Design and synthesis of 2α-(tetrazolylethyl)-1α,25-dihydroxyvitamin D3 as a high affinity ligand for vitamin D receptor

•We synthesized 2α-heteroarylethyl active vitamin D3 for SAR study.•The 2α-[2-(tetrazol-2-yl)ethyl] group enhanced transactivation activity.•X-ray cocrystallographic analyses of two hVDR-(new ligand) complexes were performed. X-ray cocrystallographic studies of the human vitamin D receptor (hVDR)-[2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (O1C3)] complex showed that the terminal hydroxy group of the 2α-functional group of O1C3 formed a hydrogen bond with Arg274 in the ligand binding domain (LBD) of hVDR to stabilize the complex; therefore, O1C3 showed 3-times greater binding affinity for VDR than the natural hormone. Here, the effects of a heteroaromatic ring on binding to hVDR instead of the terminal OH group of O1C3 and also on preliminary biological activities were studied. We synthesized 2α-[2-(tetrazol-2-yl)ethyl]-1α,25(OH)2D3 (1a) and its regioisomer 2α-[2-(tetrazol-1-yl)ethyl]-1α,25(OH)2D3 (1b), in which 1a showed much higher hVDR binding affinity and greater osteocalcin promoter transactivation activity in human osteosarcoma (HOS) cells than those of 1b. X-ray cocrystallographic analysis of the hVDR-1a complex showed new hydrogen bond formation between one of the nitrogen atoms of the tetrazole ring and Arg274. This article is part of a Special Issue entitled ‘16th Vitamin D Workshop’.