Synthesis, Structure, and Biological Activity of des‐Side Chain Analogues of 1α,25‐Dihydroxyvitamin D₃ with Substituents at C18

Abstract

An improved synthetic route to 1α,25-dihydroxyvitamin D(3) des-side chain analogues 2 a and 2 b with substituents at C18 is reported, along with their biological activity. These analogues display significant antiproliferative effects toward MCF-7 breast cancer cells and prodifferentiation activity toward SW480-ADH colon cancer cells; they are also characterized by a greatly decreased calcemic profile. The crystal structure of the human vitamin D receptor (hVDR) complexed to one of these analogues, 20(17→18)-abeo-1α,25-dihydroxy-22-homo-21-norvitamin D(3) (2 a) reveals that the side chain introduced at position C18 adopts the same orientation in the ligand binding pocket as the side chain of 1α,25-dihydroxyvitamin D(3).

Vitamin D and Its Synthetic Analogs

“…This further emphasizes the impact of vitamin D and VDR for innate and adaptive immunity and suggests that these areas should be further explored for a commercial application …”

“…The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.9b00208. Table S1 describing all 143 publically available VDR ligand crystal structures with individual hyperlinks to the PDB and PubMed databases and citations of refs − (PDF) …”

“…Table S1 describing all 143 publically available VDR ligand crystal structures with individual hyperlinks to the PDB and PubMed databases and citations of refs − (PDF)…”

The Centennial Collection of VDR Ligands: Metabolites, Analogs, Hybrids and Non-Secosteroidal Ligands

“…Figure 20 (2010-2012) [284][285][286][287][288][289][290][291][292][293][294][295][296][297][298]. 25-Diethylphosphite-1α-hydroxy-23(24)-didehydrovitamin D 3 1131 [290] was tested for antiproliferative effects on several human and murine tumor cell lines: human squamous cell carcinoma HN12, human glioma T98G, and Kaposi sarcoma SVEC vGPCR cell lines.…”

Revealing Unknown Protein Structures Using Computational Conformational Sampling Guided by Experimental Hydrogen-Exchange Data

“…To the best of our knowledge, there is no reported structure of VDR-LBD in complex with an antagonist, i.e., a ligand that would render VDR receptive to co-repressor binding. Among the 38 crystal structures we obtained from the PDB, we chose the one with the highest Verify-3D score: 3P8X [ 46 ]. The conformations of VDR-LBD in the other crystal structures are very similar to this one: the largest C root-mean-squared deviation (RMSD) we observed was only 0.35 Å.…”