Non-steroidal analogs of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] represent a most particular class of analogs because they are either not directly derived from the core 1,25(OH)2D3-structure or they have modifications in the core structure that are so drastic that the steroidal structure is lost. Non-steroidal CD-ring analogs of 1,25(OH)2D3 have been developed to study the role of the central rigid CD-ring system in the biological activity of 1,25(OH)2D3. Here we review the different classes of CD-ring analogs and highlight some representative analogs such as the fluorinated D-ring analogs CD578, WU515 and WY1113 which show markedly increased differentiating activity on human SW480-ADH colon cancer cells, characterized by a stronger induction of the invasion suppressor E-cadherin and a stronger repression of the beta-catenin/TCF target oncogene c-Myc. Correspondingly, CD578, WU515 and WY1113 are more potent inhibitors of beta-catenin/TCF signaling than 1,25(OH)2D3 and induce stronger VDR-coactivator interactions. Underlying the increased biological potency of analog CD578 are additional contacts between the side chain fluorine atoms of the analog with specific residues of helix 12 (H12) of the Vitamin D Receptor (VDR) and subsequent stronger VDR-coactivator interactions.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.jsbmb.2010.01.010 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Efficient Stereo-Selective Fluorination on Vitamin D Side-Chain Using Electrophilic Fluorination.
Biomolecules
December 2023
Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
Our research regarding side-chain fluorinated vitamin D analogues has explored a series of efficient fluorination methods. In this study, a new electrophilic stereo-selective fluorination methodology at C24 and C22 positions of the vitamin D side-chain was developed using -fluorobenzenesulfonimide (NFSI) and CD-ring imides with an Evans chiral auxiliary (,,).
View Article and Find Full Text PDFSynthesis of (22)-, (22)-22-Fluoro-, and 22,22-Difluoro-25-hydroxyvitamin D and Effects of Side-Chain Fluorination on Biological Activity and CYP24A1-Dependent Metabolism.
J Org Chem
September 2023
Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
Three novel analogues of C22-fluoro-25-hydroxyvitamin D (-) were synthesized and evaluated to investigate the effects of side-chain fluorination on biological activity and metabolism of vitamin D. These novel analogues were constructed by convergent synthesis applying the Wittig-Horner coupling reaction between CD-ring ketones (,,) and A-ring phosphine oxide (). The introduction of C22-fluoro units was achieved by stereoselective deoxy-fluorination for synthesizing and or two-step cationic fluorination for .
View Article and Find Full Text PDFSynthesis of New 26,27-Difluoro- and 26,26,27,27-Tetrafluoro-25-hydroxyvitamin D: Effects of Terminal Fluorine Atoms on Biological Activity and Half-life.
Chem Pharm Bull (Tokyo)
September 2023
Faculty of Pharmaceutical Sciences, Teikyo University.
As an extension of our research on providing a chemical library of side-chain fluorinated vitamin D analogues, we newly designed and synthesized 26,27-difluoro-25-hydroxyvitamin D (1) and 26,26,27,27-tetrafluoro-25-hydroxyvitamin D (2) using a convergent method applying the Wittig-Horner coupling reaction between CD-ring ketones (13, 14) and A-ring phosphine oxide (5). The basic biological activities of analogues, 1, 2, and 26,26,26,27,27,27-hexafluoro-25-hydroxyvitamin D [HF-25(OH)D] were examined. Although the tetrafluorinated new compound 2 exhibited higher binding affinity for vitamin D receptor (VDR) and resistance to CYP24A1-dependent metabolism compared with the difluorinated 1 and its non-fluorinated counterpart 25-hydroxyvitamin D [25(OH)D], HF-25(OH)D showed the highest activity among these compounds.
View Article and Find Full Text PDFThe First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D and Its 24-Hydroxy Derivatives: Preliminary Assessment of Biological Activities.
Molecules
August 2022
Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
In this paper, we report an efficient synthetic route for the 23,23-difluoro-25-hydroxyvitamin D () and its 24-hydroxylated analogues (,), which are candidates for the CYP24A1 main metabolites of . The key fragments, 23,23-difluoro-CD-ring precursors (-), were synthesized starting from Inhoffen-Lythgoe diol (), and introduction of the C23 difluoro unit to α-ketoester () was achieved using ,-diethylaminosulfur trifluoride (DAST). Preliminary biological evaluation revealed that 23,23-F-25(OH)D () showed approximately eight times higher resistance to CYP24A1 metabolism and 12 times lower VDR-binding affinity than its nonfluorinated counterpart 25(OH)D ().
View Article and Find Full Text PDFConvergent total synthesis of (+)-calcipotriol: A scalable, modular approach to vitamin D analogs.
Proc Natl Acad Sci U S A
May 2022
Department of Chemistry, Scripps Research, La Jolla, CA 92037.
A convergent approach for the total synthesis of calcipotriol (brand name: Dovonex), a proven vitamin D analog used for the treatment of psoriasis, and medicinally relevant synthetic analogs is described. A complete approach, not wedded to semisynthesis, toward both the A-ring and CD-ring is reported. From a retrosynthetic standpoint, hidden symmetry within the decorated A-ring is disclosed, which allowed for scalable quantities of this advanced intermediate.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!