Yun Jisu, Jeong Dayeon, Xie Zhong, Lee Sol, Kim Jiho, Surmeier D James, Silverman Richard B, Kang Soosung
College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States.
ACS Omega. 2022 Apr 12;7(16):14252-14263. doi: 10.1021/acsomega.2c00889. eCollection 2022 Apr 26.
Cyclic α-aryl β-dicarbonyl derivatives are important scaffolds in medicinal chemistry. Palladium-catalyzed coupling reactions of haloarenes were conducted with diverse five- to seven-membered cyclic β-dicarbonyl derivatives including barbiturate, pyrazolidine-3,5-dione, and 1,4-diazepane-5,7-dione. The coupling reactions of various para- or meta-substituted aryl halides occurred efficiently when Pd(-BuP), Xphos, and CsCO were used under 1,4-dioxane reflux conditions. Although the couplings of ortho-substituted aryl halides with pyrazolidine-3,5-dione and 1,4-diazepane-5,7-dione were moderate, the coupling with barbiturate was limited. Using the optimized reaction conditions, we synthesized several 5-aryl barbiturates as new scaffolds of Ca1.3 Ca channel inhibitors. Among the synthesized molecules, was the most potent Ca1.3 inhibitor with an IC of 1.42 μM.
环状α-芳基β-二羰基衍生物是药物化学中的重要骨架。卤代芳烃的钯催化偶联反应是与多种五元至七元环状β-二羰基衍生物进行的，包括巴比妥酸酯、吡唑烷-3,5-二酮和1,4-二氮杂环庚烷-5,7-二酮。当在1,4-二氧六环回流条件下使用Pd(-BuP)、Xphos和CsCO时，各种对位或间位取代的芳基卤化物的偶联反应有效地发生。尽管邻位取代的芳基卤化物与吡唑烷-3,5-二酮和1,4-二氮杂环庚烷-5,7-二酮的偶联反应中等，但与巴比妥酸酯的偶联反应有限。使用优化的反应条件，我们合成了几种5-芳基巴比妥酸酯作为Ca1.3钙通道抑制剂的新骨架。在合成的分子中， 是最有效的Ca1.3抑制剂，IC为1.42μM。
