Tubulin-Binding Agents Synthetic, Structural and Mechanistic Insight
reviews. The SAR data are discussed in light of the structural information available for each agent. The second chapter focuses on the total synthesis of the marine sponge-derived polyketide discodermolide. A comprehensive survey of the synthetic chemistr
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he Interaction of Microtubules with Stabilizers Characterized at Biochemical and Structural Levels J.F. Díaz, J.M. Andreu, and J. Jiménez-Barbero
Abstract Since the discovery of paclitaxel and its peculiar mechanism of cytotoxicity, which has made it and its analogues widely used antitumour drugs, great effort has been made to understand the way they produce their effect in microtubules and to find other products that share this effect without the undesired side effects of low solubility and development of multidrug resistance by tumour cells. This chapter reviews the actual knowledge about the biochemical and structural mechanisms of microtubule stabilization by microtubule stabilizing agents, and illustrates the way paclitaxel and its biomimetics induce microtubule assembly, the thermodynamics of their binding, the way they reach their binding site and the conformation they have when bound. Keywords Antitumour drugs, Bioconformer, Microtubule stabilizing agents, Paclitaxel Contents 1
Biochemical Background on Microtubule Stabilizing Agents. What is a Microtubule Stabilizer?........................................................................................ 1.1 Microtubules and Drugs ............................................................................................ 1.2 Function and Evolution ............................................................................................. 1.3 What an MSA is and How it Works .......................................................................... 1.4 Chemical Diversity of MSAs in Short....................................................................... 1.5 Three MSA Binding Sites in Microtubules ............................................................... 1.6 Mechanisms and Cellular Consequences of Microtubule Stabilization .................... 2 Thermodynamics and Kinetic Mechanisms of the Interaction of Stabilizing Agents with Microtubules. How do they Bind? ................................................................... 2.1 Thermodynamics of MSA Induced Microtubule Assembly. How do they Induce Assembly? ................................................................................ 2.2 Thermodynamics of MSA Binding to Microtubules. How to Make Them Sticky? ...................................................................................... J.F. Díaz (* ü ), J.M. Andreu, and J. Jiménez-Barbero Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain e-mail: [email protected],
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Kinetics of MSA Binding to Microtubules. How Do They Reach Their Site in the Microtubules? ................................................................................................. 3 The Bioactive Conformations of MSA. What Do They Look Like When Bound? ............. 3.1 Paclitaxel and Related Molecules. The Single Conformer Hypothesis..................... 3.2 Paclitaxel and Related Molecules. Flexibility ...................
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