Creation of Potent Vitamin D Receptor Agonists and Antagonists with 2α-(ω-Hydroxyalkylation) Concept to the seco-Steroid Skeleton

Abstract

2?-modification on the vitamin D skeleton with a 2?-(?-hydroxyalkyl) or 2?-(?-hydroxyalkoxy) group improves vitamin D receptor (VDR) binding affinity, lengthens the half-life in target cells because of increased resistance to CYP24A1 metabolism, and enhances biological activity. The introduced terminal hydroxy group forms an additional hydrogen bond to Arg274, which is the most important amino acid residue for recognizing the ligand hormone 1?,25-dihydroxyvitamin D3 of human VDR. According to our 2?-functionalization concept, we synthesized several hundred vitamin D analogs, and some had selective potent biological activity, such as bone formation (by AH-1) or anticancer activity (by MART-10), without the side-effects of vitamin D such as hypercalcemia. A potent hVDR antagonist NS-74c and stable 14-epi-tachysterol derivatives are also described in this short review.

2α-Substituted Vitamin D Derivatives Effectively Enhance the Osteoblast Differentiation of Dedifferentiated Fat Cells

“…Modification of the side chain of vitamin D is thought to control stability by altering the mode of binding to VDR and its interaction with transcriptional cofactors and by controlling the substrate specificity of vitamin D-metabolizing enzymes, thereby exhibiting tissue and action selectivity [ 7 ]. We previously developed vitamin D derivatives modified at the 2α position to form a hydrogen bond with Arg274 of the ligand-binding domain of VDR [ 8 , 9 ]. Among them, 2α-(3-hydroxypropyl)-1,25D 3 (O1C3) and 2α-(3-hydroxypropoxy)-1,25D 3 (O2C3) ( Figure 1 ) are superior to 1,25(OH) 2 D 3 in their ability to activate VDR in vitro, to induce leukemia cell HL60 differentiation, and to raise blood calcium in rats [ 10 , 11 , 12 , 13 ].…”

“…Among them, 2α-(3-hydroxypropyl)-1,25D 3 (O1C3) and 2α-(3-hydroxypropoxy)-1,25D 3 (O2C3) ( Figure 1 ) are superior to 1,25(OH) 2 D 3 in their ability to activate VDR in vitro, to induce leukemia cell HL60 differentiation, and to raise blood calcium in rats [ 10 , 11 , 12 , 13 ]. O1C3 and O2C3 are resistant to metabolism by the vitamin D-inactivating enzymes, such as CYP24A1 and CYP3A4 [ 8 , 14 ]. The resistance of vitamin D derivatives to inactivation may prolong the biological effects in target cells.…”