- Synthesis of vitamin D3 analogues with A-ring modifications to directly measure vitamin D levels in biological samples
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C-3-substituted 25-hydroxyvitamin D3 analogues were synthesized as tools to directly measure levels of vitamin D in biological samples. The strategy involves vinyloxycarbonylation of the 3β-hydroxy group and formation of a carbamate bond with a hydroxyl or amino group at the end of the alkyl chain. Biotinylated conjugates of synthesized derivatives were generated to be linked with vitamin D binding protein (DBP). The spacer group present in the alkyl chain is important in the binding of antibodies to the analogue-DBP complex. When compared to 25-hydroxyvitamin D3-DBP, the binding of some antibodies to the analogue-DBP complex of the 25-hydroxyvitamin D 3 derivative 10 that posses an 8-aminoctyl alkyl chain is significantly reduced, but this analogue displaced [26,27-3H]-25- hydroxyvitamin D3 from DBP. In contrast, the 8-hydroxyoctyl alkyl chain analogue 9 showed less displacement.
- Hernández-Martín, Alba,González-García, Tania,Lawlor, Margaret,Preston, Lesley,Gotor, Vicente,Fernández, Susana,Ferrero, Miguel
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Read Online
- Large-Scale Synthesis of Eldecalcitol
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Industrial-scale synthesis of eldecalcitol is described. AA highly diastereoselective epoxidation of p-methoxybenzyl (PMB) protected dienol at room temperature provides the key epoxide intermediate with a secondary hydroxyl group, which is alkylated with a triflate to set up all of the subunits at the C-1, C-2, and C-3 positions of the A-ring fragment. Selective protecting group manipulation followed by palladium-catalyzed cyclization then provides the A-ring synthon. The C/D-ring fragment is obtained by (1) direct C-H hydroxylation of Grundman's ketone using in situ prepared trifluoropropanone dioxirane and (2) protection. Finally, the coupling of the A-ring with the C/D-ring fragment, global deprotection, and recrystallization provide the highly crystalline eldecalcitol.
- Moon, Hyung Wook,Lee, Seung Jong,Park, Seong Hu,Jung, Se Gyo,Jung, In A.,Seol, Chang Hun,Kim, Seung Woo,Lee, Seon Mi,Gangganna, Bogonda,Park, Seokhwi,Lee, Kee-Young,Oh, Chang-Young,Song, Juyoung,Jung, Jaehun,Heo, Ji Soo,Lee, Kang Hee,Kim, Hae Sol,Lee, Won Taek,Baek, Areum,Shin, Hyunik
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- Total synthesis of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (ED-71)
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A convergent method for the synthesis of ED-71 has been developed. Starting from the reported epoxide 5 which could be easily prepared from D-mannitol, ED-71 was synthesized in 11 linear steps with 17% overall yield.
- Deng, Wutong,Gong, Yimou,Pu, Qingyin,Sun, Jian,Wang, Chao,Zhou, Li
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supporting information
(2020/03/13)
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- Synthesis and evaluation of third generation vitamin D3 analogues as inhibitors of Hedgehog signaling
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The Hedgehog (Hh) pathway is a developmental pathway with therapeutic potential as a target for a variety of cancers. In recent years, several vitamin D-based compounds have been identified as potent inhibitors of Hh signaling. These analogues contain aromatic phenol A-ring mimics coupled to the CD-ring side chain of vitamin D3 through modified seco-B regions. To continue structure-activity relationship studies on this class of Hh pathway inhibitors, multiple series of vitamin D-based analogues that contain an amine-based seco-B tether and/or incorporate a hydroxyl moiety on C-25 were designed and synthesized. These compounds were evaluated in multiple cell lines for their anti-Hh activity, and we identify analogues 16, 21, 22 as potent vitamin D-based Hh inhibitors (IC50 values of 110–340 nM). We also performed a series of mechanism of action studies in knockout cell lines to further explore whether these analogues inhibit the Hh pathway through a known Hh pathway component or the vitamin D receptor. While the specific cellular target that mediates these effects remains elusive, our studies suggest multiple cellular targets may mediate the anti-Hh activity of this scaffold.
- Maschinot, Chad A.,Chau, Lianne Q.,Wechsler-Reya, Robert J.,Hadden, M. Kyle
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p. 495 - 506
(2018/11/25)
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- Compounds, conjugates, reagent kit and application of reagent kit
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The invention discloses compounds, conjugates, a reagent kit for detecting vitamin D and an application of the reagent kit in detecting the vitamin D. The compounds have a structure represented by a formula (1) in the description, wherein L represents a linking arm, R1, R2 and R3 are independently selected from hydrogen, hydroxyl, C1-C3 alkoxy, C1-C3 alkyl, C2-C3 alkenyl and C2-C3 alkynyl. The compounds provided by the invention can accurately detect the vitamin D.
