Benzamides之合成及其生物活性探討

Abstract

中文摘要 根據Jay P. Powers等人所發表三環之benzamides發現具有對HSDs具有抑制的活性,由於當免疫失調時,glucocorticoids會對多重器官組織造成負面影響,而HSDs inhibitor可以改善cortisol造成的生理代謝失控的情況,也能對於免疫系統做出適當的調整; 而Nanthan合成了一系列benzamides化合物來對運送會造成Alzheimer's 的Aβ的運送蛋白RAGE來做binding的競爭,發現化合物45具有良好活性, 參考Jay和Nathan所合成的結構,我們先設計出N-(cyclohex-2-enyl)-N-phenalkylbenzamide進行不同碳鏈長度之改變,意外發現碳鏈長度n = 1的分子N-benzyl-N-(cyclohex-2-enyl)benzamide具有優異的抗發炎反應,因此本人接續進行對benzyl group進行不同的官能基取代修飾,並改變合成路徑以及提升產率之工作。 以未取代和12種取代之benzylamine做為起始物,先後進行N-alkylation以及benzoylation ,得到終產物benzamides;抗發炎活性測試發現以ortho-位置以fluorine原子取代之化合物5活性最高,次之為無取代之化合物2具有顯著抗發炎活性,並以此二終產物進行下一階段的動物活性測試。 為了討論cyclohexene的雙鍵對分子之抗發炎活性的影響,因此合成無雙鍵之benzamides,來做抗發炎活性之測試;首先根據之前所發表之相似結構的合成方法嘗試以未取代和不同取代之12種benzylamines與cyclohxeanone進行Imination和reduction,得到中間產物後,繼以benzoylation來得到終產物;但由於總產率過低,且反應耗時過長,遂進行合成路徑之重新設計,改以直接由含雙鍵之benzamides直接進行氫化反應,將雙鍵直接還原,得到無雙鍵之benzamides,而產率由原本小1 %提升至48-99 %不等,且無伴隨副產物之生成,為此類benzamides化合物提供一個因六圓環所造成立體障礙過大而無法進行 SN2反應的替代路徑。 在抗發炎活性測試中,發現不含雙鍵之benzamides除了化合物30為呈現在雙鍵消失後, 抗發炎活性上升外, 其餘化合物都呈現活性下降的趨勢; 而benzylamine 的ortho位置依然對嗜中性白血球釋出superoxide anion的抑制活性上扮演關鍵的角色。

Abstract A patent published by Jay P. Powers and his team suggested that the benzamides comprised of three rings may have activity to inhibit HSDs. When the immune system of human body loses its balance, secreted glucocorticoids might have the deleterious impacts to organs or tissues which can be tuned by the application of HSDs inhibitors. HSDs inhibitors may recover the unleashed status of physical metabolism caused by cortisol, and mediate an appropriate adjustment among the immune system. A series of benzamides designed by Nathan may compete the binding between the RAGE protein and Aβ which contribute to the occur of Alzheimer's. And they found the compound 45 would have the best activity to impede the binding of RAGE to Aβ among the compounds they synthesized. On the basis of the structures created by Jay and Nathan, the different number of carbons of N-benzyl group in N-(cyclohex-2-enyl)-N-phenalkylbenzamide suggested by our lab showed the one with n = 1 might have the excellent activity against inflammation surprisingly. Herein I continued to have the discussion of the modification on the benzyl group, and discover new pathway to elevate the yield. The scheme started from 13 kinds of benzylamines underwent N-alkylation and benzoylation in succession to generated final compounds. The compound 5 with o-F in its benzyl group has the most potent activity in anti-inflammation assay, the second one with the best potency would be compound 2. As the result, compound 2 and compound 5 exhibited the most potent activity in anti-inflammmatory assay. Both compounds were sent for further In vivo animal study. In order to investigate the influence of the double bond in cyclohex-2-enyl group on anti-inflammatory activities, a series of compounds without double bond have been synthesized. According to methods claimed by the previous papers with similar structure to construct, we synthesized 13 kinds of benzylamines to undergo imination and reduction with cyclohexanone to obtain intermediates, then followed by the benzoylation to funished final products. However the devastating demerit of the scheme as we mentioned was time-consuming and quite low yield. Thus we re-designed the scheme by directly hydrogenation of the double bond to synthesize the final compounds. The new pathway we offered without side products elevated the yield from less than one percntage to more than forty-eight to ninty-nine percentage, which indicated the new pathway for synthesizing the compounds with similar structures that might have too large steric hindrance to proceed the SN2 reaction. In the anti-inflammatory assay, benzamides without double bond showed the tendency of decline of anti-inflammatory activity except compound 30. The ortho-position of the benzylamine still play an important role in the inhibition of release of superoxide anion from neutrophils.