Synthesis and biological activities of 2β-chloro-, 2β-fluoro-, and 2β-methoxy-1α,25-dihydroxyvitamin D3

Scheddin, Dietmar; Mayer, Hubert; Schönecker, Bruno; Gliesing, S.; Reichenbächer, Manfred

doi:10.1016/s0039-128x(98)00072-5

Cited by 7 publications

(3 citation statements)

References 37 publications

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“…Much like the side chain, the A-ring counts numerous divergent modifications ranging from substitution of the six-membered Aring by a five-membered A-ring [126] to linkage of F-and Cl-atoms or NH 2 -groups to specific carbons of the A-ring [127][128][129][130]. Also homodimeric carbamate C3 analogs have been designed [131].…”

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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“…83,84 The 2b-methyl group would have some steric clash with Y143. 2b-F-1,25-(OH) 2 D 3 has higher affinity for VDR than does 1a,25-(OH) 2 D 3 (5), 86 probably because the smaller fluorine atom would not have this steric congestion with Y143. Elongation of the 2a-alkyl group reduces the affinity for VDR (ethyl, 40%; propyl, 20%), 87 but o-hydroxylation increases the potency again (hydroxymethyl, 20%; hydroxyethyl, 70%; hydroxypropyl, 300%).…”

Section: Sfr In Terms Of Vdr Structure: A-ringmentioning

confidence: 96%

Structure–function relationships of vitamin D including ligand recognition by the vitamin D receptor

Yamada

Shimizu

Yamamoto

2002

Medicinal Research Reviews

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First, the general structure and function of nuclear receptors (NRs) are described briefly to help our understanding of the mechanism of action of vitamin D mediated by the vitamin D receptor (VDR), a member of the NRs. Then we discuss the structure-function relationship (SFR) of vitamin D on the basis of ligand structures and the interaction of the ligand with the VDR. The SFR of vitamin D side chain analogs is discussed extensively in terms of our active space group concept, which was derived from conformational analyses of the side chains of vitamin D analogs and from studies with conformationally restricted 22-methyl-1,25-(OH)(2)D(3) isomers. The mobile area of the side chain of vitamin D can be grouped into five regions (E, G, EA, EG, and F), and the SFR has been analyzed in terms of these spatial regions. The SFR of ligand/VDR interaction is discussed on the basis of the crystal structure of VDR-LBD(delta 165-215), docking of various vitamin D ligands into the ligand binding pocket (LBP) of the VDR, and functional analysis of amino acids lining the LBP. Finally, we discuss total SFR, combining the results of the two approaches, and future aspects of structure-based design of vitamin D analogs.

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“…The synthesis and biological activities of 2β-fluoro-1α,25-dihydroxyvitamin D 3 ( 30 ) were reported by Scheddin et al in 1998 [ 33 ]. The synthetic route was similar to Ikekawa’s [ 31 ], as shown in Scheme 11 , and the biological evaluation revealed that the synthetic 2β-fluoro-1α,25-(OH) 2 D 3 ( 30 ) exhibited greater potency in vitro, for example, six-times higher affinity for VDR, nearly identical affinity for the vitamin D-binding protein (DBP), and 90-times higher antiproliferative activity toward C3H10T1/2 cells under serum-containing conditions, as well as five-times greater adipogenesis inhibitory activity than the natural hormone 1α,25(OH) 2 D 3 ( 1 ).…”

Section: A-ring Fluorinated Vd 3 Analoguesmentioning

confidence: 97%

Design and Synthesis of Fluoro Analogues of Vitamin D

Kawagoe

Mototani

Kittaka

2021

IJMS

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The discovery of a large variety of functions of vitamin D3 and its metabolites has led to the design and synthesis of a vast amount of vitamin D3 analogues in order to increase the potency and reduce toxicity. The introduction of highly electronegative fluorine atom(s) into vitamin D3 skeletons alters their physical and chemical properties. To date, many fluorinated vitamin D3 analogues have been designed and synthesized. This review summarizes the molecular structures of fluoro-containing vitamin D3 analogues and their synthetic methodologies.

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Synthesis and biological activities of 2β-chloro-, 2β-fluoro-, and 2β-methoxy-1α,25-dihydroxyvitamin D3

Cited by 7 publications

References 37 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

Structure–function relationships of vitamin D including ligand recognition by the vitamin D receptor

Design and Synthesis of Fluoro Analogues of Vitamin D

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