synthesis, biological evaluation and mechanism studies of deoxytylophorinine and its derivatives as potential anticancer agents合成、生物评价和机制的研究deoxytylophorinine及其衍生物作为潜在的抗癌剂.pdfVIP

Synthesis, Biological Evaluation and Mechanism Studies of Deoxytylophorinine and Its Derivatives as Potential Anticancer Agents . . Haining Lv , Jinhong Ren , Shuanggang Ma, Song Xu, Jing Qu, Zhenjia Liu, Qing Zhou, Xiaoguang Chen*, Shishan Yu* State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Abstract Previous studies indicated that (+)-13a-(S)-Deoxytylophorinine (1) showed profound anti-cancer activities both in vitro and in vivo and could penetrate the blood brain barrier to distribute well in brain tissues. CNS toxicity, one of the main factors to hinder the development of phenanthroindolizidines, was not obviously found in 1. Based on its fascinating activities, thirty- four derivatives were designed, synthesized; their cytotoxic activities in vitro were tested to discover more excellent anticancer agents. Considering the distinctive mechanism of 1 and interesting SAR of deoxytylophorinine and its derivatives, the specific impacts of these compounds on cellular progress as cell signaling transduction pathways and cell cycle were proceeded with seven representative compounds. 1 as well as three most potent compounds, 9, 32, 33, and three less active compounds, 12, 16, 35, were selected to proform this study to have a relatively deep view of cancer cell growth-inhibitory characteristics. It was found that the expressions of phospho-Akt, Akt, phospho-ERK, and ERK in A549 cells were greater down-regulated by the potent compounds than by the less active compounds in the Western blot analysis. To the best of our knowledge, this is the first report describing phenanthroindolizidines alkaloids display influence