- Design and efficient synthesis of novel vitamin D analogues bearing an aniline moiety in their side chains
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Six novel vitamin D analogues bearing an aniline moiety in their side chains were designed and synthesized using a convergent route. The CD ring fragments were prepared from Inhoffen-Lythgoe diol in five- or six-steps with high yields. Secondary amines we
- Obelleiro, Antonio,Gómez-Bouzó, Uxía,Gómez, Generosa,Fall, Yagamare,Santalla, Hugo
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supporting information
(2020/10/13)
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- Modified Julia olefination and α aminoxylation reactions mediated convergent synthesis of 1α, 24 (R)-dihydroxyvitamin D3 (tacalcitol)
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A convergent synthesis of tacalcitol has been achieved starting from inexpensive and commercially available isovaleraldehyde and easily available Inhoffen-Lythgoe diol. Key steps include a proline catalyzed α aminoxylation and a Julia-Kocienski olefination.
- Martínez, Andrea,Santalla, Hugo,Garrido, Fátima,Gómez, Generosa,Fall, Yagamare
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p. 3568 - 3570
(2017/10/06)
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- A new metabolite of Paricalcitol: stereoselective synthesis of (22Z)-isomer of 1α,25-dihydroxy-19-norvitamin D2
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Stereoselective synthesis of (22Z)-isomer of Paricalcitol, an analog of 1,25-dihydroxyergocalciferol, an active form of vitamin D2 (Ergocalciferol) has been described. The two key critical synthetic steps involved are Julia–Lythgoe's Wittig–Hor
- Samala, Ramakrishna,Sharma, Somesh,Basu, Manas K.,Mukkanti,Porstmann, Frank
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supporting information
p. 1309 - 1312
(2018/03/26)
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- Mild and selective deprotection of tert -butyl(dimethyl)silyl ethers with catalytic amounts of sodium tetrachloroaurate(III) dihydrate
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A simple and mild method for the removal of tert-butyl(dimethyl)silyl (TBS) protecting groups with catalytic amounts of sodium tetrachloroaurate(III) dihydrate is described. The procedure permits selective deprotection of aliphatic TBS ethers in good to excellent yields in the presence of aromatic TBS ethers, aliphatic triisopropylsilyl ethers, aliphatic tert-butyl(diphenyl)silyl ethers, or sterically hindered aliphatic TBS ethers. Additionally, TBS ethers can also be transformed into 4-methoxybenzyl ethers or methyl ethers in one pot by using larger quantities of the catalyst and a higher reaction temperature.
- Zhang, Qi,Kang, Xiuqin,Long, Lei,Zhu, Lijuan,Chai, Yonghai
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- Synthesis of Denosomin-Vitamin D3 Hybrids and Evaluation of Their Anti-Alzheimer's Disease Activities
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As an extension of previously conducted studies on developing an anti-Alzheimer's disease agent, denosomin (1-deoxy-24-norsominone, an artificial inducer of neurite elongation), derivatives were designed and synthesized based on the hypothesis that our denosomin would exhibit axonal extension activity via a 1,25D3-membrane-associated, rapid response steroid-binding protein (1,25D3-MARRS) pathway. The biological assay revealed that the hybridization of characteristic δ-lactone in denosomin and the triene moiety in VD3 was effective to enhance the nerve re-extension activity in amyloid β (Aβ)-damaged neurons.
