Hasegawa Futoshi, Kawamura Kazushi, Tsuchikawa Hiroshi, Murata Michio
Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
Bioorg Med Chem. 2017 Aug 15;25(16):4506-4511. doi: 10.1016/j.bmc.2017.06.042. Epub 2017 Jun 27.
We report herein the stable C-N axial chirality in a 1-phenyl-6-aminouracil scaffold owing to the presence of various functional groups at the ortho-position of the N(1)-phenyl group. Racemic 1-phenyl-6-aminouracils were first separated by chiral HPLC or converting them to the corresponding diastereomers using a chiral resolving agent. We then determined the rotational barrier of each atropisomer by a thermal racemization method and found that these compounds have rotational barriers similar to other C-N axially chiral biaryls. In addition, there was a good correlation between the rotational barriers and van der Waals radii of an ortho-substituent of the N(1)-phenyl group. To explore the possibility of the chiral 1-phenyl-6-aminouracil scaffold as a drug lead, we synthesized both atropisomers as phosphodiesterase-4 inhibitors 10. The atropisomers showed significantly different metabolic stabilities while their PDE4 inhibitory activities were somewhat similar. This finding demonstrates the potential utility of stable C-N bond atropisomers in the development of chiral drugs.
我们在此报告，由于N(1)-苯基邻位存在各种官能团，1-苯基-6-氨基尿嘧啶支架中存在稳定的C-N轴手性。外消旋1-苯基-6-氨基尿嘧啶首先通过手性高效液相色谱法分离，或使用手性拆分剂将其转化为相应的非对映异构体。然后，我们通过热消旋化方法测定了每种阻转异构体的旋转势垒，发现这些化合物的旋转势垒与其他C-N轴手性联芳基类似。此外，旋转势垒与N(1)-苯基邻位取代基的范德华半径之间存在良好的相关性。为了探索手性1-苯基-6-氨基尿嘧啶支架作为药物先导物的可能性，我们合成了两种阻转异构体作为磷酸二酯酶-4抑制剂10。这些阻转异构体表现出显著不同的代谢稳定性，而它们的PDE4抑制活性有些相似。这一发现证明了稳定的C-N键阻转异构体在开发手性药物中的潜在效用。
