- General Synthetic Approach to Rotenoids via Stereospecific, Group-Selective 1,2-Rearrangement and Dual S N Ar Cyclizations of Aryl Fluorides
-
A general synthetic approach to rotenoids is described, featuring 1) stereospecific, group-selective 1,2-rearrangements of epoxy alcohols, and 2) S N Ar oxy-cyclizations of aryl fluorides. The common intermediate epoxyketone, en route to (-)-rotenone and (-)-deguelin, was prepared from d -araboascorbic acid in five steps. Also described is the conversion of (-)-deguelin into oxidized congeners, (-)-tephrosin and (+)-12a- epi -tephrosin.
- Matsuoka, Seiya,Nakamura, Kayo,Ohmori, Ken,Suzuki, Keisuke
-
p. 1139 - 1156
(2019/02/26)
-
- Concise Total Synthesis of (±)-Deguelin and (±)-Tephrosin Using a Vinyl Iodide as a Key Building Block
-
A concise and protecting-group-free total synthesis of the antiproliferative natural product (±)-deguelin (2) was accomplished in four steps and 62% overall yield from commercially available precursors. The key transformation employed a vinyl iodide as the pivotal building block to construct the 4-acylchromene substructure present in deguelin. Subsequent Cu2O-mediated α-hydroxylation of deguelin (2) afforded tephrosin (3) in 90% yield.
- Xu, Shengtao,Wang, Guangyu,Xu, Feijie,Li, Wenlong,Lin, Aijun,Yao, Hequan,Xu, Jinyi
-
p. 1055 - 1059
(2018/05/07)
-
- Stereocontrolled semi-syntheses of deguelin and tephrosin
-
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.
-
p. 1593 - 1596
(2017/02/23)
-
- Total synthesis of (-)-deguelin via an iterative pyran-ring formation strategy
-
Enantioselective synthesis of (-)-deguelin was accomplished via an iterative pyran-ring formation approach. The key features involve the anionic addition of a chromene unit to aryloxy alkyl aldehyde for the double cyclization precursor and iterative pyran ring formation by Pd-catalyzed O-arylation and C-arylation, respectively. This journal is
- Lee, Seungbeom,An, Hongchan,Chang, Dong-Jo,Jang, Jaebong,Kim, Kyeojin,Sim, Jaehoon,Lee, Jeeyeon,Suh, Young-Ger
-
p. 9026 - 9029
(2015/05/27)
-
- NOVEL COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, AND PHARMACEUTICAL COMPOSITION CONTAINING SAME AS ACTIVE INGREDIENT
-
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.
- -
-
-
- NOVEL COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, AND PHARMACEUTICAL COMPOSITION CONTAINING SAME AS ACTIVE INGREDIENT
-
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.
- -
-
-
- A concise enantioselective synthesis and cytotoxic evaluation of the anticancer rotenoid deguelin enabled by a tandem Knoevenagel/conjugate addition/decarboxylation sequence
-
(-)-Deguelin is a rotenoid natural product that possesses significant potential as a chemopreventive and chemotherapeutic agent. While several racemic syntheses of deguelin have been reported, a formal evaluation of the anticancer activity of both the natural and unnatural enantiomers remains lacking. We describe herein the successful application of a flexible and selective thiourea-catalyzed cyclization strategy toward the enantioselective total synthesis of deguelin, which allows access to either stereoisomer for biological studies. The synthesis was completed in six steps (longest linear) with no protecting groups. The evaluation of both enantiomers of the natural product demonstrated potent inhibition of several cancer cell lines by these compounds, but interestingly showed that the unnatural (+)-deguelin preferentially inhibited the growth of MCF-7 breast cancer and HepG2 liver carcinoma cells when compared to the natural product.
- Farmer, Rebecca L.,Scheidt, Karl A.
-
p. 3304 - 3309
(2013/07/26)
-
- Design, synthesis, and biological evaluation of novel deguelin-based heat shock protein 90 (HSP90) inhibitors targeting proliferation and angiogenesis
-
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
-
p. 10863 - 10884
(2013/03/13)
-
- Concise modular asymmetric synthesis of deguelin, tephrosin and investigation into their mode of action
-
(Figure Presented) The concise nature and modularity of the synthesis described for deguelin and tephrosin (retrosynthetic analysis depicted) should facilitate access to labeled analogues to dissect the mechanism of action of this important pharmacophore.
