- Synthesis of the fatty sterol bound protein for a new sterol antibody
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For the purpose of applying the particular antibodies as a new diagnostic procedure for atherosclerosis and related diseases, we successfully achieved the synthesis of the fatty sterol with a linker, then linked the target protein to this sterol. Synthesis was started from pregnenolone and achieved by the Grignard reaction with pentenyl magnesium bromide, regioselective photo-addition of thiolacetic acid toward the 25-double bond, esterification of 3-OH with linoleic anhydride, in situ conjunction of the cross-linker (MBS) to the thiol group after selective deprotection from its acetyl ester, and finally by the reaction with protein such as KLH or albumin through this linker. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Kim, Byung Ju,Yamada, Satoshi,Funada, Tadashi,Kadoma, Yoshihito,Morita, Hiroyuki
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Read Online
- ACETYLENIC CHOLESTERYL DERIVATIVES AS IRREVERSIBLE INHIBITORS OF ECDYSONE BIOSYNTHESIS
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Two series of acetylenic derivatives of cholesterol were synthesized from stigmasterol and pregnenolone.These compounds carry an acetylenic function at C-22 and were devised with the aim to inhibit the C-22hydroxylation of ecdysone biosynthesis by a suicide-substrate mechanism.Two of these compounds (15a, 15f) inhibit the synthesis of ecdysone in follicular cells under in vitro conditions.The inhibition is selective of the C-22 hydroxylase system.
- Burger, Alain,Colobert, Francoise,Hetru, Charles,Luu, Bang
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Read Online
- Synthesis of new C-25 and C-26 steroidal acids as potential ligands of the nuclear receptors DAF-12, LXR and GR
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A new methodology to obtain C-25 and C-26 steroidal acids starting from pregnenolone is described. Construction of the side chain was achieved by applying the Mukaiyama aldol reaction with a non-hydrolytic work-up to isolate the trapped silyl enol ether with higher yields. Using this methodology we synthesized three new steroidal acids as potential ligands of DAF-12, Liver X and Glucocorticoid nuclear receptors and studied their activity in reporter gene assays. Our results show that replacement of the 21-CH3 by a 20-keto group in the side chains of the cholestane scaffold of DAF-12 or Liver X receptors ligands causes the loss of the activity.
- Dansey, María V.,del Fueyo, María C.,Veleiro, Adriana S.,Di Chenna, Pablo H.
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Read Online
- STEREOSPECIFIC SYNTHESIS OF HYDROXYLATED STEROID SIDE CHAINS. SYNTHESIS OF 25,28-DIHYDROXY-7,8-DIHYDROERGOSTEROL AND ITS C-24 EPIMER VIA SIGMATROPIC REARRANGEMENT.
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An efficient, stereospecific synthesis of hydroxylated ergosterol and C-24 epi-ergosterol side chains has been developed using a C-20 keto-steroid as starting material.The side chain is elaborated via stereoselective hydroboration, asymmetric reduction and a stereospecific sigmatropic rearrangement.
- Midland, M. Mark,Kwon, Young C.
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Read Online
- Synthesis of withanolide A, biological evaluation of its neuritogenic properties, and studies on secretase inhibition
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Neurons on steroids: A stereoselective synthesis of the neuritogenic steroid lactone withanolide A was achieved by singlet oxygen ene reaction, Wharton transposition, a Corey-Seebach homologation, and a vinylogous aldol reaction. Biological evaluation demonstrated neurite outgrowth, which supports the potential neuritogenic role of this compound in traditional Indian medicine.
- Jana, Chandan Kumar,Hoecker, Johannes,Woods, Tom M.,Jessen, Henning J.,Neuburger, Markus,Gademann, Karl
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Read Online
- Identification of Inhibitors of Cholesterol Transport Proteins Through the Synthesis of a Diverse, Sterol-Inspired Compound Collection
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Cholesterol transport proteins regulate a vast array of cellular processes including lipid metabolism, vesicular and non-vesicular trafficking, organelle contact sites, and autophagy. Despite their undoubted importance, the identification of selective modulators of this class of proteins has been challenging due to the structural similarities in the cholesterol-binding site. Herein we report a general strategy for the identification of selective inhibitors of cholesterol transport proteins via the synthesis of a diverse sterol-inspired compound collection. Fusion of a primary sterol fragment to an array of secondary privileged scaffolds led to the identification of potent and selective inhibitors of the cholesterol transport protein Aster-C, which displayed a surprising preference for the unnatural-sterol AB-ring stereochemistry and new inhibitors of Aster-A. We propose that this strategy can and should be applied to any therapeutically relevant sterol-binding protein.
