2,2-Functionalized analogues of 1α,25-dihydroxyvitamin D3, the potent inducers of cell differentiation

Fujishima, Toshie; Kittaka, Atsushi; Kurihara, Masaaki; Saito, Nozomi; Honzawa, Shinobu; Kishimoto, Seishi; Sugiura, Takayuki; Waku, Keizo; Takayama, Hiroaki

doi:10.1016/j.jsbmb.2004.03.053

Cited by 8 publications

(5 citation statements)

References 13 publications

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“…In silico docking of a 2β-methyl group in VDR LBD indicates that for this conformer the methyl group makes bad contacts with Tyr-143. The resulting destabilization is likely to explain the marked decrease of the affinity of the 2β-methyl 1α,25(OH) 2 D 3 . In line with these observations, the 2-methylene group in the rVDR 22 crystal structure displays contacts similar to those of the 2α-methyl group in the hVDR LBD.…”

Section: Resultssupporting

confidence: 60%

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Probing a Water Channel near the A-Ring of Receptor-Bound 1α,25-Dihydroxyvitamin D3 with Selected 2α-Substituted Analogues

et al. 2006

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The crystal structure of the vitamin D receptor (VDR) in complex with 1 alpha,25(OH)2D3 revealed the presence of several water molecules near the A-ring linking the ligand C-2 position to the protein surface. Here, we report the crystal structures of the human VDR ligand binding domain bound to selected C-2 alpha substituted analogues, namely, methyl, propyl, propoxy, hydroxypropyl, and hydroxypropoxy. These specific replacements do not modify the structure of the protein or the ligand, but with the exception of the methyl substituent, all analogues affect the presence and/or the location of the above water molecules. The integrity of the channel interactions and specific C-2 alpha analogue directed additional interactions correlate with the binding affinity of the ligands. In contrast, the resulting loss or gain of H-bonds does not reflect the magnitude of HL60 cell differentiation. Our overall findings highlight a rational approach to the design of more potent ligands by building in features revealed in the crystal structures.

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Section: Resultssupporting

confidence: 60%

“…The resulting destabilization is likely to explain the marked decrease of the affinity of the 2β-methyl 1R,25-(OH) 2 D 3 . 25 In line with these observations, the 2-methylene group in the rVDR 22 crystal structure displays contacts similar to those of the 2R-methyl group in the hVDR LBD.…”

Section: Resultssupporting

confidence: 59%

Probing a Water Channel near the A-Ring of Receptor-Bound 1α,25-Dihydroxyvitamin D3 with Selected 2α-Substituted Analogues

et al. 2006

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“…(9), the results with the 2,2-substituted A-ring compounds (58,59) imply that the LBD of VDR in the vicinity of the C2 position is quite narrow, although it can accommodate the long substituent either in the 2 -or in the 2 -orientation (Fig. (10)) [14,[49][50][51]. …”

Section: Recent Developments Of Fluorinated Analoguesmentioning

confidence: 92%

Synthesis and Biological Activity of Fluorinated Vitamin D

Fujishima¹,

Fujii²,

Harayama

2010

COC

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The active metabolite of vitamin D, 1 ,25-dihydroxyvitamin D3 (1), has a wide range of biological activities, making its analogues promising therapeutic agents for the treatment of cancer, psoriasis and osteoporosis. In particular, the stability of the carbonfluorine bond to oxidation has aided in the development of fluorinated vitamin D analogues as catabolism inhibitors. The analogues were synthesized either by classical steroidal approaches or by convergent methods, depending on the sites of fluorination. The incorporation of fluorine has provided numerous advantages for studying the structurally flexible hormone 1 ,25-dihydroxyvitamin D3 1, including helping to define its molecular mode of actions. Biological evaluation of the fluorinated analogues suggested that fluorine substitution would not only change the metabolism, but also have direct effects on the vitamin D receptor, resulting in compounds with unique activity profiles.

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“…The A-ring parts were prepared from methyl 3-hydroxy-2,2-dimethylpropionate (for 31) [83,84], or Diels-Alder reaction of a pyrone derivative (for 32) [85], or 2,2-dimethyl-1,3-cyclohexanedione (for 33) [85], or D-glucose (for 34, 35a-d) [86]. Some biological properties are described in each reference.…”

Section: 2-disubstituted 1α25-dihydroxyvitamin D 3 Analogsmentioning

confidence: 99%

Recent Results on A-Ring Modification of 1α,25-Dihydroxyvitamin D3: Design and Synthesis of VDR-Agonists and Antagonists with High Biological Activity

Saito¹,

Honzawa²,

Kittaka

2006

CTMC

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The structure-activity relationships of 1alpha,25-dihydroxyvitamin D3 on simultaneous modification at both C2alpha and CD-ring side chain, including 20-epimerization, double side chain (gemini), and vitamin D receptor (VDR) antagonists TEI-9647 and TEI-9648 lactone rings, and also on simultaneous modifications at both C2 and C10 positions, i.e., C2 modified active 19-norvitamin D3, have been studied in our laboratory to find new seeds of B-seco-steroidal medicine for treating bone diseases, psoriasis, secondary hyperparathyroidism, and certain kinds of cancers. We developed an efficient and systematic route to the 2alpha-substituted 1alpha,25-dihydroxyvitamin D3 analogs, i.e., VDR-agonists (20-epi-2-4, double side chain 13a-c, 19-nor 15a-c) and antagonists (36a-c, 37a-c). The A-ring precursors (11a-o) for these analogs were synthesized from D-glucose as a chiral template. In the 19-nor series, we used radical coupling reaction for preparing the A-ring parts from (-)-quinic acid, and the resulting 2-substituted A-ring moiety was coupled with 25-hydroxy Grundmann's ketone utilizing Julia olefination to connect between the C5 and C6 positions. We also synthesized the highly potent VDR-antagonists by introducing the 2alpha-functional group to the TEI-9647 and TEI-9648 skeletons.

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2,2-Functionalized analogues of 1α,25-dihydroxyvitamin D3, the potent inducers of cell differentiation

Cited by 8 publications

References 13 publications

Probing a Water Channel near the A-Ring of Receptor-Bound 1α,25-Dihydroxyvitamin D3 with Selected 2α-Substituted Analogues

Probing a Water Channel near the A-Ring of Receptor-Bound 1α,25-Dihydroxyvitamin D3 with Selected 2α-Substituted Analogues

Synthesis and Biological Activity of Fluorinated Vitamin D

Recent Results on A-Ring Modification of 1α,25-Dihydroxyvitamin D3: Design and Synthesis of VDR-Agonists and Antagonists with High Biological Activity

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2,2-Functionalized analogues of 1α,25-dihydroxyvitamin D3, the potent inducers of cell differentiation

Cited by 8 publications

References 13 publications

Probing a Water Channel near the A-Ring of Receptor-Bound 1α,25-Dihydroxyvitamin D3 with Selected 2α-Substituted Analogues

Probing a Water Channel near the A-Ring of Receptor-Bound 1α,25-Dihydroxyvitamin D3 with Selected 2α-Substituted Analogues

Synthesis and Biological Activity of Fluorinated Vitamin D

Recent Results on A-Ring Modification of 1&#945;,25-Dihydroxyvitamin D3: Design and Synthesis of VDR-Agonists and Antagonists with High Biological Activity

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Recent Results on A-Ring Modification of 1α,25-Dihydroxyvitamin D3: Design and Synthesis of VDR-Agonists and Antagonists with High Biological Activity