Design and synthesis of active vitamin D analogs

Vitamin D receptor agonists’ anti‐inflammatory properties

“…Steroid nuclear receptors, when bound to their agonist hormone, bind to chromatin at hormone response elements to affect the expression of downstream genes and mediate chromatin remodeling, epigenetic modifications, receptor recycling, and ultimately gene expression . It is recognized that only 1α,25(OH) 2 D and VDR agonists have high affinity to bind VDRs and, when bound, heterodimerize with the retinoic acid X receptor. Afterwards, this complex binds to the vitamin D–responsive element and acts as a transcriptional factor to enhance or repress gene transcription .…”

“…In the VDR–LBD complex, the A‐ring of D hormone or its agonist adopts a β‐chair conformation with the 1‐OH and 3‐OH groups in equatorial and axial orientations, respectively . This is likely why it was shown that VDR agonists with an OH group in 1α position have the highest specificity of binding to VDR …”

“…34 This is likely why it was shown that VDR agonists with an OH group in 1␣ position have the highest specificity of binding to VDR. 19 There are several biochemically different types of VDR agonists, which are going to be described briefly, but for a detailed description the reader is referred to an informative review by Carlsberg and Molnar. 22 Most D hormone analogs (VDR agonists) carry only minor modifications compared to the natural hormone having the same secosteroidal structure and forming the same agonistic VDR conformation.…”

Seco-B-Ring Steroidal Dienynes with Aromatic D Ring: Design, Synthesis and Biological Evaluation

“…Taking the above-described facts into consideration, we have decided to broaden the structure-activity studies in this area and synthesize similar seco-B steroidal compounds 5 and 6 characterized by a presence of an aromatic D ring. It should be added that the first report on a new class of vitamin D analogs with a benzene D ring was published by Mouriño et al in 2010 [ 35 ]. However, the synthesized compound 7 slowly equilibrated into a more stable previtamin form.…”

Synthesis of A‐Ring Precursors of 1α,25‐Dihydroxyvitamin D3 Analogues Functionalized at C‐2

“…The discovery of the VDR in more than 30 tissues including skin, brain, heart, pancreas, kidney, intestine, colon, prostate, ovary, and breast led to the study of the possible use of 1,25D in the treatment of metabolic bone diseases, psoriasis, cancers and immune disorders , . The solution of the crystal structure of 1,25D in complex with VDR (LBD) opens up the possibility of rational design of 1,25D analogues and mimics as potential therapeutic agents . The availability of space around the A‐ring in the binding pocket that could be used for the introduction of different substituents has led to the design and synthesis of various biologically active 1,25D analogues functionalized at C‐2 .…”