Design, Synthesis, Evaluation, and Structure of Vitamin D Analogues with Furan Side Chains

Abstract

Based on the crystal structures of human vitamin D receptor (hVDR) bound to 1α,25-dihydroxy-vitamin D(3) (1,25 D) and superagonist ligands, we previously designed new superagonist ligands with a tetrahydrofuran ring at the side chain that optimize the aliphatic side-chain conformation through an entropy benefit. Following a similar strategy, four novel vitamin D analogues with aromatic furan side chains (3a, 3b, 4a, 4b) have now been developed. The triene system has been constructed by an efficient stereoselective intramolecular cyclization of an enol triflate (A-ring precursor) followed by a Suzuki-Miyaura coupling of the resulting intermediate with an alkenyl boronic ester (CD-side chain, upper fragment). The furan side chains have been constructed by gold chemistry. These analogues exhibit significant pro-differentiation effects and transactivation potency. The crystal structure of 3a in a complex with the ligand-binding domain of hVDR revealed that the side-chain furanic ring adopts two conformations.

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)…”

Synthesis and Biological Evaluation of 1α,25-Dihydroxyvitamin D3Analogues with a Long Side Chain at C12 and Short C17 Side Chains

“…It is worth noting that this theoretical hydrogen bonding pattern of analogue 5b is similar to that observed in the crystallographic structures of Gemini and the superagonist Gemini72 analogues, in complex with a wild-type zebrafish VDR(LBD). We have previously found that 1,25D analogues that bind significantly in silico are also biologically active . The promising docking results for 5a – c accordingly encouraged us to pursue their synthesis to further study the structure–activity relationships of vitamin D analogues.…”

“…We recently designed and synthesized new active analogues of 1α,25-(OH) 2 D 3 on the basis of simulation studies of their docking in the human VDR(LBD) . In silico, all these new analogues bind significantly to the Moras VDR(LBD) .…”