- Stereocontrolled semi-syntheses of deguelin and tephrosin
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We describe stereocontrolled semi-syntheses of deguelin and tephrosin, anti-cancer rotenoids isolated from Tephrosia vogelii. Firstly, we present a new two-step transformation of rotenone into rot-2′-enonic acid via a zinc-mediated ring opening of rotenone hydrobromide. Secondly, following conversion of rot-2′-enonic acid into deguelin, a chromium-mediated hydroxylation provides tephrosin as a single diastereoisomer. An étard-like reaction mechanism is proposed to account for the stereochemical outcome. Our syntheses of deguelin and tephrosin are operationally simple, scalable and high yielding, offering considerable advantages over previous methods.
- Russell, David A.,Freudenreich, Julien J.,Ciardiello, Joe J.,Sore, Hannah F.,Spring, David R.
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supporting information
p. 1593 - 1596
(2017/02/23)
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- NOVEL COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, AND PHARMACEUTICAL COMPOSITION CONTAINING SAME AS ACTIVE INGREDIENT
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The present invention relates to a compound inhibiting Hsp90 and a pharmaceutical composition comprising the same as an active ingredient. The compounds represented by formula 1 and formula 2 of the present invention suppress the expression of Hsp90 so that they can inhibit the accumulation of HIF-1α, the Hsp90 client protein, and also efficiently inhibit the activation of VEGF. In addition, these compounds display low cytotoxicity, so that they can be effectively used as an active ingredient of an anti-cancer agent, a diabetic retinopathy treating agent, and an anti-arthritic agent.
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Paragraph 0324-0327
(2015/07/15)
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- NOVEL COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, AND PHARMACEUTICAL COMPOSITION CONTAINING SAME AS ACTIVE INGREDIENT
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The present invention relates to a novel compound inhibiting Hsp 90 and to a pharmaceutical composition including same as an active ingredient. Compounds of formula 1 and formula 2 according to the present invention inhibit the accumulation of HIF-1α protein, which is an Hsp90 client protein, by suppressing Hsp90 expression, and effectively inhibit the activity of vascular endothelial growth factor (VEGF). Furthermore, said compounds have low cytotoxicity and can thus be used as an active ingredient for the treatment of diabetic retinopathy and arthritis.
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Paragraph 0225-0230
(2015/05/26)
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- Design, synthesis, and biological evaluation of novel deguelin-based heat shock protein 90 (HSP90) inhibitors targeting proliferation and angiogenesis
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Deguelin exhibits potent apoptotic and antiangiogenic activities in a variety of transformed cells and cancer cells. Deguelin also exhibits potent tumor suppressive effects in xenograft tumor models for many human cancers. Our initial studies confirmed that deguelin disrupts ATP binding to HSP90 and consequently induces destabilization of its client proteins such as HIF-1α. Interestingly, a fluorescence probe assay revealed that deguelin and its analogues do not compete with ATP binding to the N-terminus of HSP90, unlike most HSP90 inhibitors. To determine the key parts of deguelin that contribute to its potent HSP90 inhibition, as well as its antiproliferative and antiangiogenic activities, we have established a structure-activity relationship (SAR) of deguelin. In the course of these studies, we identified a series of novel and potent HSP90 inhibitors. In particular, analogues 54 and 69, the B- and C-ring-truncated compounds, exhibited excellent antiproliferative activities with IC50 of 140 and 490 nM in the H1299 cell line, respectively, and antiangiogenic activities in zebrafish embryos in a dose dependent manner (0.25-1.25 μM).
- Chang, Dong-Jo,An, Hongchan,Kim, Kyoung-Suk,Kim, Hyun Ho,Jung, Jinkyung,Lee, Jung Min,Kim, Nam-Jung,Han, Young Taek,Yun, Hwayoung,Lee, Sujin,Lee, Geumwoo,Lee, Seungbeom,Lee, Ju Sung,Cha, Jong-Ho,Park, Ji-Hyeon,Park, Ji Won,Lee, Su-Chan,Kim, Sang Geon,Kim, Jeong Hun,Lee, Ho-Young,Kim, Kyu-Won,Suh, Young-Ger
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p. 10863 - 10884
(2013/03/13)
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- Contrast agents for myocardial perfusion imaging
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The present disclosure is directed, in part, to compounds and methods for imaging myocardial perfusion, comprising administering to a patient a contrast agent which comprises a compound that binds MC-1, and an imaging moiety, and scanning the patient using diagnostic imaging.
