Recent Results on A-Ring Modification of 1α,25-Dihydroxyvitamin D3: Design and Synthesis of VDR-Agonists and Antagonists with High Biological Activity

Abstract

The structure-activity relationships of 1alpha,25-dihydroxyvitamin D3 on simultaneous modification at both C2alpha and CD-ring side chain, including 20-epimerization, double side chain (gemini), and vitamin D receptor (VDR) antagonists TEI-9647 and TEI-9648 lactone rings, and also on simultaneous modifications at both C2 and C10 positions, i.e., C2 modified active 19-norvitamin D3, have been studied in our laboratory to find new seeds of B-seco-steroidal medicine for treating bone diseases, psoriasis, secondary hyperparathyroidism, and certain kinds of cancers. We developed an efficient and systematic route to the 2alpha-substituted 1alpha,25-dihydroxyvitamin D3 analogs, i.e., VDR-agonists (20-epi-2-4, double side chain 13a-c, 19-nor 15a-c) and antagonists (36a-c, 37a-c). The A-ring precursors (11a-o) for these analogs were synthesized from D-glucose as a chiral template. In the 19-nor series, we used radical coupling reaction for preparing the A-ring parts from (-)-quinic acid, and the resulting 2-substituted A-ring moiety was coupled with 25-hydroxy Grundmann's ketone utilizing Julia olefination to connect between the C5 and C6 positions. We also synthesized the highly potent VDR-antagonists by introducing the 2alpha-functional group to the TEI-9647 and TEI-9648 skeletons.

Novel Vitamin D Analogs for Prostate Cancer Therapy

“…For example, a substitution with 2 α -methyl, 2 α -(3-hydroxypropyl), or 2 α -(3-hydroxypropoxy) group increased its binding affinity for the VDR two- to fourfold compared to 1 α ,25(OH) 2 D 3 [43–45]. Similarly, several highly potent VDR antagonists, which belong to a series of TEI-9647 analogs with C2 α functionalization as well as the 24-alkyl modification on the lactone ring, have been synthesized [46].…”

Synthesis of 2β-substituted-14-epi-previtamin D3 and testing of its genomic activity

“…Small excess amounts of the A-ring fragment worked well and we obtained the coupled products 14a-c in moderate yields. At this point, isomerization to the previtamin D form was seldom observed, probably because TBS groups at the A-ring should have steric hindrance to prevent from reaching the transition state for the [1,7]-sigmatropic hydrogen shift between the vitamin D form and the previtamin D form. Then, all silyl groups in 14a-c were removed in one step with excess TBAF, and most of the deprotected compounds remained in the vitamin D form (14-epi-1a-c), and small amounts of the previtamin D form (14-epi-pre-1a-c) were produced under these reaction conditions.…”

“…It is well established that vitamin D 3 is present in thermal equilibrium with previtamin D 3 via [1,7]-sigmatropic rearrangement. In this equilibrium, the vitamin D form (A) with the 6-s-trans triene structure is more stable and dominant than the 6-cis isomer of the previtamin D form (B) (Scheme 1).…”

“…Previously, we found that 2␣-alkyl and 2␣-(-hydroxyalkyl) substitution afforded great enhancements for VDR binding affinity and the subsequent genomic actions [7]. In the preceding paper, we reported the synthesis and biological evaluations of 2␣-substituted 14-epi-pre-1 [8].…”

MART-10 represses cholangiocarcinoma cell growth and high vitamin D receptor expression indicates better prognosis for cholangiocarcinoma

“…Since 1α,25(OH) 2 D 3 exerts its genomic functions through binding with vitamin D receptor (VDR) and 24-OHase (CYP24A1) is responsible for the degradation of 1α,25(OH) 2 D, the fact that MART-10 has higher VDR binding affinity42 and better resistance to CYP24A1-mediated degradation4344 leads to the expectable higher VDR transactivation effect of MART-10 than 1α,25(OH) 2 D 3 .…”