Abstract

In order to obtain new dihydrocoptisine-type compounds with stable structure and activating XBP1 transcriptional activity, (±)-8-trifluoromethyldihydrocoptisine derivatives as target compounds were synthesized from quaternary ammonium chlorides of coptisine alkaloids as starting materials by a one-step reaction. The structures of the synthesized compounds were confirmed by ¹H-, ¹³C-, and ¹⁹F-NMR as well as HRESIMS methods. These compounds showed more significant structural stability and activating XBP1 transcription activity in vitro than dihydrocoptisine as positive control. No obvious cytotoxicity on normal cell in vitro was observed with (±)-8-trifluoromethyldihydrocoptisines. Trifluoromethylation can be used as one of the fluorine modification strategies for dihydrocoptisines to guide follow-up studies on structural modification of coptisine-type alkaloids and on anti-Ulcerative colitis drugs with coptisines.

摘要

为获得结构稳定、激活XBP1转录活性的新型二氢黄连碱类化合物，以黄连碱类季铵盐氯化物为起始原料，通过一步反应合成(±)-8-三氟甲基二氢黄连碱衍生物作为目标化合物。通过¹ H-、¹³ C- 和¹⁹ F-NMR 以及 HRESIMS 方法确认了合成化合物的结构。与作为阳性对照的二氢黄连素相比，这些化合物在体外显示出更显着的结构稳定性和激活 XBP1 转录活性。体外对正常细胞无明显细胞毒性用 (±)-8-trifluoromethyldihydrocoptisines 观察到。三氟甲基化可作为二氢黄连素的氟修饰策略之一，指导后续对黄连碱类生物碱的结构修饰和黄连碱类抗溃疡性结肠炎药物的研究。