炎症与多种疾病有关,仍然需要开发更有效和更安全的抗炎药。在这里,我们合成了,已解决,并表征了八种对映体纯的马松酮J1(1),equinoloneJ2(2),4\'-去甲氧基亚马酮J1(3),和4'-去甲氧基亚马酮J2(4)。扩展了关键的合成步骤,并在4-芳基处修饰了34个外消旋类似物,N位,并设计合成了吡喃环。所有合成的化合物均在RAW264.7细胞中评估其抗炎活性,其中13个化合物在0.1μM的浓度下显示出对一氧化氮(NO)产生的显着抑制,比消炎痛更有效。此外,化合物(-)-3,(-)-4,5h,和6g以50nM的浓度降低了LPS刺激的RAW264.7细胞中IL-6的产生。初步SAR显示3'-Br(5h),4-苯基上的4'-NO2(6g)和N-位的3-溴苄基(7f)是最有效的取代基。这是对抗炎的龙珠酮生物碱的首次报道,本研究为开发这一系列高效的衍生物用于新的抗炎药提供了证据。
Inflammation is connected with a variety of diseases and there is still a need to develop more effective and safer anti-inflammatory drugs. Herein, we synthesized, resolved, and characterized eight enantiopure isomers of yaequinolone J1 (1), yaequinolone J2 (2), 4\'-desmethoxyyaequinolone J1 (3), and 4\'-desmethoxyyaequinolone J2 (4). The key synthetic steps were extended and 34 racemic analogues modified at the 4-aryl, the N-position, and the pyran ring were designed and synthesized. All the synthesized compounds were evaluated for their anti-inflammatory activities in RAW 264.7 cells of which 13 compounds showed significant inhibition of nitric oxide (NO) production at a concentration of 0.1 μM, which was more potent than that of indomethacin. Furthermore, compounds (-)-3, (-)-4, 5h, and 6g reduced the production of IL-6 in LPS-stimulated RAW 264.7 cells at a concentration of 50 nM. A preliminary SAR indicated that 3\'-Br (5h), 4\'-NO2 (6g) on 4-phenyl and 3-bromobenzyl (7f) on the N-position were the most effective substituents. This is the first report of the anti-inflammatory yaequinolone alkaloids and the present study provided evidence for exploiting this series of highly efficacious derivatives for new anti-inflammatory agents.