- Laraia, Luca,Olsen, Asger Hegelund,Whitmarsh-Everiss, Thomas
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supporting information
p. 26755 - 26761
(2021/11/17)
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- Elucidation of Distinct Modular Assemblies of Smoothened Receptor by Bitopic Ligand Measurement
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Class F G protein-coupled receptors are characterized by a large extracellular domain (ECD) in addition to the common transmembrane domain (TMD) with seven α-helixes. For smoothened receptor (SMO), structural studies revealed dissected ECD and TMD, and th
- Zhao, Fei,Wu, Yiran,Zhou, Fang,Xue, Dongxiang,Zhao, Simeng,Lu, Wanglong,Liu, Xiaoyan,Hu, Tao,Qiu, Yanli,Li, Rongyan,Gu, Tangjie,Xu, Yueming,Xu, Fei,Zhong, Guisheng,Jiang, Zhongxing,Zhao, Suwen,Tao, Houchao
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supporting information
p. 13830 - 13840
(2021/09/28)
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- Smooth receptor ligand
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The invention relates to the technical field of biology, particularly to a smooth receptor ligand, and provides a smooth receptor ligand or an isomer prodrug, a solvate and a pharmaceutically acceptable salt thereof, wherein the structural formula of the smooth receptor ligand is A-linker-B, A is an extracellular domain ligand structure, B is a transmembrane domain ligand structure, and Linker isa linear subunit inactive to the smooth receptor. According to the novel double-end small molecule ligand for the smooth receptor, by combining the crystal structure data of the smooth receptor, a linker is introduced into the proper sites of an extracellular domain ligand and a transmembrane domain ligand to obtain brand-new double-end ligand small molecules, so that the interaction between the ligand and the receptor and the biological activity of the ligand are enhanced.
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Paragraph 0085; 0094; 0096; 0105
(2020/04/01)
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- OXYSTEROLS THAT ACTIVATE LIVER X RECEPTOR SIGNALING AND INHIBIT HEDGEHOG SIGNALING
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This invention relates, e.g., to compositions comprising oxysterol compounds represented by Formula I or Formula II, e.g., comprising one or more of Oxy 16, Oxy 22, Oxy30, Oxy 31, Oxy35, Oxy37, Oxy43, Oxy44, Oxy45 or Oxy47. The compounds are shown to be Hedgehog pathway inhibiting, and to act as agonists for liver X receptor (LXR). Also disclosed are methods of using compositions of the invention to inhibit Hedgehog signaling effects, such as cell proliferation, including treating subjects in need thereof, and pharmaceutical compositions and kits for implementing methods of the invention.
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Paragraph 0109
(2016/08/17)
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- Isotope-Labeling Studies Support the Electrophilic Compound i Iron Active Species, FeO3+, for the Carbon-Carbon Bond Cleavage Reaction of the Cholesterol Side-Chain Cleavage Enzyme, Cytochrome P450 11A1
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The enzyme cytochrome P450 11A1 cleaves the C20-C22 carbon-carbon bond of cholesterol to form pregnenolone, the first 21-carbon precursor of all steroid hormones. Various reaction mechanisms are possible for the carbon-carbon bond cleavage step of P450 11A1, and most current proposals involve the oxoferryl active species, Compound I (FeO3+). Compound I can either (i) abstract an O-H hydrogen atom or (ii) be attacked by a nucleophilic hydroxy group of its substrate, 20R,22R-dihydroxycholesterol. The mechanism of this carbon-carbon bond cleavage step was tested using 18O-labeled molecular oxygen and purified P450 11A1. P450 11A1 was incubated with 20R,22R-dihydroxycholesterol in the presence of molecular oxygen (18O2), and coupled assays were used to trap the labile 18O atoms in the enzymatic products (i.e., isocaproaldehyde and pregnenolone). The resulting products were derivatized and the 18O content was analyzed by high-resolution mass spectrometry. P450 11A1 showed no incorporation of an 18O atom into either of its carbon-carbon bond cleavage products, pregnenolone and isocaproaldehyde. The positive control experiments established retention of the carbonyl oxygens in the enzymatic products during the trapping and derivatization processes. These results reveal a mechanism involving an electrophilic Compound I species that reacts with nucleophilic hydroxy groups in the 20R,22R-dihydroxycholesterol intermediate of the P450 11A1 reaction to produce the key steroid pregnenolone.
