- Investigations directed at the total synthesis of ouabain. Lessons learned from degradation studies
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A procedure has been developed for transforming pentacyclic Heck product (8) to enone (10), an intermediate having appropriate functionality for future elaboration of the C1 and C3 diol functionality of ouabagenin. The plant-derived cardiac glycoside ouabain has been degraded to analogs (17) and (20) that contain, respectively, a Δ9.11 double bond and C17 nitrile. These intermediates should be useful in future efforts to develop chemistry for functionalizing the Δ9.11 double bond of 8 to incorporate C11 oxidation and for elaborating the β C17 nitrile of this advanced synthetic intermediate to a β butenolide.
- Overman, Larry E.,Rucker, Paul V.
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- A convergent total synthesis of ouabagenin
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A convergent total synthesis of ouabagenin, an aglycon of cardenolide glycoside ouabain, was achieved by assembly of the AB-ring, D-ring and butenolide moieties. The multiply oxygenated cis-decalin structure of the AB-ring was constructed from (R)-perillaldehyde through the Diels-Alder reaction and sequential oxidations. The intermolecular acetal formation of the AB-ring and D-ring fragments, and combination of the intramolecular radical and aldol reactions, assembled the requisite steroidal skeleton in a stereoselective fashion. Finally, stereoselective installation of the C17-butenolide via the Stille coupling and hydrogenation led to ouabagenin. This journal is
- Mukai, Ken,Kasuya, Satoshi,Nakagawa, Yuki,Urabe, Daisuke,Inoue, Masayuki
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- Modular Total Synthesis and Cell-Based Anticancer Activity Evaluation of Ouabagenin and Other Cardiotonic Steroids with Varying Degrees of Oxygenation
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A Cu(II)-catalyzed diastereoselective Michael/aldol cascade approach is used to accomplish concise total syntheses of cardiotonic steroids with varying degrees of oxygenation including cardenolides ouabagenin, sarmentologenin, 19-hydroxysarmentogenin, and 5-epi-panogenin. These syntheses enabled the subsequent structure activity relationship (SAR) studies on 37 synthetic and natural steroids to elucidate the effect of oxygenation, stereochemistry, C3-glycosylation, and C17-heterocyclic ring. Based on this parallel evaluation of synthetic and natural steroids and their derivatives, glycosylated steroids cannogenol-l-α-rhamnoside (79a), strophanthidol-l-α-rhamnoside (92), and digitoxigenin-l-α-rhamnoside (97) were identified as the most potent steroids demonstrating broad anticancer activity at 10-100 nM concentrations and selectivity (nontoxic at 3 μM against NIH-3T3, MEF, and developing fish embryos). Further analyses indicate that these molecules show a general mode of anticancer activity involving DNA-damage upregulation that subsequently induces apoptosis.
- Khatri, Hem Raj,Bhattarai, Bijay,Kaplan, Will,Li, Zhongzheng,Curtis Long, Marcus John,Aye, Yimon,Nagorny, Pavel
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supporting information
p. 4849 - 4860
(2019/03/26)
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- Development of a concise synthesis of ouabagenin and hydroxylated corticosteroid analogues
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The natural product ouabagenin is a complex cardiotonic steroid with a highly oxygenated skeleton. This full account describes the development of a concise synthesis of ouabagenin, including the evolution of synthetic strategy to access hydroxylation at the C19 position of a steroid skeleton. In addition, approaches to install the requisite butenolide moiety at the C17 position are discussed. Lastly, methodology developed in this synthesis has been applied in the generation of novel analogues of corticosteroid drugs bearing a hydroxyl group at the C19 position.(Chemical Equation Presented).
- Renata, Hans,Zhou, Qianghui,Dünstl, Georg,Felding, Jakob,Merchant, Rohan R.,Yeh, Chien-Hung,Baran, Phil S.