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Paragraph 0056; 0059; 0060
(2018/03/01)
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- Preparation method of activated vitamin D3 drug CD ring intermediate
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The invention relates to a preparation method of an activated vitamin D3 drug CD ring intermediate. The preparation method comprises the following steps: carrying out iodine substitution on a diol derivative 2 to obtain a compound 3, carrying out hydroxyl reaction on the compound 3 to obtain a compound 4, carrying out Michael addition reaction on the compound 4 to obtain a compound 5, carrying out nucleophilic addition reaction on the compound 5 to obtain a compound 6, carrying out deprotection reaction on the compound 6 to obtain a compound 7, and carrying out oxidation reaction on the compound 7 to obtain a compound 1, namely, the activated vitamin D3 drug CD ring intermediate (25-hydroxy Grundmann's one). The preparation method provided by the invention has the advantages that the steps are simple, the product yield is high, and massive 25-hydroxy Grundmann's one can be prepared.
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- VITAMIN D3 DERIVATIVES AND PHARMACEUTICAL USE THEREOF
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The present invention relates to vitamin D3 derivatives of the following formula, wherein each symbol has the same meaning as defined herein, and pharmaceutical or medical use thereof for treating metabolic disease, liver disease, obesity, diabetes, cardiovascular disease, or cancer in a patient in need thereof.
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- Fluoride-mediated elimination of allyl sulfones: Application to the synthesis of a 2,4-dimethyl-A-ring vitamin D3 analogue
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A coupling strategy for the synthesis of 2,4-dimethyl-1α,25(OH) 2D3 is achieved which involves methylation of a pro-A ring vinyl sulfone and in situ traping of the allyl sulfonyl anion with a CD ring allyl chloride. TBAF-promoted 1,2-eliminative desulfonylation and concomitant silyl ether deprotection gives the vitamin D3 analogue.
- Sikervar, Vikas,Fleet, James C.,Fuchs, Philip L.
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experimental part
p. 5132 - 5138
(2012/07/28)
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- Synthesis of C-11 linked active ester derivatives of vitamin D3 and their conjugations to 42-residue helix-loop-helix peptides
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Derivatives of vitamin D3 carrying an 8-carbon linker at C-11 terminating in an active ester were synthesized from commercial vitamin D3 using a disassembly-reassembly strategy. Vitamin D3 was cleaved at the C6-C7 double b
- Zhang, Qi,Norberg, Thomas,Bergquist, Jonas,Baltzer, Lars
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scheme or table
p. 4577 - 4586
(2010/07/05)
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- Pd-catalyzed carbocyclization-negishi cross-coupling cascade: A novel approach to 1α,25-dihydroxyvitamin D3 and analogues
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(Chemical Equation Presented) A mild palladium-catalyzed cascade has been used for the synthesis of the hormone 1α,25-dihydroxyvitamin D3 (calcitriol, 1a) and its analogues 1b and 1c. This one-pot process involves two consecutive transformations at room temperature: An initial palladium-catalyzed 6-exo-cyclocarbopalladation of vinyl triflates followed by a Negishi cross-coupling reaction with an alkenyl zinc. This novel strategy opens new possibilities for the preparation of a variety of new vitamin D analogues of therapeutic potential, particularly with modifications at the triene and/or ring-A.
- Gomez-Reino, Clara,Vitale, Cristian,Maestro, Miguel,Mourino, Antonio
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p. 5885 - 5887
(2007/10/03)
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- An efficient synthesis of the 25-hydroxy Windaus-Grundmann ketone
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A short and efficient synthesis of the 25-hydroxy Windaus-Grundmann ketone from the Inhoffen-Lythgoe diol is described (seven steps, 70% overall). The most relevant feature of the synthesis is the preparation of the Wittig reagent 3 from cheap and commerc
- Fall,Vitale,Mourino
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p. 7337 - 7340
(2007/10/03)
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- Synthesis of vitamin D3 and calcitriol dimers as potential chemical inducers of vitamin D receptor dimerization
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The design and synthesis of vitamin D3 dimers 2 and 3 and, 1α,25-dihydroxyvitamin D3 (calcitriol) dimers 4 and 5 are described. The dimers were designed with a view to doubly binding the vitamin D receptor (VDR) and inducing the receptor homodimerization. In the dimers the units are linked through the C-11 position in ring C by an alkyl side chain of six or 10 carbon atoms, far from the hydroxy groups responsible for the VDR binding. The linker is formed by olefin metathesis of an olefinic side chain at the C-11 position introduced by stereoselective cuprate addition. The syhthesis, which is both short and convergent, uses the Wittig-Horner approach to construct the vitamin D triene system and allows the preparation of dimers with a linker of modulated length with the purpose of optimizing the vitamin D3-VDR interaction.
- Perez Sestelo,Mourino,Sarandeses
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p. 8290 - 8296
(2007/10/03)
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- Design and synthesis of a 1α,25-dihydroxyvitamin D3 dimer as a potential chemical inducer of vitamin D receptor dimerization
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(matrix presented) A dimer comprising two 1α,25-dihydroxyvitamin D3 units linked by an alkyl side chain at C-11 was synthesized with a view to the simultaneous binding of two vitamin D receptor (VDR) molecules and the consequent induction of VD
- Sestelo, José Pérez,Mouri?o, Antonio,Sarandeses, Luis A.
