Kim Jin Han, Jeong Hui Rak, Jung Da Woon, Yoon Hong Bin, Kim Sun Young, Kim Hyoung Ja, Lee Kyung-Tae, Gadotti Vinicius M, Huang Junting, Zhang Fang-Xiong, Zamponi Gerald W, Lee Jae Yeol
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea.
Molecular Recognition Research Center, Future Convergence Research Division, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
Bioorg Med Chem. 2017 Sep 1;25(17):4656-4664. doi: 10.1016/j.bmc.2017.07.010. Epub 2017 Jul 8.
As a bioisosteric strategy to overcome the poor metabolic stability of lead compound KYS05090S, a series of new fluoro-substituted 3,4-dihydroquinazoline derivatives was prepared and evaluated for T-type calcium channel (Ca3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound 8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Ca3.2 currents (>90% inhibition) at 10μM concentration and exhibited cytotoxic effect (IC=5.9μM) in A549 non-small cell lung cancer cells that was comparable to KYS05090S. Furthermore, 8h showed approximately a 2-fold increase in liver metabolic stability in rat and human species compared to KYS05090S. Based on these overall results, 8h (KCP10068F) may therefore represent a good backup compound for KYS05090S for further biological investigations as novel cytotoxic agent. In addition, compound 8g (KCP10067F) was found to partially protect from inflammatory pain via a blockade of Ca3.2 channels.
作为一种生物电子等排体策略，用于克服先导化合物KYS05090S代谢稳定性差的问题，我们制备了一系列新的氟取代3,4-二氢喹唑啉衍生物，并对其T型钙通道（Ca3.2）阻断作用、细胞毒性效应和肝微粒体稳定性进行了评估。其中，含有4-氟苄基酰胺和4-环己基苯基环的化合物8h（KCP10068F）在10μM浓度下能有效阻断Ca3.2电流（抑制率>90%），并在A549非小细胞肺癌细胞中表现出与KYS05090S相当的细胞毒性效应（IC = 5.9μM）。此外，与KYS05090S相比，8h在大鼠和人类物种中的肝代谢稳定性提高了约2倍。基于这些总体结果，8h（KCP10068F）因此可能代表A KYS05090S的良好备用化合物以供进一步作为新型细胞毒性剂进行生物学研究。此外还发现，化合物8g（KCP10067F）通过阻断Ca3.2通道可部分减轻炎性疼痛。