- Sugimoto, Kenji,Yajima, Hisanari,Hayashi, Yusuke,Minato, Daishiro,Terasaki, Sayuri,Tohda, Chihiro,Matsuya, Yuji
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supporting information
p. 5910 - 5913
(2015/12/11)
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- Analogues of the Inhoffen-Lythgoe diol with anti-proliferative activity
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The anti-proliferative activity of a series of ester- and amide-linked Inhoffen-Lythgoe side chain analogues is reported. Whereas the Inhoffen-Lythgoe diol was inactive in these studies, a number of aromatic and aliphatic ester-linked side chains demonstr
- Deberardinis, Albert M.,Lemieux, Steven,Hadden, M. Kyle
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p. 5367 - 5370
(2013/09/23)
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- Synthesis of a trans-hydrindanone, precursor for the preparation of vitamin D analogues
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We developed a very efficient and practical method for the large-scale synthesis of a trans-hydrindan derivative related to vitamin D, based on the Criegee rearrangement. This ketone is a valuable synthon for the preparation of Gemini-type vitamin D analogues or other calcitriol analogues modified at C-20, C-21 or the D-ring. Our methodology is superior to those previously reported when considering efficiency and expediency. The Criegee rearrangement was the key step for a large-scale synthesis of a trans-hydrindan derivative related to vitamin D. This work is superior to previous approaches with regards to efficiency and expediency. Copyright
- Gandara, Zoila,Rivadulla, Marcos L.,Perez, Manuel,Gomez, Generosa,Fall, Yagamare
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p. 5678 - 5682
(2013/09/12)
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- Design, synthesis, evaluation, and structure of vitamin D analogues with furan side chains
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Based on the crystal structures of human vitamin D receptor (hVDR) bound to 1α,25-dihydroxy-vitamin D3 (1,25 D) and superagonist ligands, we previously designed new superagonist ligands with a tetrahydrofuran ring at the side chain that optimize the aliphatic side-chain conformation through an entropy benefit. Following a similar strategy, four novel vitamin D analogues with aromatic furan side chains (3 a, 3 b, 4 a, 4 b) have now been developed. The triene system has been constructed by an efficient stereoselective intramolecular cyclization of an enol triflate (A-ring precursor) followed by a Suzuki-Miyaura coupling of the resulting intermediate with an alkenyl boronic ester (CD-side chain, upper fragment). The furan side chains have been constructed by gold chemistry. These analogues exhibit significant pro-differentiation effects and transactivation potency. The crystal structure of 3 a in a complex with the ligand-binding domain of hVDR revealed that the side-chain furanic ring adopts two conformations. Copyright
- Fraga, Ramon,Zacconi, Flavia,Sussman, Fredy,Ordonez-Moran, Paloma,Munoz, Alberto,Huet, Tiphaine,Molnar, Ferdinand,Moras, Dino,Rochel, Natacha,Maestro, Miguel,Mourino, Antonio
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p. 603 - 612
(2012/02/15)
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- Total synthesis of a CD-ring: Side-chain building block for preparing 17-epi-calcitriol derivatives from the Hajos-Parrish dione
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An efficient synthesis of the key building block for 17-epi-calctriol from the Hajos-Parrish dione involving a sequence of diastereoselective transformation of the azulene core and the side-chain construction is presented.
- Michalak, Karol,Wicha, Jerzy
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experimental part
p. 6906 - 6911
(2011/10/18)
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- Synthesis and preliminary biological evaluation of 20-epi-eldecalcitol [20-epi-1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3: 20-epi-ED-71]
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Eldecalcitol [1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3, developing code: ED-71] is an analog of active vitamin D3, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] that possesses a hydroxypropoxy substituent at the 2β-position of 1,25(OH)2D3. Eldecalcitol has potent biological effects on bone and is now in preparation for approval as a promising medicine for the treatment of osteoporosis in Japan. To explore chemical structure-biological activity relationships between eldecalcitol and related analogs, we have already synthesized 1-epi-eldecalcitol, 3-epi-eldecalcitol, and 1,3-diepi-eldecalcitol with inherent biological interests of each targeted analog and evaluated their biological responses. It has been reported that 20-epi-1,25(OH)2D3, a diastereomer of 1,25(OH)2D3 that possesses an inverted methyl substituent at the 20-position of the side chain, shows remarkably enhanced biological activities compared to parental compound, 1,25(OH)2D3. As a continuation of our modification studies on eldecalcitol, we took great interest in 20-epi-eldecalcitol and its biological responses. In this paper, the synthesis of 20-epi-eldecalcitol by the Trost coupling reaction between the A-ring fragment and the C/D-ring fragment as well as in vitro preliminary biological evaluation of 20-epi-eldecalcitol are described. In the induction of human myeloid leukemia cell (HL-60) differentiation, inhibition of the human histiocytic lymphoma cell (U937) proliferation, and increase in osteocalcin concentration in the human osteosarcoma cell (MG-63), 20-epi-eldecalcitol showed significantly enhanced activity compared to eldecalcitol.
