Optimización de la interacción microtúbulo-taxol: diseño de taxanos de alta afinidad
Author
Matesanz Rodríguez, RuthAdvisor
Díaz Pereira, J. FernandoEntity
UAM. Departamento de Biología MolecularDate
2009-02-17Subjects
Tubulinas-Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 17-02-2009Abstract
Developed resistance to drugs is one of the causes of cancer
chemotherapy failure. The effect of drug-site interaction optimization to fight
against resistance have been studied in cells resistant to taxanes by two
different mechanisms, P-glycoprotein mediated multidrug resistance and
mutations in the taxane site.
To design drugs with high affinity for the taxane site microtubule
binding affinities of a series of synthetic taxanes have been measured. From
these measurements we could dissect individual group contributions and
obtain a rationale for the design of novel compounds with the ability to
overcome P-glycoprotein-mediated drug resistance. As previously observed for
epothilones, contributions of the different substituents to the binding free
energy are cumulative. Combination of the most favourable substitutions in one
single analogue increased the binding affinity 500-fold over that of taxol.
Structural models built in this study assigned an important role to the
interactions of C2 and C13 substituents with the protonated side chain of
His229 in β-tubulin. The relative orientation of these groups was found to be in
agreement with NMR data obtained for microtubules-bound docetaxel.
The cytotoxicities of the compounds in A2780 cells correlate with their
affinities with an apparent cytotoxicity limit in the nanomolar range. Taxane
resistance index plotted versus binding affinity fits a bell-shaped curve showing
that the P-gp-overexpressing cells (A2780AD) are sensitive to the highest and
lowest affinity compounds, whereas resistance indexes in the range of 100 to
1000 were obtained for those ligands whose binding affinities for tubulin and Pgp
are similar. This finding strongly indicates that for a series of compounds
with similar pharmacokinetic and bioavailability properties, optimization of the
ligand-target interaction is a good strategy to overcome multidrug resistance
mediated by efflux pumps. Moreover same high-affinity compounds seem to
avoid resistance in cells with mutated tubulins as probed with their
cytotoxicities in cells PTX10 and PTX22 when compared with the parental 1A9cell line wich contains wild type tubulin.
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