Laboratory of Drug Design and Medicinal Chemistry , Showa Pharmaceutical University , 3-3165 Higashi-Tamagawagakuen , Machida, Tokyo 194-8543 , Japan.
J Med Chem. 2018 Jul 26;61(14):6339-6349. doi: 10.1021/acs.jmedchem.8b00774. Epub 2018 Jul 11.
We designed and synthesized vitamin D analogues with an electrophile as covalent modifiers for the vitamin D receptor (VDR). Novel vitamin D analogues 1-4 have an electrophilic enone group at the side chain for conjugate addition to His301 or His393 in the VDR. All compounds showed specific VDR-binding potency and agonistic activity. Covalent bond formations of 1-4 with the ligand-binding domain (LBD) of VDR were evaluated by electrospray ionization mass spectrometry. All compounds were shown to covalently bind to the VDR-LBD, and the abundance of VDR-LBD corresponding conjugate adducts of 1-4 increased with incubation time. Enone compounds 1 and 2 showed higher reactivity than the ene-ynone 3 and dienone 4 compounds. Furthermore, we successfully obtained cocrystals of VDR-LBD with analogues 1-4. X-ray crystallographic analysis showed a covalent bond with His301 in VDR-LBD. We successfully synthesized vitamin D analogues that form a covalent bond with VDR-LBD.
我们设计并合成了具有亲电试剂的维生素 D 类似物，作为维生素 D 受体（VDR）的共价修饰物。新型维生素 D 类似物 1-4 在侧链上具有亲电烯酮基团，可与 VDR 中的 His301 或 His393 发生共轭加成。所有化合物均表现出特异性的 VDR 结合能力和激动活性。通过电喷雾电离质谱评估了化合物 1-4 与 VDR 配体结合域（LBD）的共价键形成。所有化合物均被证明与 VDR-LBD 发生共价结合，并且随着孵育时间的延长，VDR-LBD 相应的共轭加合物 1-4 的丰度增加。烯酮化合物 1 和 2 比烯-炔 3 和二烯酮 4 化合物具有更高的反应性。此外，我们成功获得了 VDR-LBD 与类似物 1-4 的共晶。X 射线晶体学分析显示 VDR-LBD 中与 His301 形成了共价键。我们成功合成了与 VDR-LBD 形成共价键的维生素 D 类似物。