- Yoshimoto, Francis K.,Jung, I-Ji,Goyal, Sandeep,Gonzalez, Eric,Guengerich, F. Peter
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p. 12124 - 12141
(2016/10/03)
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- Synthesis and Biological Evaluation of Vitamin D3 Metabolite 20S,23S-Dihydroxyvitamin D3 and Its 23R Epimer
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The vitamin D3 metabolite, 20S,23S-dihydroxyvitamin D3, was chemically synthesized for the first time and identified to be the same as the enzymatically produced metabolite. The C23 absolute configurations of both 20S,23S/R-dihydroxyvitamin D3 epimers were unambiguously assigned by NMR and Mosher ester analysis. Their kinetics of CYP27B1 metabolism were investigated during the production of their 1α-hydroxylated derivatives. Bioactivities of these products were compared in terms of vitamin D3 receptor activation, anti-inflammatory, and antiproliferative activities.
- Lin, Zongtao,Marepally, Srinivasa R.,Ma, Dejian,Kim, Tae-Kang,Oak, Allen Sw.,Myers, Linda K.,Tuckey, Robert C.,Slominski, Andrzej T.,Miller, Duane D.,Li, Wei
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p. 5102 - 5108
(2016/06/13)
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- Oxysterols for activation of hedgehog signaling, osteoinduction, antiadipogenesis, and Wnt signaling
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Synthetic oxysterols can be made and can be used for the treatment of bone disorders, obesity, cardiovascular disorders, and neurological disorders.
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Page/Page column 26
(2017/01/19)
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- BONE-SELECTIVE OSTEOGENIC OXYSTEROL-BONE TARGETING AGENTS
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Compounds and compositions for the treatment of bone disorders are presented. Oxysterol compounds and compositions for the treatment of bone disorders are presented. The compounds are conjugates or derivatives of (3S,5S,6S,8R,9S,10R,13S,14S,17S)-17-[(2S)-2-hydroxyoctan-2-yl]-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17- tetradecahydro-1H-cyclopenta[a]phenanthrene-3,6-diol with a BTA-linker, such as from a tetracycline fragment, attached to 3-position, 6-position, or 20-position. These osteogenic oxysterol compounds stimulate hedgehog signaling pathway. The various linker units are susceptible to certain esterases.
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Paragraph 0032
(2014/11/13)
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- Novel oxysterols activate the Hedgehog pathway and induce osteogenesis
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Localized induction of bone formation is essential during orthopedic procedures that involve skeletal repair, such as surgical treatment of non-union bone fractures and degenerative disk disease. Herein we disclose the synthesis and biological evaluation of novel oxysterol derivatives designed as anabolic bone growth agents. Structure-activity relationship studies of oxysterol 4 have identified analogues such as 18, 21 and 30. These new analogues are characterized by higher potency in an osteoblast differentiation assay and/or by increased metabolic stability in human liver microsomes. Oxysterols 4, 18 and 21 were evaluated in vivo in a rat spinal fusion model.
- Stappenbeck, Frank,Xiao, Wei,Epperson, Matt,Riley, Mariko,Priest, Aaron,Huang, Danwen,Scott Thies, R.,Farouz, Francine,Nguyen, Khanhlinh,Jung, Michael E.
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p. 5893 - 5897,5
(2020/07/31)
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- Substrate analog studies of the ω-regiospecificity of Mycobacterium tuberculosis cholesterol metabolizing cytochrome P450 enzymes CYP124A1, CYP125A1 and CYP142A1
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We report the synthesis and evaluation of a series of cholesterol side-chain analogs as mechanistic probes of three important Mycobacterium tuberculosis cytochrome P450 enzymes that selectively oxidize the ω-position of the methyl-branched cholesterol side-chain. To probe the structural requirements for the thermodynamically disfavored ω-regiospecificity we compared the binding of these substrate analogs to each P450, determined the turnover rates, and characterized the enzymatic products. The results are discussed in the context of the structure-activity relationships of the enzymes and how their active sites enforce ω-oxidation.
- Johnston, Jonathan B.,Singh, Arti A.,Clary, Anaelle A.,Chen, Chiung-Kuan,Hayes, Patricia Y.,Chow, Sharon,De Voss, James J.,Ortiz De Montellano, Paul R.
