2-Methylene 19-nor-25-dehydro-1α-hydroxyvitamin D3 26,23-lactones: Synthesis, biological activities and molecular basis of passive antagonism

Yoshimoto, Nobuko; Inaba, Yuka; Yamada, Sachiko; Makishima, Makoto; Shimizu, Masato; Yamamoto, Keiko

doi:10.1016/j.bmc.2007.09.017

Cited by 26 publications

(35 citation statements)

References 39 publications

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“…It is interesting that GEMINI and compound 2 induce a common and characteristic cavity to accommodate the second side chain, but GEMINI works as a VDR agonist whereas 2 works as a VDR antagonist. These results imply that the antagonistic activity of compound 2 is related to decreased interactions with helix 12 [5,8]. We also found that 22S-butyl-1␣,24R-dihydroxyvitamin D 3 3, which contains the three carbons absent from the side chain of 2, showed the agonistic activity, albeit weakly [5].…”

Section: Introductionmentioning

confidence: 62%

22S-Butyl-1α,24R-dihydroxyvitamin D3: Recovery of vitamin D receptor agonistic activity

Inaba

Nakabayashi

Itoh

et al. 2010

The Journal of Steroid Biochemistry and Molecular Biology

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Section: Introductionmentioning

confidence: 62%

22S-Butyl-1α,24R-dihydroxyvitamin D3: Recovery of vitamin D receptor agonistic activity

Inaba

Nakabayashi

Itoh

et al. 2010

The Journal of Steroid Biochemistry and Molecular Biology

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“…In addition, the synthesis and biological properties of two lactones LAC67a and LAC67b structurally identical to our HLV and GC-3 have been recently reported by a different group. 28 A perfect chemical shift overlapping of diagnostic NMR signals between LAC67a and HLV and between LAC67b and GC-3 was observed, yielding further evidence of the correct assignment of the stereochemistry at C 23 for compounds HLV and GC-3 .…”

Section: Resultsmentioning

confidence: 68%

“…Furthermore, during completion of the biological testing and the preparation of this manuscript two reports became available describing the in vitro biological activity of the same compounds presented in this manuscript 25,28 : LAC67b (GC-3) and LAC67a (HLV) . In the second of these two reports, the investigators stated that these compounds acted as antagonists in Cos7 and HEK293 cells.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis and biological properties of 2-methylene-19-nor-25-dehydro-1α-hydroxyvitamin D3-26,23-lactones—weak agonists

Chiellini

Grzywacz

Plum

et al. 2008

Bioorganic & Medicinal Chemistry

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In a continuing effort to explore the 2-methylene-1α-hydroxy-19-norvitamin D3 class of pharmacologically important vitamin D compounds, two novel 2-methylene-19-nor-25-dehydro-1α-hydroxyvitamin D3-26,23-lactones, GC-3 and HLV, were synthesized and biologically tested. Based on reports of similarly structured molecules, it was hypothesized that these compounds might act as antagonists, at least in vitro. The pathway designed to synthesize these compounds was based on two key steps: first, the Lythgoe-type Wittig–Horner coupling of Windaus–Grundmann-type ketone 18, with phosphine oxide 15, followed, later in the synthesis, by the Zn-mediated Reformasky-type allylation of aldehyde 20 with methylbromomethylacrylate 8. Our biological data show that neither compound has antagonistic activity but acts as weak agonists in vitro and in vivo.

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“…However, in COS7 monkey kidney cells, both compounds behaved as transcriptional antagonists in the presence of 1,25-(OH) 2 D 3 (71, 72). Interestingly, only GC-3 was able to promote the binding between VDR and RXR, although both compounds reduced the VDR–RXR interaction in the presence of 1,25-(OH) 2 D 3 .…”

Section: Vdr Antagonists or Allosteric Inhibition Of The Vdr–coregmentioning

confidence: 95%

Inhibitors for the Vitamin D Receptor–Coregulator Interaction

Teske

2016

Vitamin D Hormone

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The vitamin D receptor (VDR) belongs to the superfamily of nuclear receptors and is activated by the endogenous ligand 1,25-dihydroxyvitamin D3. The genomic effects mediated by VDR consist of the activation and repression of gene transcription, which includes the formation of multi-protein complexes with coregulator proteins. Coregulators bind many nuclear receptors and can be categorized according their role as coactivators (gene activation) or corepressors (gene repression). Herein, different approaches to develop compounds that modulate the interaction between VDR and coregulators are summarized. This include coregulator peptides that were identified by creating phage display libraries. Subsequent modification of these peptides including the introduction of a tether or non-hydrolysable bonds resulted in the first direct VDR–coregulator inhibitors. Later, small molecules that inhibit VDR–coregulator inhibitors were identified using rational drug design and high throughput screening. Early on, allosteric inhibition of VDR–coregulator interactions was achieved with VDR antagonists that change the conformation of VDR and modulate the interactions with coregulators. A detailed discussion of their dual agonist/antagonist effects is given as well as a summary of their biological effects in cell-based assays and in vivo studies.

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2-Methylene 19-nor-25-dehydro-1α-hydroxyvitamin D3 26,23-lactones: Synthesis, biological activities and molecular basis of passive antagonism

Cited by 26 publications

References 39 publications

22S-Butyl-1α,24R-dihydroxyvitamin D3: Recovery of vitamin D receptor agonistic activity

22S-Butyl-1α,24R-dihydroxyvitamin D3: Recovery of vitamin D receptor agonistic activity

Synthesis and biological properties of 2-methylene-19-nor-25-dehydro-1α-hydroxyvitamin D3-26,23-lactones—weak agonists

Inhibitors for the Vitamin D Receptor–Coregulator Interaction

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