201136-73-4Relevant 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.
scheme or table, 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.
Synthesis of 16-desmethylepothilone B: Improved methodology for the rapid, highly selective and convergent construction of epothilone B and analogues
Nicolaou,Hepworth, David,Finlay, M. Ray V.,King, N. Paul,Werschkun, Barbara,Bigot, Antony
, p. 519 - 520 (2007/10/03)
During a synthesis of 16-desmethylepothilone B new methods for the convergent and highly stereoselective synthesis of epothilone B and analogues were developed.
Total synthesis of 26-hydroxy-epothilone B and related analogs via a macrolactonization based strategy
Nicolaou,Finlay, M. Ray V.,Ninkovic, Sacha,Sarabia, Francisco
, p. 7127 - 7166 (2007/10/03)
The chemical synthesis of a series of 26-substituted epothilones B is described. Fully protected 26-hydroxydesoxy-epothilone B (7), prepared via the macrolactonization strategy, served as a common precursor to the designed epothilones described. The synthesized compounds were members of a large epothilone library whose biological screening led to the identification of a number of highly potent antitumor agents.
Total synthesis of 26-hydroxyepothilone B and related analogues
Nicolaou,Ninkovic, Sacha,Finlay, M. Ray V.,Sarabia, Francisco,Li, Tianhu
, p. 2343 - 2344 (2007/10/03)
A series of 26-substituted epothilones B (3, 22, 23a-n and 24a-h,j-l,o) have been constructed by total synthesis involving a selective Wittig olefination, an aldol reaction and a macrolactonization as key steps.