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supporting information; scheme or table
p. 4064 - 4081
(2012/09/22)
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- Structure-activity relationships for side chain oxysterol agonists of the hedgehog signaling pathway
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Oxysterols (OHCs) are byproducts of cholesterol oxidation that are known to activate the Hedeghog (Hh) signaling pathway. While OHCs that incorporate hydroxyl groups throughout the scaffold are known, those that act as agonists of Hh signaling primarily contain a single hydroxyl on the alkyl side chain. We sought to further explore how side chain hydroxylation patterns affect oxysterol-mediated Hh activation, by performing a structure-activity relationship study on a series of synthetic OHCs. The most active analogue, 23(R)-OHC (35), demonstrated potent activation of Hh signaling in two Hh-dependent cell lines (EC50 values 0.54-0.65 μM). In addition, OHC 35 was approximately 3-fold selective for the Hh pathway as compared to the liver X receptor, a nuclear receptor that is also activated by endogenous OHCs. Finally, 35 induced osteogenic differentiation and osteoblast formation in cultured cells, indicating functional agonism of the Hh pathway.
- Corman, Audrey,Deberardinis, Albert M.,Hadden, M. Kyle
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p. 828 - 833
(2013/01/15)
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- Stereoselective synthesis and antimicrobial activity of steroidal C-20 tertiary alcohols with thiazole/pyridine side chain
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Stereoselective synthesis of novel steroidal C-20 tertiary alcohols with thiazole and pyridine side chain using Grignard reaction of steroidal ketones and thiazole/pyridine magnesium bromide have been realized. These molecules were evaluated in vitro for their antifungal and antibacterial activities. Most of the compounds exhibited significant antifungal and antibacterial activity against all the tested strains.
- Shingate, Bapurao B.,Hazra, Braja G.,Salunke, Deepak B.,Pore, Vandana S.,Shirazi, Fazal,Deshpande, Mukund V.
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p. 3681 - 3689
(2011/11/06)
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- INHIBITION OF PPAR GAMMA EXPRESSION IN PREADIPOCYTE CELLS BY OXYSTEROLS
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This invention relates, e.g., to methods and agents to inhibit peroxisome proliferator activated receptor expression (PPAR) in preadipocytes.
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Page/Page column 33
(2011/02/24)
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- Bioorthogonal chemical tagging of protein cholesterylation in living cells
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We report the first chemical probe for bioorthogonal chemical tagging of post-translationally cholesterylated proteins with an azide in living cells. This enables rapid multiplexed fluorescence detection and affinity labelling of protein cholesterylation, as exemplified by Sonic hedgehog protein, opening up new approaches for the de novo identification of cholesterylated proteins.
- Heal, William P.,Jovanovic, Biljana,Bessin, Sara,Wright, Megan H.,Magee, Anthony I.,Tate, Edward W.
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supporting information; experimental part
p. 4081 - 4083
(2011/06/21)
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- Efficient Process for Preparing Steroids and Vitamin D Derivatives With the Unnatural Configuration at C20 (20 Alpha-Methyl) from Pregnenolone
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Disclosed herein are methods for preparing steroids and Vitamin D derivatives having the unnatural beta (usually S) configuration at C20, the methods comprising the use of compounds of the formula: wherein R is as defined herein. Also disclosed are steroids and Vitamin D derivatives made using the methods disclosed herein and pharmaceutical compositions comprising said steroids and Vitamin D derivatives.
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Page/Page column 52
(2008/12/06)
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- OXYSTEROL COMPOUNDS AND THE HEDGEHOG PATHWAY
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This invention relates, for example, to synthetic oxysterols. Also described are methods for using the compounds, including treating subjects in need thereof, and pharmaceutical compositions and kits for implementing methods of the invention.
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Page/Page column 46
(2010/11/28)
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- Stereoselective syntheses of 20-epi cholanic acid derivatives from 16-dehydropregnenolone acetate
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A stereoselective total synthesis of naturally occurring 20-epi cholanic acid derivatives has been realized, starting from readily available 16-dehydropregnenolone acetate. The key step of these syntheses involves an ionic hydrogenation of a C-20,22-ketene dithioacetal and deoxygenation of steroidal C-20 tert-alcohols, to set up the unnatural C(20R) configuration with 100% stereoselectivity. The unnatural C-22 aldehydes with C(20R) stereocenters thus obtained were elaborated to 20-epi cholanic acid derivatives. Two derivatives of 20-epi cholanic acid were synthesized and their structures have been confirmed by single crystal X-ray analysis. Catalytic hydrogenation of 16-dehydropregnenolone acetate and 16-dehydropregnenolone in ethanol affords C-5,C-16 tetrahydro products. Crystal structure analysis of one of these products revealed C-5α and C-17α configurations of the hydrogen atoms.
