Studies on the Synthesis of Vitamin D Analogs with Aromatic D-Ring

Herein, we describe our studies on the synthesis of 1α,25-dihydroxyvitamin D3 analogs possessing a benzene ring replacing the natural 5-membered D-ring by the Wittig-Horner and dienyne approaches. A key feature is the synthesis of a Cr(CO)3-complexed previtamin D derivative that enables the construction of vitamin D analogs with aromatic D-ring through a thermal [1,7]-H sigmatropic shift. This study establishes the basis for the design of new vitamin D analogs containing aromatic D-ring, complexed or uncomplexed to Cr(CO)3 type moieties for specific molecular recognition and drug research and developmentWe thank Xunta de Galicia (project GPC2014/001) and for financial support. Silvina Eduardo thanks the Spanish MEC for a fellowship. Rita Sigüeiro thanks Xunta de Galicia for a post-doctoral fellowship (Axudas posdoutorais, plan I2C, mod B)S

1α,25(OH)2-3-Epi-Vitamin D3, a Natural Physiological Metabolite of Vitamin D3: Its Synthesis, Biological Activity and Crystal Structure with Its Receptor

Background: The 1 alpha,25-dihydroxy-3-epi-vitamin-D(3) (1 alpha,25(OH)(2)-3-epi-D(3)), a natural metabolite of the seco-steroid vitamin D(3), exerts its biological activity through binding to its cognate vitamin D nuclear receptor (VDR), a ligand dependent transcription regulator. In vivo action of 1 alpha,25(OH)(2)-3-epi-D(3) is tissue-specific and exhibits lowest calcemic effect compared to that induced by 1 alpha,25(OH)(2)D(3). To further unveil the structural mechanism and structure-activity relationships of 1 alpha,25(OH)(2)-3-epi-D3 and its receptor complex, we characterized some of its in vitro biological properties and solved its crystal structure complexed with human VDR ligand-binding domain (LBD). Methodology/Principal Findings: In the present study, we report the more effective synthesis with fewer steps that provides higher yield of the 3-epimer of the 1 alpha,25(OH)(2)D(3). We solved the crystal structure of its complex with the human VDR-LBD and found that this natural metabolite displays specific adaptation of the ligand-binding pocket, as the 3-epimer maintains the number of hydrogen bonds by an alternative water-mediated interaction to compensate the abolished interaction with Ser278. In addition, the biological activity of the 1 alpha,25(OH)(2)-3-epi-D(3) in primary human keratinocytes and biochemical properties are comparable to 1 alpha,25(OH)(2)D(3). Conclusions/Significance: The physiological role of this pathway as the specific biological action of the 3-epimer remains unclear. However, its high metabolic stability together with its significant biologic activity makes this natural metabolite an interesting ligand for clinical applications. Our new findings contribute to a better understanding at molecular level how natural metabolites of 1 alpha,25(OH)(2)D(3) lead to significant activity in biological systems and we conclude that the C3-epimerization pathway produces an active metabolite with similar biochemical and biological properties to those of the 1 alpha,25(OH)(2)D(3)

An expeditious route to 1α,25-dihydroxyvitamin D3 and its analogues by an aqueous tandem palladium-catalyzed a-ring closure and suzuki coupling to the C/D unit

Chemical equation presented Daily vitamins: A mild, general, and highly stereoselective Pd0-catalyzed cascade to the triene system of the hoi mone 1α,25-dihydroxyvitamin D3 and six representative analogues is reported. The intramolecular cyclization of an enol-triflate (lower fragment) followed in situ by Suzuki Miyaura coupling with an alkenyl boronic ester (upper fragment, also efficiently prepared by Pd0-catalyzed coupling) in equimolar amounts under protic conditions is ideal for the preparation of small amounts of new vitamin D analogues for biological testing (see scheme). © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.Fil: Gogoi, Pranjal. Universidad de Santiago de Compostela; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Sigüeiro, Rita. Consejo Superior de Investigaciones Científicas; España. Universidad de Santiago de Compostela; EspañaFil: Eduardo, Silvina Laura. Consejo Superior de Investigaciones Científicas; España. Universidad de Santiago de Compostela; España. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mouriño, Antonio. Consejo Superior de Investigaciones Científicas; España. Universidad de Santiago de Compostela; Españ

Studies on the Synthesis of Vitamin D Analogs with Aromatic D-Ring

ABSTRACT Herein, we describe our studies on the synthesis of 1α,25-dihydroxyvitamin D3 analogs possessing a benzene ring replacing the natural 5-membered D-ring by the Wittig-Horner and dienyne approaches. A key feature is the synthesis of a Cr(CO)3-complexed previtamin D derivative that enables the construction of vitamin D analogs with aromatic D-ring through a thermal [1,7]-H sigmatropic shift. This study establishes the basis for the design of new vitamin D analogs containing aromatic D-ring, complexed or uncomplexed to Cr(CO)3 type moieties for specific molecular recognition and drug research and development

Studies on the Synthesis of Vitamin D Analogs with Aromatic D-Ring

<div><p>ABSTRACT Herein, we describe our studies on the synthesis of 1α,25-dihydroxyvitamin D3 analogs possessing a benzene ring replacing the natural 5-membered D-ring by the Wittig-Horner and dienyne approaches. A key feature is the synthesis of a Cr(CO)3-complexed previtamin D derivative that enables the construction of vitamin D analogs with aromatic D-ring through a thermal [1,7]-H sigmatropic shift. This study establishes the basis for the design of new vitamin D analogs containing aromatic D-ring, complexed or uncomplexed to Cr(CO)3 type moieties for specific molecular recognition and drug research and development.</p></div

Advances in vitamin D receptor function and evolution based on the 3D structure of the lamprey ligand binding domain

International audience1α,25-dihydroxyvitamin D 3 (1,25D 3) regulates many physiological processes in vertebrates by binding to the Vitamin D Receptor (VDR). Phylogenetic analysis indicates that jawless fishes are the most basal vertebrates exhibiting a VDR gene. To elucidate the mechanism driving VDR activation during evolution, we determined the crystal structure of the VDR ligand binding domain complex from the basal vertebrate Petromyzon marinus, sea lamprey (lVDR). Comparison of 3D crystal structure of lVDR-1,25D 3 complex with higher vertebrates VDR-1,25D 3 structures suggest that 1,25D 3 binds to lVDR similarly to human VDR (hVDR), but with unique features for lVDR around linker regions between H11 and H12 and between H9 and H10. These structural differences may contribute to the marked species differences in transcriptional responses. Further, residue co-evolution analysis among vertebrates VDR identifies amino-acid positions in H9 and the large insertion domain (iD) VDR LBD specific

Design and synthesis of active vitamin D analogs

A review of the design and synthesis of structural analogs of the vitamin D hormone recently investigated in our laboratories, and the first report on a new class of vitamin D analogs characterized by an aromatic D-ring, is described.Fil: Eduardo, Silvina Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Santiago de Compostela; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Fraga, Ramón. Universidad de Santiago de Compostela; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Sigüeiro, Rita. Universidad de Santiago de Compostela; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Marco, Maria. Universidad de Santiago de Compostela; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Rochel, Natacha. Universite Louis Pasteur; FranciaFil: Moras, Dino. Universite Louis Pasteur; FranciaFil: Mouriño, Antonio. Universidad de Santiago de Compostela; España. Consejo Superior de Investigaciones Científicas; Españ

Aromatic-Based Design of Highly Active and Noncalcemic Vitamin D Receptor Agonists

International audienc