- Hatakeyama, Susumi,Yoshino, Madoka,Eto, Kohei,Takahashi, Keisuke,Ishihara, Jun,Ono, Yoshiyuki,Saito, Hitoshi,Kubodera, Noboru
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- Synthesis of 20-epi-eldecalcitol [20-epi-1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3: 20-epi-ED-71]
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A convergent synthesis of biologically interesting 20-epi-eldecalcitol which possesses an inverted C-21 methyl substituent at the 20-position of the side chain of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (eldecalcitol) is described.
- Yoshino, Madoka,Eto, Kohei,Takahashi, Keisuke,Ishihara, Jun,Hatakeyama, Susumi,Ono, Yoshiyuki,Saito, Hitoshi,Kubodera, Noboru
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experimental part
p. 381 - 394
(2010/09/05)
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- Vitamin D receptor agonist/histone deacetylase inhibitor molecular hybrids
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Incorporation of zinc-binding groups into the side-chain of 1α,25-dihydroxyvitamin D3 (1,25D) fully bifunctional hybrid molecules which act both as vitamin D receptor agonists and histone deacetylase inhibitors. These bifunctional hybrids displ
- Lamblin, Marc,Dabbas, Basel,Spingarn, Russell,Mendoza-Sanchez, Rodrigo,Wang, Tian-Tian,An, Beum-Soo,Huang, Dao Chao,Kremer, Richard,White, John H.,Gleason, James L.
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experimental part
p. 4119 - 4137
(2010/08/06)
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- HYBRID MOLECULES HAVING MIXED VITAMIN D RECEPTOR AGONISM AND HISTONE DEACETYLASE INHIBITORY PROPERTIES
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Hybrid molecules comprising a vitamin D receptor agonist moiety and an HDAC inhibitor moiety are described herein. The HDAC inhibitor moiety can be derived from an HDAC inhibitor comprising a functionality selected from the group consisting of an N-hydrox
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- VITAMIN D RECEPTOR ACTIVATORS AND METHODS OF MAKING
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The invention relates to compounds that are vitamin D receptor activators, compositions comprising such compounds, methods of using such compounds and compositions, processes for preparing such compounds, and intermediates obtained during such processes.
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Page/Page column 26
(2009/05/28)
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- HYBRID MOLECULES HAVING MIXED VITAMIN D RECEPTOR AGONISM AND HISTONE DEACETYLASE INHIBITORY PROPERTIES
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Hybrid molecules comprising a vitamin D receptor agonist moiety and an HDAC inhibitor moiety are described herein The HDAC inhibitor moiety can be modelled after an HDAC inhibitor selected from the group consisting of tπchostatm A, sodium butyrate, valpro
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Page/Page column 60-61
(2008/06/13)
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- 2alpha-Methyl and 2beta-methyl analogs of 19,26,27-trinor-(20S)-1alpha-hydroxyvitamin D3 and their uses
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This invention discloses 2α-methyl and 2β-methyl analogs of 19,26,27-trinor-(20S) -1α-hydroxyvitamin D3 and pharmaceutical uses therefor. These compounds exhibit pronounced activity in arresting the proliferation of undifferentiated cells and i
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Page/Page column 4
(2010/11/08)
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- 2-METHYLENE-19,26,27-TRINOR-(20S)-1α-ALPHA-HYDROXYVITAMIN D3 AND ITS USES
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This invention discloses 2-methylene-19,26,27-trinor-(20S)-vitamin D analogs, and specifically 2-methylene-19,26,27-trinor-(20S)-lα-hydroxyvitamirt D3 and pharmaceutical uses therefor. This compound exhibits pronounced activity in arresting the
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Page/Page column 11
(2010/11/08)
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- 19,26,27-TRINOR-1α,25-DIHYDROXYVITAMIN D3 COMPOUNDS
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Compounds of formula (1) are provided where X1, X2, and X3 are independently selected from H or hydroxy protecting groups, and R1 and R2 have the definitions provided herein. Such compounds may be used in preparing pharmaceutical compositions and are useful in treating a variety of biological conditions.