- Shingate, Bapurao B.,Hazra, Braja G.,Pore, Vandana S.,Gonnade, Rajesh G.,Bhadbhade, Mohan?M.
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p. 5622 - 5635
(2008/01/06)
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- Stereoselective synthesis of (22R)- and (22S)-castasterone/ponasterone a hybrid compounds and evaluation of their molting hormone activity
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Two stereoisomers of a castasterone/ponasterone A hybrid compound, the (20R,22R) and (20R,22S)-isomers of 2α,3α,20,22-tetrahydroxy- 5α-cholestan-6-one, were synthesized stereoselectively and their binding activity to the ecdysteroid receptor was determined. From the concentration-response curve for the inhibition of the incorporation of tritiated ponasterone A into ecdysteroid receptor containing insect cells, the concentration (IC50) required to inhibit 50% of the incorporation of radioactivity into cells was evaluated. The IC50 values of the (22R)- and (22S)-isomers were determined to be 0.30 and 38.9 μM against Kc cells, respectively, indicating that the (22R)-isomer is about 100 times more potent than the corresponding (22S)-isomer. IC50 values of these compounds against lepidopteran Sf-9 cells were determined to be 0.36 and 12.9 μM, respectively. The molting hormonal effect was examined in a Chilo suppressalis integument system and the 50% effective concentration for the stimulation of N-acetylglucosamine incorporation into the cultured integument was determined to be 2.7 μM for the (22R)-isomer, while the (22S)-isomer was inactive. On the other hand, both isomers did not show brassinolide-like activity in the rice lamina inclination assay.
- Watanabe, Bunta,Nakagawa, Yoshiaki,Ogura, Takehiko,Miyagawa, Hisashi
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p. 483 - 493
(2007/10/03)
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- Stereoselective synthesis of a new hexanor(C23-C28) castasterone-20,22-ethyl diether from 16-dehydropregnenolone acetate and its plant growth promoting activity
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Stereoselective synthesis of a new hexanor(C23-C28)castasterone-20,22-ethyl diether 22 has been achieved in sixteen steps from cheap and readily available 16-dehydropregnenolone acetate. This new brassinosteroid has shown typical brassin activity in mung bean epicotyl bioassay.
- Hazra, Braja G.,Basu, Sourav,Bahule, Bharat B.,Pore, Vandana S.,Vyas, Brahmanand N.,Ramraj, Velaswamy M.
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p. 4909 - 4920
(2007/10/03)
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- Stereoselective synthesis of (22R,23R,24S)-3β-Hydroxy-5-ene-22,23-dihydroxy-24-methyl-cholestane: A Brassinolide Intermediate from 16-Dehydropregnenolone Acetate
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A new synthesis of the important aldehyde 1 from easily available 16-Dehydropregnenolone acetate (16-DPA) in high yield is described.The aldehyde 1 is converted to triol 24, involving a stereoselective generation of all the four chiral centers in the brassinolide side chain.The important features of this synthesis is stereospecific generation of the acetate 14 through ene reaction using three different catalysts as well as regioselective wittig reaction on the acetoxy aldehyde 20.Conversion of triol 24 to brassinolide is known, hence this constitutes a formal total synthesis of brassinolide.
- Hazra, Braja G.,Joshi, Padmakar L.,Bahule, Bharat B.,Argade, Narshinha P.,Pore, Vandana S.,Chordia, Mahendra D.
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p. 2523 - 2532
(2007/10/02)
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- Synthesis of an ecdysteroid inhibitor of ecdysone biosynthesis
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The hydroboration-oxidation of a Δ5,7 pregnadiene leads to a Δ76α-hydroxyderivative. This is converted to an acetylenic analogue of ecdysteroids, which is an inhibitor of their biosynthesis in vitro.
- Mauvais, Antony,Hetru, Charles,Luu, Bang
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p. 5171 - 5174
(2007/10/02)
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