摘要/Abstract

合成了N-水杨醛腙修饰的11-氮杂青蒿素及去氧类似物. 采用紫外、荧光、核磁共振以及分子模拟等技术分析了二聚体(3R,5aS,6R,8aS,9R,12S,12aR)-11-(((E)-2-羟基-5-(4-羟基-3-((E)-(((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-三甲基-10-氧代十氢-3,12-环氧[1,2]二氧杂[4,3-i]异喹啉-11(12H)-基)亚氨基)甲基)苄基)亚苄基)氨基)-3,6,9-三甲基十氢-3,12-环氧[1,2]二氧杂[4,3-i]异喹啉-10(3H)-酮(3)的优势构像; 探索了它与血红素的作用行为; 研究了它与杯[4]咔唑的结合、识别及被增溶性能. 结果表明, 因水杨醛腙键的OH与席夫碱N原子之间的分子内氢键作用, 3呈现分子钳状的优势构像, 使其得以识别血红素. 此外, 3可被杯[4]咔唑的疏水空腔封装, 且结合作用强(结合常数K_a=2.8×10 ⁵ L?mol ^–1), 因而其水溶性得以改善, 这为今后生物活性测试奠定了基础.
关键词: 大环, 分子识别, 杯芳烃, 咔唑, 青蒿素
N-Salicylaldehyde hydrazone modified 11-azaartemisinins and their deoxy analogues were designed and synthesized. By using various techniques including UV-vis, fluorescence, NMR as well as molecular modeling, the conformations of (3R,5aS,6R,8aS,9R,12S,12aR)-11-(((E)-2-hydroxy-5-(4-hydroxy-3-((E)-(((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyl-10- oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)imino)methyl)benzyl)benzylidene)amino)-3,6,9-trimethyldecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-10(3H)-one (3) was analyzed, the binding behavior between 3 and hemin was measured, and the solubility-enhancing property of 3 by calix[4]carbazole was evaluated. The results show that the intramolecular hydrogen binding between the N atom of Schiff base in N-salicylaldehyde hydrazone bond and the OH favors the formation of tweezer-like conformation of 3, which enables it to interact with hemin in 1∶1 ratio. Moreover, the poor solubility of 3 in water could be enhanced due to its interaction with calix[4]carbazole, which pave the way for the further evaluation of the bioactivities of 3 in the future.
Key words: macrocycle, molecular recognition, carbazole, artemisinin


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