- Garcia, Jose,Barluenga, Sofia,Beebe, Kristin,Neckers, Len,Winssinger, Nicolas
-
supporting information; experimental part
p. 9767 - 9771
(2010/10/21)
-
- Contrast agents for myocardial perfusion imaging
-
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.
- -
-
Page/Page column 34; 35
(2010/02/13)
-
- Concise Synthesis of the Chemopreventitive Agent (±)-Deguelin via a Key 6-Endo Hydroarylation
-
(Equation presented) A concise total synthesis of (±)-deguelin was achieved with a longest linear sequence of six steps in 68% yield. A key step was the platinum-catalyzed 6-endo hydroarylation of an alkynone intermediate.
- Pastine, Stefan J.,Sames, Dalibor
-
p. 4053 - 4055
(2007/10/03)
-
- Synthesis of trans-B/C-Rotenoids: X-Ray and NMR Data for cis- and trans-Forms of Isorotenone
-
Reduction of 6a,12a-didehydrorotenoids with diisobutylaluminium hydride gives clean 1,4-reduction leading to unstable trans-B/C-fusions, not previously known for enolisable rotenoids: they are epimerised to stable cis-forms under acid conditions.Applied initially to isorotenone, the method is extended to trans-B/C-deguelin, α-toxicarol, the 'core' rotenoid structure and the 6aS,12aR,5'R- and 6aR,12aS,5'R-rotenone stereoisomers. 1H and 13C NMR data are compared for the cis- and trans-forms and the geometry and conformations of the isorotenones are compared by X-ray analysis, providing insight into the reasons for the instability of the trans-forms.Reduction of the ridge-tile-like cis-isorotenone by sodium borohydride occurs from one face to give a cis-12α-hydroxy product, whilst the flatter trans-structure is attacked from both faces to give trans-12α- and 12β-hydroxy products.
- Begley, Michael J.,Crombie, Leslie,Hadi, Hamid bin A.,Josephs, Jonathan L.
-
p. 2605 - 2614
(2007/10/02)
-
- Structural elucidation and chemical conversion of amorphispironone, a novel spironone from Amorpha fruticosa, to rotenoids
-
To search for possible antitumor promoters, we carried out an investigation of the leaves of Amorpha fruticosa L. (Leguminosae). The novel spironone type rotenoid, amorphispironone (1), was isolated together with four known rotenoids, tephrosin (2), amorphigenin (3), 12a-hydroxyamorphigenin (4) and 12a-hydroxydalpanol (5). Some of these compounds were inhibitors of Epstein-Barr virus early antigen activation induced by 12-O-tetradecanoylphorbol-13-acetate. The structure of 1 was determined from 2D-NMR spectral data and difference NOE experiments. Amorphispironone (1) was also converted to known rotenoids in order to confirm the proposed structure.
- Terada,Kokumai,Konoshima,Kozuka,Haruna,Ito,Estes,Li,Wang,Lee
-
p. 187 - 190
(2007/10/02)
-
- 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
-
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.
-
p. 1685 - 1698
(2007/10/02)
-
- Synthesis of Novel Labile Rotenoids with Unnatural trans-B/C Ring Systems
-
6a,12a-Dehydrorotenoids are cleanly reduced in 1,4-fashion by DIBAL to give rotenoids having the unstable, unnatural, trans-B/C fusion, readily epimerised by acid to the cis-forms: an X-ray structure for (+/-)-trans-isorotenone confirms the nature of the ring fusion.
- Begley, Michael J.,Crombie, Leslie,Hadi, A. Hamid bin A.,Josephs, Jonathan L.
-
p. 204 - 205
(2007/10/02)
-
- Biosynthetic Origin of the 2,2-Dimethylchromen Ring: Formation of Deguelin by a Cyclase Enzyme from Tephrosia vogellii
-
An enzyme from Tephrosia vogellii which converts rot-2'-enoic acid into the 6',6'-dimethylchromen deguelin has been isolated and purified; the 5'-hydroxy-6',6'-dimethyl compound is not an intermediate, nor has an intermediate been observed.
- Crombie, Leslie,Rossiter, John,Whiting, Donald A.
-
p. 352 - 353
(2007/10/02)
-
