- Introduction of fluorine atoms to vitamin D3 side-chain and synthesis of 24,24-difluoro-25-hydroxyvitamin D3
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During our ongoing studies of vitamin D, we focused on the vitamin D3 side-chain 24-position, which is the major metabolic site of human CYP24A1. In order to inhibit the metabolism of vitamin D3, 24,24-difluorovitamin D3analogues are important candidates. In this paper, we report the practical introduction of the difluoro-unit to the 24-position to synthesize 24,24-difluoro-CD ring (1) and 24,24-difluoro-25-hydroxyvitamin D3 (2).
- Kawagoe, Fumihiro,Mototani, Sayuri,Yasuda, Kaori,Nagasawa, Kazuo,Uesugi, Motonari,Sakaki, Toshiyuki,Kittaka, Atsushi
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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
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To investigate the molecular mechanism of vitamin D receptor (VDR) antagonists having no structurally bulky group interfering with helix 12 of the ligand-binding domain of the VDR, we have synthesized four diastereomers at C(20) and C(23) of 19-nor-1α-hydroxyvitamin D3 25-methylene-26,23-lactone bearing a 2MD-type A-ring. All four analogs showed significant VDR affinity. Transactivation was tested by using Cos7 cells and HEK293 cells. In both types of cells, LAC67a showed little transactivation potency and inhibited the activation induced by the natural hormone concentration-dependently, indicating that LAC67a works as an antagonist for the VDR in these cells. LAC67b, LAC82a and LAC82b similarly acted as VDR antagonists in Cos7 cells, but in HEK293 cells they behaved as potent VDR agonists. Docking of four lactones into the VDR-LBD, followed by structural analysis, demonstrated that each lactone lacks the hydrophobic interaction with helix12 necessary for maintaining the active conformation of the VDR, indicating that these lactones are passive-type antagonists. Furthermore, each docking structure explained the characteristic transactivation profiles of the four lactones. On the basis of our present findings, we suggest that the ligand acts as an agonist if there are appropriate coactivators in the cells to bind to the looser VDR-ligand complex, and as an antagonist if there are no such appropriate coactivators. The molecular basis of the passive antagonism is discussed in detail.
- Yoshimoto, Nobuko,Inaba, Yuka,Yamada, Sachiko,Makishima, Makoto,Shimizu, Masato,Yamamoto, Keiko
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p. 457 - 473
(2008/09/17)
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- 2-Methylene-19-nor-(23S)-25-dehydro-1alpha-hydroxyvitamin D3-26,23-lactone and 2-methylene-19-nor-(23R)-25-dehydro-1alpha-hydroxyvitamin D3-26,23-lactone
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Compounds of formula 1A and 1B are provided where X1 and X2 are independently selected from H or hydroxy protecting groups. Such compounds may be used in preparing pharmaceutical compositions and are useful in treating a variety of b
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Page/Page column 6-7; 9
(2008/06/13)
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- HIGHLY ANTIPROLIFERATIVE, LOW-CALCEMIC, ANALOGS OF THE HORMONE 1α, 25-DIHYDROXYVITAMIN D3 WITH CARBONYL SIDE CHAINS
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The present invention discloses a series of new carbonyl side chain anlogs of calcitriol (I). Unexpectedly, several of these ketone analogs, such as the 24- and 25-tert-butyl ketones, amides, hydroxymate esters and a hetero atom ketones even though lacking the classical side-chain tertiary hydroxyl group, are considerably more antiproliferative in vitro than the hormone calcitriol (I) even at physiologically relevant low nanomolar concentrations and are less calcemic than calcitriol (I) in vivo.
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Page/Page column 42-43
(2008/06/13)
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- An efficient stereoselective synthesis of 1α,24(R)-dihydroxyvitamin D3 by the dienyne route
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1α,24(R)-Dihydroxyvitamin D3 (5e) was synthesized. The key step in the preparation of the side-chain was opening of the chiral epoxide 10 by the α-anion of the nitrile 9. The triene system was synthesized by the dienyne route.
- Fall, Yagamare,Torneiro, Mercedes,Castedo, Luis,Mourino, Antonio
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p. 4703 - 4714
(2007/10/03)
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- A nitrile approach to the synthesis of the side chain of vitamin D metabolites and analogues
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An efficient new method for the construction of vitamin D hydroxylated side chains is described which is based on the alkylation and opening of epoxides by the α-anions derived from nitriles 6 and 7.
- Fall,Torneiro,Castedo,Mourino
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p. 6683 - 6686
(2007/10/02)
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