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Effect of 2′-OH acetylation on the bioactivity and conformation of 7-O-[N-(4′-fluoresceincarbonyl)-l-alanyl]taxol. A NMR-fluorescence microscopy study

AutorBarbero, José Luis ; Souto, André A.; Abal, Miguel; Barasoain, Isabel ; Evangelio, Juan A.
Palabras claveFluorescence
Microtubule probes
Paclitaxel structure–activity relationship
Fecha de publicaciónoct-1998
EditorPergamon Press
CitaciónBioorganic and Medicinal Chemistry, 6, 1857-1863 (1998)
ResumenThe relationship between conformation, 2′-OH acetylation, and bioactivity of two fluorescent taxoids has been investigated by a combination of NMR and fluorescence microscopy techniques. These taxoids present the structure of taxol with the 7-OH group esterified with the N-(4′-fluoresceincarbonyl)-l-alanine group and with the 2′-OH group free (taxoid 2) or acetylated (taxoid 3). The larger water solubility of 2 and 3 compared with taxol allowed a detailed NMR study in DMSO-d6/D2O (3/7), showing that both taxoids adopt a similar collapsed conformation in which the hydrophobic groups 2-O-benzoyl, 3′-phenyl and 4-O-acetyl are in close proximity, with the fluorescein group displaying unrestricted motion. On the other hand, while taxoid 2 retains essentially the ability of taxol to induce in vitro microtubule assembly and to bind to cell microtubules, the 2′-acetylated derivative 3 does not show immediate activity. However, when taxoid 3 is left in the cell culture, the slow hydrolysis of the 2′-acetate group in the medium liberates the cytotoxic, microtubule-specific taxoid 2. The intense emission of this active derivative (2) allows the accurate recording of the drug-cell interaction from the very initial steps using fluorescence microscopy. These experiments show conclusively, for the first time in cell cultures, that a free 2′-OH group in taxol is essential for the recognition of the drug by the binding site of cellular microtubules
Versión del editorhttp://dx.doi.org/10.1016/S0968-0896(98)00149-7
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