用5,6,7,8-四氫-1,6-萘啶結構作為主架構。將該主結構依序透過氯化、親核性取代反應合成化合物61，去乙醯基反應後與不飽和側鏈進行偶合得到化合物63a-b。根據酵素抑制實驗結果顯示，四氫-1,6-萘啶衍生化合物63a-b對mTOR蛋白質皆失去抑制活性。接著透過細胞毒性的測試發現，化合物63b失去對於癌細胞的毒殺效果。推測此兩系列化合物皆失去對於mTOR蛋白之抑制活性的原因為結構四號位置在空間中會有自由旋轉的可能，使得該官能基無法貼近mTOR蛋白的疏水性口袋，無法發揮作用力。
The aim of this thesis is to design and synthesize tetrahydropyrido[4,3-d]pyrimidine derivatives as potential mTOR kinase inhibitors by replacing the skeleton of pyrido[4,3-d]pyrimidine of Torin2 (12) with new the designated scaffold. In the first target compound, tetrahydropyrido[4,3-d]pyrimidine core structure with different substitutions were connected with saturated or unsaturated side chains after debenzylation, finally afforded the target compounds 29a-b, 29f-h, 30a-e, 48 and 54. Compounds 26a-b, 29a, 29f-h, 30a-e and 54 were then subjected to enzymatic assay and did not show any significant inhibitory activity against mTOR kinase at 10 M concentration. In addition, compounds 29f, 29h, 30c, 48 and 54 were also conducted antiproliferative assay against a variety of cancer cell lines. However, compounds 29f, 29h and 54 showed weak activity against breast cancer cell lines at µM range. In the second target compound, we changed the skeleton with tetrahydro-1,6-naphthyridine core structure which were then connected with unsaturated side chains after deacetylation, finally afforded the target compounds 63a-b. Compounds 63a-b did not show any activity against mTOR kinase. We conclude that the synthesized compounds lost activity against mTOR probably due to the core structures of two types of compounds too flexible. We further propose that the more rigid and plain skeleton of compounds will be better fitting into the active site of mTOR instead of the flexible one.
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