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p. 1330 - 1340
(2015/02/19)
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- Cardiac glycoside activities link Na+/K+ ATPase ion-transport to breast cancer cell migration via correlative SAR
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The cardiac glycosides ouabain and digitoxin, established Na+/K+ ATPase inhibitors, were found to inhibit MDA-MB-231 breast cancer cell migration through an unbiased chemical genetics screen for cell motility. The Na+/K+ ATPase acts both as an ion-transporter and as a receptor for cardiac glycosides. To delineate which function is related to breast cancer cell migration, structure-activity relationship (SAR) profiles of cardiac glycosides were established at the cellular (cell migration inhibition), molecular (Na+/K+ ATPase inhibition), and atomic (computational docking) levels. The SAR of cardiac glycosides and their analogs revealed a similar profile, a decrease in potency when the parent cardiac glycoside structure was modified, for each activity investigated. Since assays were done at the cellular, molecular, and atomic levels, correlation of SAR profiles across these multiple assays established links between cellular activity and specific protein-small molecule interactions. The observed antimigratory effects in breast cancer cells are directly related to the inhibition of Na+/K+ transport. Specifically, the orientation of cardiac glycosides at the putative cation permeation path formed by transmembrane helices αM1-M6 correlates with the Na+ pump activity and cell migration. Other Na+/K+ ATPase inhibitors that are structurally distinct from cardiac glycosides also exhibit antimigratory activity, corroborating the conclusion that the antiport function of Na+/K+ ATPase and not the receptor function is important for supporting the motility of MDA-MB-231 breast cancer cells. Correlative SAR can establish new relationships between specific biochemical functions and higher-level cellular processes, particularly for proteins with multiple functions and small molecules with unknown or various modes of action.
- Magpusao, Anniefer N.,Omolloh, George,Johnson, Joshua,Gascn, Jos,Peczuh, Mark W.,Fenteany, Gabriel
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p. 561 - 569
(2015/05/04)
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- Strategic redox relay enables A scalable synthesis of ouabagenin, a bioactive cardenolide
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Here, we report on a scalable route to the polyhydroxylated steroid ouabagenin with an unusual take on the age-old practice of steroid semisynthesis. The incorporation of both redox and stereochemical relays during the design of this synthesis resulted in efficient access to more than 500 milligrams of a key precursor toward ouabagenin-and ultimately ouabagenin itself-and the discovery of innovative methods for carbon-hydrogen (C-H) and carbon-carbon activation and carbon-oxygen bond homolysis. Given the medicinal relevance of the cardenolides in the treatment of congestive heart failure, a variety of ouabagenin analogs could potentially be generated from the key intermediate as a means of addressing the narrow therapeutic index of these molecules. This synthesis also showcases an approach to bypass the historically challenging problem of selective C-H oxidation of saturated carbon centers in a controlled fashion.
- Renata, Hans,Zhou, Qianghui,Baran, Phil S.
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- Total synthesis of ouabagenin and ouabain
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A full account of the total synthesis of ouabagenin and ouabain is described. A highly stereocontrolled anionic cycloaddition for the rapid construction of the basic steroid skeleton is a pivotal conversion for the whole strategy. A careful study was need
- Reddy, Maddi Sridhar,Zhang, Hongxing,Phoenix, Serge,Deslongchamps, Pierre
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p. 725 - 741
(2011/06/25)
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- Total synthesis of ouabagenin and ouabain
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(Chemical Equation Presented) The highly oxygenated steroid ouabagenin (1b) and its glycoside ouabain (1a) were prepared by a strategy based on a polyanionic cyclization. Starting building blocks A and B were combined to give the key intermediate C and transformed into 1b in 27 steps. Finally, ouabagenin (1b) was converted into ouabain (1a) in six steps (see scheme).
- Zhang, Hongxing,Sridhar Reddy, Maddi,Phoenix, Serge,Deslongchamps, Pierre
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p. 1272 - 1275
(2008/12/22)
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