Novel 1α,25-Dihydroxyvitamin D<sub>3</sub>Analogues with the Side Chain at C12

Gonzalez-Avion, Xosé C.; Mouriño, Antonio; Rochel, Natacha; Moras, Dino

doi:10.1021/jm049016g

Cited by 16 publications

(7 citation statements)

References 34 publications

(60 reference statements)

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“…Also homodimeric carbamate C3 analogs have been designed [131]. For the CD-ring system, even analogs with a side chain on C12 have been designed [132]. However, a detailed description of each of these modifications lies beyond the scope of this review.…”

Section: Other A-ring and Cd-ring Modificationsmentioning

confidence: 99%

Mechanism and Potential of the Growth-Inhibitory Actions of Vitamin D and Analogs

Eelen

Gysemans²,

Verlinden³

et al. 2007

CMC

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1alpha,25-Dihydroxyvitamin D(3) [1,25-(OH) (2)D(3)] can exert its biological actions through binding with the nuclear vitamin D receptor (VDR), a ligand-activated transcription factor. Next to control of bone and mineral homeostasis, these actions include an immunomodulatory effect and a potent growth-inhibitory, antiproliferative or prodifferentiating action on a wide variety of cell types. The molecular mechanisms underlying this antiproliferative action form an intriguing research topic and they remain, although thoroughly studied, not completely understood. Important cell cycle regulators are involved such as cyclins, cyclin dependent kinases and their corresponding inhibitors as well as E2F transcription factors and accompanying pocket proteins. Whether 1,25-(OH)(2)D(3) influences the expression of all these proteins directly through the nuclear VDR or rather in an indirect manner is not always clear. The antiproliferative action makes 1,25-(OH) (2)D(3) a possible therapeutic tool to treat hyperproliferative disorders, among which different types of cancer. Clinical application, however, is severely hampered by calcemic effects such as hypercalcemia, hypercalciuria and increased bone resorption. Rational design of chemically modified 1,25-(OH) (2)D(3)-analogs tries to overcome this problem. As such, several thousands of analogs have been synthesized and evaluated, some of which display the desired dissociation between beneficial antiproliferative and unwanted calcemic effects. A number of those analogs are 'superagonistic' and have a several-fold stronger antiproliferative action than the parent compound. This review focuses on recent findings about the complex mechanisms behind the antiproliferative and prodifferentiating effect of 1,25-(OH) (2)D(3). Furthermore, the mode of action and possible clinical application of chemically modified 1,25-(OH) (2)D(3)-analogs will be discussed.

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Section: Other A-ring and Cd-ring Modificationsmentioning

confidence: 99%

Mechanism and Potential of the Growth-Inhibitory Actions of Vitamin D and Analogs

Eelen

Gysemans²,

Verlinden³

et al. 2007

CMC

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“…Covalent bond formations of 1−4 with the rat VDR-LBD were evaluated by electrospray ionization mass spectrometry (ESI-MS). 20 Figure 3 shows the ESI-MS spectra of the VDR-LBD in the absence and presence of ligands. We obtained a peak of m/z = 30,553 for apo VDR-LBD as shown in Figure 3a.…”

Section: ■ Resultsmentioning

confidence: 99%

Identification of the Histidine Residue in Vitamin D Receptor That Covalently Binds to Electrophilic Ligands

et al. 2018

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We designed and synthesized vitamin D analogues with an electrophile as covalent modifiers for the vitamin D receptor (VDR). Novel vitamin D analogues 1-4 have an electrophilic enone group at the side chain for conjugate addition to His301 or His393 in the VDR. All compounds showed specific VDR-binding potency and agonistic activity. Covalent bond formations of 1-4 with the ligand-binding domain (LBD) of VDR were evaluated by electrospray ionization mass spectrometry. All compounds were shown to covalently bind to the VDR-LBD, and the abundance of VDR-LBD corresponding conjugate adducts of 1-4 increased with incubation time. Enone compounds 1 and 2 showed higher reactivity than the ene-ynone 3 and dienone 4 compounds. Furthermore, we successfully obtained cocrystals of VDR-LBD with analogues 1-4. X-ray crystallographic analysis showed a covalent bond with His301 in VDR-LBD. We successfully synthesized vitamin D analogues that form a covalent bond with VDR-LBD.

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“…Ketone 5a was prepared from 13b by selective protection of the primary hydroxyl group with TBSCl, followed by oxidation of the secondary hydroxyl group with PDC (92% yield for the two steps). We decided to try the Wittig–Horner coupling with unmasked hydroxy ketone 5a . , Indeed, the reaction of ketone 5a with the anion of the phosphine oxide 4a , generated by treatment with n -BuLi, took place in moderate yield to stereoselectively deliver the partially protected vitamin D 14 (45%, 81% based on recovered starting material). Finally, deprotection of 14 with TBAF in THF gave in 80% yield the desired vitamin D 3 analogue 2 , whose structure was fully characterized by 1 H NMR, 13 C NMR, UV, and mass spectral data.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Evaluation of 1α,25-Dihydroxyvitamin D₃Analogues Hydroxymethylated at C-26

et al. 2011

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We designed by docking and synthesized two novel analogues of 1α,25-dihydroxyvitamin D(3) hydroxymethylated at C-26 (2 and 3). The syntheses were carried out by the convergent Wittig-Horner approach via epoxide 12a as a common key intermediate. The antiproliferative and transactivation potency of the compounds was evaluated in colon and breast cancer cell lines. The analogues showed a similar but reduced activity compared to 1,25(OH)(2)D(3). Analogue 3 was more potent than analogue 2, and in some assays it exhibited potency similar to that of the natural ligand.

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Novel 1α,25-Dihydroxyvitamin D₃Analogues with the Side Chain at C12

Cited by 16 publications

References 34 publications

Mechanism and Potential of the Growth-Inhibitory Actions of Vitamin D and Analogs

Mechanism and Potential of the Growth-Inhibitory Actions of Vitamin D and Analogs

Identification of the Histidine Residue in Vitamin D Receptor That Covalently Binds to Electrophilic Ligands

Synthesis and Biological Evaluation of 1α,25-Dihydroxyvitamin D₃Analogues Hydroxymethylated at C-26

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Novel 1α,25-Dihydroxyvitamin D3Analogues with the Side Chain at C12

Cited by 16 publications

References 34 publications

Mechanism and Potential of the Growth-Inhibitory Actions of Vitamin D and Analogs

Mechanism and Potential of the Growth-Inhibitory Actions of Vitamin D and Analogs

Identification of the Histidine Residue in Vitamin D Receptor That Covalently Binds to Electrophilic Ligands

Synthesis and Biological Evaluation of 1α,25-Dihydroxyvitamin D3Analogues Hydroxymethylated at C-26

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Product

Resources

About

Novel 1α,25-Dihydroxyvitamin D₃Analogues with the Side Chain at C12

Synthesis and Biological Evaluation of 1α,25-Dihydroxyvitamin D₃Analogues Hydroxymethylated at C-26