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Page/Page column 34; 35
(2010/02/13)
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- Biosynthesis of Rotenone and Amorphigenin. Study of the Origins of Isopropenyl-substituted Dihydrofuran E-Rings using Isotopically Labelled Late Precursors
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Whilst epoxidation of rot-2'-enonic acid is the most likely source of dalpanol in Amorpha fruticosa seedlings, administration of (5'R,6'S)-dalpanol shows that it is not an intermediate on the path to rotenone and amorphigenin.Labelled 4'-hydroxy- or 5'-hydroxy-rot-2'-enonic acid also do not qualify as intermediates in rotenone biosynthesis, but they are each converted into amorphigenin with chemospecific attack on the methyl group.By administration and re-isolation of amorphigenin from A. fruticosa seedlings, our earlier conclusion that hydroxylation ofrotenone to form amorphigenin proceeds with even label scrambling between C-7' and C-8', probably via an allylic radical, is confirmed.Competitive double-labelling experiments are employed to support a scheme in which rotenone derives directly from rot-2'-enonic acid by an enzyme-induced radical-type reaction without the intervention of an hydroxylated intermediate, and the two labelled hydroxyrot-2'-enonic acids are similarly cyclised using their methyl groups.The incorporations into amorphigenin of labelled 4- and 5-hydroxyrot-2'-enonic acids, both of which are shown to occur naturally in A. fruticosa, are similar, but only about one sixth that of rotenone.This, and our related biosynthetic work, rests on an extensive programme of isotopic labelling and reconstructive synthesis.Our earlier method for making -rotenone has been improved, and similar procedures adapted for - and -amorphigenin. 8'-Labelled rotenones are made by a positional interchange using addition of benzeneselenenyl chloride and elimination of the selenoxide, whilst -amorphigenin is made via addition of phenylselenophthalimide.Unlabelled amorphigenin can be isotopically labelled by oxidation to the aldehyde and reduction using sodium borodeuteride or borotritide and a method additional to those we have described earlier is given for tritium labelling of rot-2'-enonic acid. - and -Labelling in the 5'-position of 4'- and 5'-hydroxyrot-2'-enonic acids can be attained through the catalytic hydrogenolysis of amorphigenin though special methods must be used to scrub the samples totally free from the latter.Methods based on the hydrolysis of labelled 4'-bromorot-2'-enonic acid are also described, and 4'-tritium-labelled 4'-hydroxyrot-2'-enonic acid is made from unlabelled material, or from rot-2'-enonic acid, by simple oxidation/reduction methods.
- Bhandari, Prabha,Crombie, Leslie,Kilbee, Geoffrey W.,Pegg, Stephen J.,Proudfoot, Geoffrey,et al.
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p. 851 - 864
(2007/10/02)
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- Mechanism and Stereochemistry of the Enzyme-catalysed Formation of a 2,2-Dimethylchromene Ring from a Prenylated Phenol: Conversion of Rot-2'-enonic Acid into Deguelin by Deguelin Cyclase
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The stereochemistry of the enzymic conversion of rot-2'-enonic acid into deguelin, mediated by deguelin cyclase, has been studied.Using both an enzyme preparation and seedlings of Tephrosia vogellii, it is shown that (6aS,12aS,5'R/S)-5-hydroxy-4',5'-dihydrodeguelin is not an acceptable intermediate: no evidence for other oxygenated intermediates was found.The (pro-R)- and (pro-S)-6'-methyl groups of deguelin were identified by synthesis from rot-2'-enonic acid.Addition of benzeneselenenyl chloride gives two diastereoisomeric 5'-(phenylselenides) of 4',5'-dihydrodeguelin which are separated and their stereochemistry established by X-ray crystallography.Elimination of selenoxide from the (5'S)-stereoisomer then gives (6'R)-deguelin (δC 28.20): (6'S)-deguelin has δC 28.52.Although a chemical conversion of rot-2'-enonic acid into labelled deguelin produces a 1:1 distribution of label between the (pro-R)- and (pro-S)-6'-methyls, the enzyme-mediated conversion results unexpectedly in a 76percent incorporation into the (pro-R)- and 24percent into the (pro-S)-form.The stereochemistry of the removal of the key 1'-hydrogens in rot-2'-enonic acid was therefore examined.Addition of benzenesulfenyl chloride to deguelin gave a highly reactive