218614-13-2Relevant academic research and scientific papers
Total synthesis and evaluation of C26-hydroxyepothilone D derivatives for photoaffinity labeling of β-tubulin
Reiff, Emily A.,Nair, Sajiv K.,Henri, John T.,Greiner, Jack F.,Reddy, Bollu S.,Chakrasali, Ramappa,David, Sunil A.,Chiu, Ting-Lan,Amin, Elizabeth A.,Himes, Richard H.,Vander Velde, David G.,Georg, Gunda I.
experimental part, p. 86 - 94 (2010/04/26)
(Chemical Equation Presented) Three photaffinity labeled derivatives of epothilone D were prepared by total synthesis, using efficient novel asymmetric synthesis methods for the preparation of two important synthetic building blocks. The key step for the asymmetric synthesis of (S,E)-3-(tert- butyldimethylsilyloxy)-4-methyl-5-(2-methylthiazol-4-yl)pent-4-enal involved a ketone reduction with (R)-Me-CBS-oxazaborolidine. For the synthesis of (5S)-5,7-di[(tert-butyldimethylsilyl)oxy]-4,4-dimethylheptan-3-one an asymmetric Noyori reduction of a β-ketoester was employed. The C26 hydroxyepothilone D derivative was constructed following a well-established total synthesis strategy and the photoaffinity labels were attached to the C26 hydroxyl group. The photoaffinity analogues were tested in a tubulin assembly assay and for cytotoxicity against MCF-7 and HCT-116 cancer cell lines. The 3- and 4-azidobenzoic acid analogues were found to be as active as epothilone B in a tubulin assembly assay, but demonstrated significantly reduced cellular cytotoxicity compared to epothilone B. The benzophenone analogue was inactive in both assays. Docking and scoring studies were conducted that suggested that the azide analogues can bind to the epothilone binding site, but that the benzophenone analogue undergoes a sterically driven ligand rearrangement that interrupts all hydrogen bonding and therefore protein binding. Photoaffinity labeling studies with the 3-azidobenzoic acid derivative did not identify any covalently labeled peptide fragments, suggesting that the phenylazido side chain was predominantly solvent-exposed in the bound conformation. 2009 American Chemical Society.
Multi-step application of immobilized reagents and scavengers: A total synthesis of epothilone C
Storer, R. Ian,Takemoto, Toshiyasu,Jackson, Philip S.,Brown, Dearg S.,Baxendale, Ian R.,Ley, Steven V.
, p. 2529 - 2547 (2007/10/03)
The total synthesis of the cytotoxic antitumour natural product epothilone C has provided a stage for the exploitation and further development of immobilized reagent methods. A stereoselective convergent synthetic strategy was applied, incorporating polymer-supported reagents, catalysts, scavengers and catch-and-release techniques to avoid frequent aqueous work-up and chromatographic purification.
A total synthesis of epothilones using solid-supported reagents and scavengers
Storer, R. Ian,Takemoto, Toshiyasu,Jackson, Philip S.,Ley, Steven V.
, p. 2521 - 2525 (2007/10/03)
A total synthesis of epothilone C(1) with concomitant formal synthesis of epothilone A is described, using immobilized reagents and scavengers to effect multistep synthetic transformations and purifications.
Total Syntheses of Epothilones B and D
Mulzer, Johann,Mantoulidis, Andreas,Oehler, Elisabeth
, p. 7456 - 7467 (2007/10/03)
Total syntheses of the microtubule stabilizing antitumor drugs epothilone B and D are described, starting from optically pure (S)-malic acid and methyl (R)-3-hydroxy-2-methylpropionate. The synthesis is highly convergent by coupling the three fragments C1-C6 (fragment D), C7-C10 (fragment C), and C11-C21 (fragment B). Key steps are two stereoselective Wittig type olefinations to generate the 12,13- and 16,17-double bonds, an enantioselective Mukaiyama aldol addition to synthesize fragment D, and a sulfone anion allyl iodide alkylation to connect fragments B and C. Finally fragment D was attached to the B + C fragment via aldol addition.
Epothilone B and its derivatives as novel antitumor drugs: Total and partial synthesis and biological evaluation
Mulzer, Johann
, p. 205 - 238 (2007/10/03)
Microtubule stabilizing natural products, as exemplified by paclitaxel (taxolR), are being considered as novel drugs against malignant therapy resistent solid tumors. Among these compounds, epothilone B and some of its derivatives have emerged as particularly promising candidates for industrial development. The total and partial syntheses of these compounds are described in detail, and some of the most important recent results on their biological activity are discussed.
Easy access to the epothilone family - Synthesis of epothilone B
Mulzer, Johann,Mantoulidis, Andreas,Oehler, Elisabeth
, p. 8633 - 8636 (2007/10/03)
An easy access to four out of five naturally occurring epothilones (A- E, 1-5) is reported. Key steps are an enantioselective Mukaiyama type aldol reaction, (E)- and (Z)-selective olefinations, and a sulfone alkylation.
