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Design, Synthesis and Biological Evaluation of Hydroxyalkyl Substituted 8-Hydroxyl/Alkoxyquinolines with Multifunctional Activities against Alzheimer’s Disease
|Publication Year :||2013|
|Abstract:||本論文設計構想是以天然物小葉水蓑衣中所分離出的正二十六烷醇及具有螯合金屬離子能力而達到溶解類澱粉斑塊功能的氯碘羥喹作為先導化合物並融合二者成為8-羥基喹啉-2-烷基醇衍生物作為目標化合物。以2-胺基酚在酸性條件下進行環化合成8-羥基喹啉，並以苄基化對羥基進行保護。接著在二位連接烷基醇及移除保護基便得到目標化合物5。同時以之前實驗室化合物J2326 的研究為基礎，設計及合成一系列8-烷氧基喹啉-2-烷基醇衍生物。其生物活性測試結果證實確可減少類澱粉蛋白的聚集、誘發神經軸突生長以及促進神經細胞增生。除此之外，目標化合物對細胞無毒性以及在類澱粉蛋白所誘發神經退化的老鼠實驗中可改善其記憶。綜合以上所述，以化合物23o、23p、27i 及33i 最具有潛力並可作為未來進一步研究所需之試劑。
由於8-烷氧基喹啉-2-烷基醇衍生物溶解度普遍不佳且與鋅離子的作用力比8-羥基喹啉-2-烷基醇弱，本論文嘗試於喹啉環上2 位導入含氮原子的神經滋養功能基團替代長鏈烷基醇來改善性質。將喹啉環二位的甲基進行氧化成醛後再進行還原性胺化及可得到目標化合物。雖然其結果顯示僅有少數化合物在減少類澱粉蛋白聚集以及活化神經滋養效果與J2326 相仿，但其溶解度確實大幅改善並可提供更大的彈性以利未來的優化。總結來說，本論文開發出新穎羥烷基取代八羥基/烷氧基喹啉衍生物做為多效性神經滋養試劑的策略將來或許可應用於治療因蛋白質缺陷及堆積所造成的退化性神經疾病如阿茲海默症，帕金森氏症，杭丁頓舞蹈症及肌萎縮性側索硬化症。
8-Hydroxyquinolin-2-ylalkyl alcohol derivatives were designed by merging two leads, hexacosanol which was isolated from natural plant Hygrophilia erecta Hochr
(Acanthaceae) and clioquinol which possessed metal chelation ability to dissolve fAβ as target compounds in this dissertation. 2-Aminophenol was cyclized under acidic
condition to afford 8-hydroxyquinoline and the hydroxyl group was protected by benzylation. Subsequently, alkyl alcohol was introduced to C2 position and removal of
protecting group to obtain target compound 5. Meanwhile, on the basis of previous study of J2326, a series of 8alkoxyquinolin-2-ylalkyl alcohol derivatives were
designed and synthesized. The biological evaluation demonstrated that these compounds definitely reduce formation of Aβ aggregates, induce neurite outgrowth and
stimulate neuron proliferation. Further, target compounds are nontoxic to the cells and improve the memory of fAβ-lesioned mice with neuron degeneration. In summary,
compounds 23o, 23p, 27i and 33i are the most promising and serve as potential agents for further investigation in the future.
Since poor solubility and weaker interaction with zinc ions of 8-alkoxyquinolin-2-ylalkyl alcohol derivatives were observed in comparison with 8-hydroxyquinolin-2-ylalkyl alcohol derivatives, neurotrophic functional moieties with nitrogen atom were introduced onto C2-position of quinoline ring to replace alkyl alcohols for the purpose of improving the properties. Methyl group on C2-position of quinoline ring was oxidized to aldehyde and subsequently reductive amination to afford target compounds. Although very few compounds are comparable to J2326 in anti-fAβ and activation of neurotrophic activities, solubility was definitely improved to provide more flexibility for compound optimization in the future. In conclusion, the strategy in the development of novel hydroxyalkyl substituted 8hydroxyl/alkoxyquinolines as multifunctional neurotrophic agents might be applied to other neurodegenerative diseases treatments with aberrant proteins aggregation such as Alzheimer, Parkinson, Huntington diseases and Amyotrophic lateral sclerosis.
|Appears in Collections:||藥學系|
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