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Page/Page column 21-22
(2010/11/24)
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- Strained polycycles by H5C5x free-radical cascades
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An H5C5x-type free-radical chain reaction selectively generates up to three new bonds and three new stereocenters in one pot. This previously unexploited strategy provides a straightforward route to the tricyclic cyclopenta[c]indene
- Moman, Edelmiro,Nicoletti, Daniel,Mourino, Antonio
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p. 1249 - 1251
(2007/10/03)
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- Vitamin D analogs for obesity prevention and treatment
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Methods for treating and preventing obesity, inhibiting adipocyte differentiation, inhibiting increased SCD-1 gene transcription, and/or reducing body fat in a subject include administering at least one analog of 1α,25-dihydroxyvitamin D3 or 1α
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- 2-Methylene-19-nor-20(S)-25-methyl-1alpha-hydroxycalciferol and its uses
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This invention provides a novel vitamin D analog, namely, 2-methylene-19-nor-20(S)-25-methyl-1α-hydroxycalciferol. The compound has the formula: This 2-substituted compound is characterized by relatively high intestinal calcium transport activity and rela
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Page/Page column 4; 9
(2010/02/10)
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- Vitamin D receptor antagonists and their use in treating asthma
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Various compounds such as those having the formula I and XIV where the variables have the values described herein antagonize the vitamin D receptor and are useful in treating conditions such as asthma and in preparing medicaments for use in antagonizing the vitamin D receptor or treating conditions such as asthma
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Page/Page column 13; 14
(2010/02/13)
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- 2-methylene-19-nor-20(S)-25-methyl-1α-hydroxycalciferol and its uses
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This invention provides a novel vitamin D analog, namely, 2-methylene-19-nor-20(S)-25-methyl-1α-hydroxycalciferol. The compound has the formula: This 2-substituted compound is characterized by relatively high intestinal calcium transport activity and rela
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- Vitamin D heterocyclic analogues. Part 1: A stereoselective route to CD systems with pyrazole rings in their side chains
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Efficient preparation of two vitamin D CD ring system synthons with pyrazole rings in their side chains is based on the formation of the pyrazole ring from an α-acetylenic ketone.
- Fall, Yagamare,Barreiro, Candida,Fernández, Carlos,Mouri?o, Antonio
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p. 1433 - 1436
(2007/10/03)
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- Parallel synthesis of a vitamin D3 library in the solid-phase
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A highly efficient synthesis of the vitamin D3 system on solid support is described. Two synthetic strategies for the solid-phase synthesis of vitamin D3 were developed. One is for 11-hydroxy analogues, and the other is for most other synthetic analogues. In the latter strategy, the sulfonate-linked CD-ring 58 was initially immobilized on PS-DES resin to give solid-supported CD-ring 63 (Scheme 10). Similarly, solid-supported CD-ring 63 was prepared by attachment of the CD-ring 10 to the chlorosulfonate resin 64. The vitamin D3 system was synthesized by Horner-Wadsworth-Emmons reaction of the A-ring phosphine oxide to a solid-supported CD-ring, followed by simultaneous introduction of the side chain and cleavage from resin with a Cu1-catalyzed Grignard reagent. Parallel synthesis of the vitamin D3 analogues was accomplished by a split and pool methodology utilizing radio frequency encoded combinatorial chemistry, and a manual parallel synthesizer for side chain diversification and deprotection. Additionally, we demonstrated the synthesis of various A-rings in a similar protocol for efficient preparation of building blocks.