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p. 1005 - 1007
(2008/02/09)
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- 14-Epi stereoisomers of 25-hydroxy- and 1α,25-dihydroxyvitamin D3: Synthesis, isomerization to previtamins, and biological studies
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The C-14 epimers of vitamin D, 14-epi-25-hydroxyvitamin D3 (4) and 14- epi-1α,25-dihydroxyvitamin D3 (5), were synthesized, and their isomerization via [1,7]-sigmatropic hydrogen shifts to the corresponding previtamin forms (4' and 5
- Maynard,Trankle,Norman,Okamura
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p. 2387 - 2393
(2007/10/02)
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- Stereoselective Synthesis of Cyclopentanones by Reductive Cleavage of 6-Oxonorbornane-2-carboxylates and Its Application to the Synthesis of 1α,25-Dihydroxyvitamin D3 CD Ring
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A novel chiral synthesis of the CD-ring 2 of 1α,25-dihydroxyvitamin D3 (1a) is described.The optically active D-ring keto ester 3c was prepared by reductive cleavage of 6-oxonorbornane-2-carboxylate 4c with lithium naphthalenide. 1,2-Transposit
- Nagasawa, Kazuo,Matsuda, Naoto,Noguchi, Yasuo,Yamanashi, Masahiro,Zako, Yoshiro,Shimizu, Isao
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p. 1483 - 1490
(2007/10/02)
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- Oxidation of Natural Targets by Dioxiranes. 2. Direct Hydroxylation at the Side-Chain C-25 of Cholestane Derivatives and of Vitamin D3 Windaus-Grundmann Ketone
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The direct, high-yield oxyfunctionalization of the side-chain C-25 of 5α-cholestan-3-one, 3β-acetoxy-5α-cholestane, and 5α,6β-Br2-3β-acetoxycholestane as well as of the vitamin D3-derived Windaus-Grundmann ketone has been achieved under mild conditions employing either dimethyldioxirane or its trifluoromethyl analogue.
- Bovicelli, Paolo,Lupattelli, Paolo,Mincione, Enrico,Prencipe, Teresa,Curci, Ruggero
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p. 5052 - 5054
(2007/10/02)
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- Chemical conversion of vitamin D3 to its 1,25-dihydroxy metabolite
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Vitamin D3 (6) has been converted to the 1,25-dihydroxy vitamin D3 metabolite (1) and the 1α-fluoro derivative 2 via a new process. The strategy involved the cleavage of the ring A portion from the CD portion in vitamin D3
- Kiegiel,Wovkulich,Uskokovic
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p. 6057 - 6060
(2007/10/02)
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- A novel O-quinodimethane strategy for an active metabolite of vitamin D3. A total synthesis of 25-hydroxy Windaus-Grundmann ketone
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A highly diastereoselective total synthesis of 25-hydroxy Windaus-Grundmann ketone (2) was achieved via a novel regiocontrolled C-C bond formation by an intramolecular epoxide ring opening reaction of the bissulfonyl epoxide (19) as a key step, which was
- Nemoto,Ando,Fukumoto
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p. 6205 - 6208
(2007/10/02)
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- Stereocontrolled Total Synthesis of 1α,25-Dihydroxycholecalciferol and 1α,25-Dihydroxyergocalciferol
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1α,25-dihydroxycholecalciferol (4) and 1α,25-dihydroxyergocalciferol (7), the hormonally active forms of vitamin D3 (1) and vitamin D2 (5), were synthesized by a Horner-Wittig reaction of the phosphine oxide 11 with the ketones 10 and 12, respectively.The synthon 11 was obtained by a sequence that involves the stereospecific opening of epoxide 15, with sodium acetate in acetic acid, followed by oxidative degradation of the isopropenyl side chain and dehydration of the intermediate 22.Photoisomerisation of the resulting 23 gave 24, which was finally converted to 11.The hydroxylated ketone 10 was obtained from the known intermediate 28.The introduction of the 25-hydroxy side chain was achieved by reaction of the lithium derivative of 30 with the tosylate 29 to give 31, which was catalytically hydrogenated to 32 and then converted to 10.The ketone 12 was prepared by a stereocontrolled route that involves as the key step, the dipolar cycloaddition of nitrone 35 with methyl 3,3-dimethylacrylate (36) to give a 1:1 mixture of isoxazolidines 37 and 38.Stereochemical control was achieved by taking advantage of the thermal reversibility of the cycloaddition, which allows the reequilibration of undesired 37.Isoxazolidine 38 was readily transformed to 43 by reduction, followed by elimination of the nitrogen function, and finally oxidation to 12.
- Baggiolini, Enrico G.,Iacobelli, Jerome A.,Hennessy, Bernard M.,Batcho, Andrew D.,Sereno, John F.,Uskokovic, Milan R.
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p. 3098 - 3108
(2007/10/02)
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