NF-κB為一個重要的核轉錄因子，當細胞受外界刺激時，NF-κB會活化造成細胞異常增生與死亡，導致病變的發生。由於IMD-0354對於NF-κB的活性具有良好的抑制效果，故本實驗以IMD-0354為先導化合物，設計合成苯甲醯胺(Benzamide)所衍生出三種系列之衍生物，再與IMD0354的抑制活性效果進行比較，並探討結構與活性間的關係。第一系列以雙分子親核性取代反應(SN2)與DCC偶合反應合成苯甲醯胺衍生物，第二系列以Horner-Wadsworth-Emmons反應合成苯乙烯衍生物，第三系列則以兩種方法合成??衍生物，第一種為Sonogashira coupling 經環化作用反應，第二種為tandem amidation-Suzuki反應。根據實驗結果發現若使用Sonogashira coupling反應方法，當炔類起始物量過多與反應溫度過高時，會形成非預期的副產物，此副產物的結構可用來推測可能的反應機制。歸納生物活性的結果，得知IMD-0354結構上CF3的取代基，對於抑制活性具重要影響，並且推測苯醯端3號位置推拉電子基與取代基的立體障礙，對於抑制活性無確切的相對關係。主體結構中若以特定取代時，NH上氫鍵的形成為影響抑制活性效果的關鍵。 Nuclear factor (NF)-κB is an important transcription factor. When a cell is stimulated by stress, over activated NF-κB would result in unexpected proliferation or death of the cell. Several studies demonstrated that IMD-0354 was a good inhibitor for NF-κB, we therefore synthesized three series of benzamide analogs and attempted to establish their structure-activity relationship. The benzamide analogs were synthesized by nucleophilic substitution and DCC coupling reaction while the stilbene analogs were synthesized by Horner-Wadsworth-Emmons reaction. Two methods were used to synthesize indole analogs. Some analogs were synthesized by Sonogashira coupling reaction followed by cyclization, and some were synthesized by tandem amidation-Suzuki reaction. The NF-κB inhibition of benzamide analogs showed that the trifluoromethyl group of IMD-0354 was essential for inhibition. Neither electronic nor steric effects imposed upon substitutions at third position of benzoyl group affected the NF-κB inhibition. The hydrogen on amide moiety seemed to influence NF-κB inhibition, which implied that hydrogen bond between NH of amide is critical for analog binding.