- Hijikuro,Doi,Takahashi
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p. 3716 - 3722
(2007/10/03)
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- Efficient synthesis and biological evaluation of all A-ring diastereomers of 1α,25-dihydroxyvitamin D3 and its 20-epimer
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An improved synthesis of the diastereomers of 1α,25-dihydroxyvitamin D3 (1) was accomplished utilizing our practical route to the A-ring synthon. We applied this procedure to synthesize for the first time all possible A- ring diastereomers of 20-epi-1α,25-dihydroxyvitamin D3 (2). Ten-step conversion of 1-(4-methoxyphenoxy)but-3-ene (6), including enantiomeric introduction of the C-3 hydroxyl group to the olefin by the Sharpless asymmetric dihydroxylation, provided all four possible stereoisomers of A- ring enynes (3), i.e., (3R,5R)-, (3R,5S)-, (3S,5R)- and (3S,5S)-bis[(tert- butyldimethylsilyl)oxy]oct-1-en-7-yne, in good overall yield. Palladium- catalyzed cross-coupling of the A-ring synthon with the 20-epi CD-ring portion (5), (E)-(20S)-de-A,B-8-(bromomethylene)cholestan-25-ol, followed by deprotection, afforded the requisite diastereomers of 20-epi-1α,25- dihydroxyvitamin D3 (2). The biological profiles of the synthesized stereoisomers were assessed in terms of affinities for vitamin D receptor (VDR) and vitamin D binding protein (DBP), HL-60 cell differentiation- inducing activity and in vivo calcium-regulating potency in comparison with the natural hormone. (C) 2000 Elsevier Science Ltd.
- Fujishima, Toshie,Konno, Katsuhiro,Nakagawa, Kimie,Kurobe, Mayuko,Okano, Toshio,Takayama, Hiroaki
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p. 123 - 134
(2007/10/03)
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- Synthesis and biological activity of 2-methyl-20-epi analogues of 1α,25-dihydroxyvitamin D3
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Synthesis and biological evaluation of all eight possible A-ring diastereomers of 2-methyl-20-epi-1,25-dihydroxyvitamin D3 are described. Among the analogues synthesized, 2α-methyl-20-epi-1α,25-dihydroxyvitamin D3 exhibited exceptionally high potency. The double modification of 2- methyl substitution and 20-epimerization yielded analogues with unique activity profiles.
- Fujishima, Toshie,Liu, Zhaopeng,Miura, Daishiro,Chokki, Manabu,Ishizuka, Seiichi,Konno, Katsuhiro,Takayama, Hiroaki
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p. 2145 - 2148
(2007/10/03)
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- Antiproliferative hybrid analogs of the hormone 1α,25-dihydroxyvitamin D3: Design, synthesis, and preliminary biological evaluation
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The combination of 10-12 kbar pressure plus Lewis acidic zinc dichloride promotes highly regioselective and stereoselective Diels-Alder cycloaddition between 3-bromo-2-pyrone, prepared in a new way, and unactivated terminal alkene 4-(tert-butyldimethylsiloxy)-1-butene. The conjugate base of A-ring allylic phosphine oxide 20 adds chemospecifically to the C-8 keto group of some C-8,C-24-diketones to form directly metabolically resistant 24-oxo analogs of 1α,25-dihydroxyvitamin D3 (calcitriol). Several of these new hybrid analogs are as efficacious in vitro as calcitriol at inhibiting growth of murine keratinocytes even at physiologically relevant 10-100 nanomolar concentrations.
- Posner,Lee,White,Hutchings,Dai,Kachinski,Dolan,Kensler
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p. 3299 - 3314
(2007/10/03)
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- α,25-Dihydroxyvitamin D3 analogs featuring aromatic and heteroaromatic rings: Design, synthesis, and preliminary biological testing
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Aromatic compounds 2a-c, analogs of 1α,25-dihydroxyvitamin (calcitriol, 1), and heteroaromatic compounds 4a-c and 5a-c, analogs of 19-nor-1α,25- dihydroxyvitamin D3 (3), were designed to simulate the topology of their biologically potent parent
- Posner,Li,White,Vinader,Takeuchi,Guggino,Dolan,Kensler
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p. 4529 - 4537
(2007/10/03)
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- Studies on the Synthesis of Side-Chain Hydroxylated Metabolites of Vitamin D. 3. Synthesis of 25-Ketovitamin D3 and 25-Hydroxyvitamin D3
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A general method for the synthesis of the principal vitamin D3 metabolites whether unlabeled or with radiolabeled side chains is described.The synthesis of the key de-A,B-(ethylenedioxy)cholestanone derivative 7d is based on the coupling between the iodid
- Mascarenas, J. L.,Mourino, A.,Castedo, L.
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p. 1269 - 1272
(2007/10/02)
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