chloro sulfide by syn-addition through attack from the less hindered β-face of the molecule.Treatment with sodium cyanoborohydride displaced the reactive chlorine with complete inversion to give (6aS,12aS,5'S)-5'-phenylthio-4',5'-dihydrodeguelin.Ring-E scission of the latter proceeded satisfactorily using sodium naphthalenide only after reduction of the 1,2-carbonyl to the alcohol: periodinane oxidation then produced rot-2'-enonic acid.Replacement of the unlabelled cyanoborohydride by cyanoborotritide gave the desired (6aS,12aS,1'S)-rot-2'-enonic acid.The (6aS,12aS,1'R)--counterpart was made by first preparing deguelin by syn-elimination from the sulfoxide formed from (6aS,12aS,4'R,5'S)-5'-phenylthio-4',5'-dihydro-deguelin.Addition of benzenesulfenyl chloride to the deguelin, followed by a sequence parallelling that above, using unlabelled sodium cyanoborohydride, gave the required (6aS,12aS,1'R)-rot-2'-enonic acid.Enzymic conversion of each -labelled rot-2'-enonic acid into deguelin along with a -labelled monitor, shows that a 73percent loss of (pro-4'S-H) in rot-2'-enonic acid correlates with a 76percent attainment of a (pro-6'R-Me) in deguelin, whilst a 27percent loss of (pro-4'R-H) in the former correlates with a 24percent attainment of a (pro-6'S-Me) in the latter.The possible enzymic mechanism of the reaction is discussed and related to a similar mechanism we have suggested for the enzymic formation of rotenone from rot-2'-enonic acid.
- Bhandari, Prabha,Crombie, Leslie,Harper, Mark F.,Rossiter, John T.,Sanders, Mark,Whiting, Donald A.
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p. 1685 - 1698
(2007/10/02)
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- The Stereospecific Generation of Chirally Labelled Benzylic Centres in o-Prenylphenols: 1'-R- and 1'-S-3H>-Rotenonic Acid
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The problem of generating rot-2'-enonic acid stereospecifically with tritium in the 1'-R- and 1'-S-benzylic positions of the prenyl group is solved by a method generally applicable to o-prenylphenols: chiral centres are constructed on a ring system, with
- Bhandari, Prabha,Crombie, Leslie,Harper, Mark H.,Sanders, M.,Whiting, Donald A.
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p. 981 - 982
(2007/10/02)
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- Regioselective Ether Cleavages of Rotenoids: Spiro-ether Formation and Stereoselective Isotopic Labelling of (E)- or (Z)-Phenyl Methyl Groups in (6aS, 12aS)-Rot-2'-enonic Acid
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Treated with boron tribromide (-)-(6aS,12aS,5'R)-rotenone is converted first into a primary allylic bromide by ring-E cleavage, then into the 2-de-O-methyl and finally the 2,3-dide-O-methyl derivatives.With (6aS,12aS,5'R)-6',7'-dihydrorotenone and (6aS,12aS)-isorotenone, ring-E cleavage does not take place.The main reaction is 2-, followed by 2,3-demethylation: this supports a stereospecific pericyclic mechanism for the rotenone ring-E cleavage.Treatment of the geometrically pure (E)-bromide with cyanoboro-deuteride or -tritide leads to (E)-4'-labelled (6aS,12aS)-rot-2'-enonic acid without reduction of the 12-carbonyl group.By using -rotenone, (E)-rot-2'-enonic acid is accessible.Trimethylsilyl iodide can cleave the 2-methoxy-group of rotenonewithout rupturing ring E, and remethylation with - or -diazomethane represents a convenient method for preparing a general tracer molecule.On treatment with sodium hydride, 3-de-O-methylisorotenone (but not the 2-isomer) rearranges into a spiroether, thus confirming the position of initial de-O-methylation as deduced from 1H and 13C n.m.r. data.Because of this rearrangement, methylenation (NaH-CH2I2) of 2,3-dide-O-methylisorotenone gives mainly the methylenedioxy-spiro-ether, with small yields of methylenedioxy-rotenoid.Deuteriogenolysis of (-)-rotenone over palladium catalyst in (2H5)pyridine gives (E)-rot-2'-enonic acid, but experiments using rotenone indicate stereoselectivity rather than stereospecificity, ca. 12percent of (Z)--accompanying the major (E)-product.A similar specimen of rotenonic acid has been prepared.A hydrogenolysis route from amorphigenin, via rotenone, to (Z)-rot-2'-enonic acid is described.
- Carson, David,Crombie, Leslie,Kilbee, Geoffrey W.,Moffatt, Frank,Whiting, Donald A.
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p. 779 - 788
(2007/10/02)
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