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Topics in Current Chemistry
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Topics in Current Chemistry
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Tubulin-Binding Agents
Synthetic, Structural and Mechanistic
Insights
Volume Editor: Teresa Carlomagno
With Contributions by
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The series Topics in Current Chemistry presents critical reviews of the present and future trends in
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Topics in Current Chemistry e-ISSN 1436-5049
ISBN 978-3-540-69036-8 e-ISBN 978-3-540-69039-9
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Editorial Board
Prof. Vincenzo Balzani Professor Jean-Marie Lehn
Dipartimento di Chimica “G. Ciamician” ISIS
University of Bologna 8, allée Gaspard Monge
via Selmi 2 BP 70028
I-40126 Bologna, Italy 67083 Strasbourg Cedex, France
[email protected] [email protected]
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Institut für Organische Chemie University Chemical Laboratory
der Georg-August-Universität Lensfield Road
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University of California Chemical Laboratories
Department of Chemistry and Biochemistry Harvard University
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USA USA
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TU München Universität Hamburg
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86747 Garching, Germany 20146 Hamburg, Germany
[email protected] [email protected]
vi Editorial Board
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USA The University of Chicago
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vii
Preface
The multifaceted conformational properties of tubulin have represented a challenge
for mechanistic and structural studies of the protein for the past 20 years. The con-
formational equilibrium between the dimeric and polymeric form of tubulin can be
controlled by different solvents (HO, DO, DMSO), cofactors (divalent ions, as
2 2
for example Mg2+, GTP/GDP), or small molecules. Alternatively, depending on the
environment and concentration, tubulin can assemble in rings, protofilaments
sheets, or even amorphous aggregates. Small organic molecules bind to tubulin at
several, often flexible, sites, usually stabilizing the protein in one conformational
form. All in all, the large number of structural entities that tubulin can build,
together with the easy inter-conversion among them as a response to external con-
ditions, underlies an intrinsic flexibility of the protein and an amazing capacity of
rearranging the tertiary interaction network of well-defined structural domains.
In this book we review the current knowledge of the mechanistic and structural
aspects of the conformation switches triggered in tubulin by small organic mole-
cules. Despite years of research by many groups around the world, the structural
basis of the mechanisms of action of many tubulin binders is still unknown.
Mapping of a consistent pharmacophore at specific tubulin interaction sites is
tricky, due to the fact that each binding pocket in tubulin can accommodate mole-
cules with very diverse chemical scaffolds. The case of the microtubules stabilizing
agent Epothilone (Chapters 1, 3, 4, and 5) is exemplary: despite the presence of
activity data for hundreds of derivatives, no consensus has been reached either for
the bioactive conformation or for the binding mode to the protein, with two contra-
dicting models having been proposed by Nuclear Magnetic Resonance spectros-
copy (NMR, Chapter 4) and Electron Microscopy (EM, Chapter 5) studies. This
contradiction might reflect the different tubulin structural forms used in the two
studies or might be indicative of a constitutive problem encountered in the endeav-
our to describe the structural properties of a very flexible complex.
Tubulin binders are usually large and complex natural products. The difficulties
and challenges encountered in the chemical synthesis of these molecules and their
derivatives, with the goal of building solid structure-activity relationship (SAR)
datasets, are described in the first and second chapters of the book.
The first chapter focuses on the total synthesis of macrolide-based microtubules
stabilizing agents and on SAR data thereof, which have not been covered in other
ix
x Preface
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 chemistry
efforts of several groups over a 14-year period is provided together with a compari-
son of the different approaches.
The third chapter describes a comprehensive study of the mechanisms of activity
of microtubules stabilizing drugs. Thermodynamic, kinetic, structural and func-
tional data on microtubules stabilizing drugs are discussed in an interdisciplinary
manner to generate a “time-resolved” picture of the interaction of the drugs with
different tubulin forms.
The fourth and fifth chapters review the efforts and achievements made in the
characterization of the structure of the complexes of tubulin with microtubules
stabilizing agents by NMR (Chapter 4) and EM (Chapter 5). Especially evident is
the discrepancy of the results obtained for epothilones, where the two techniques
deliver radically different structures of the bound drug. Both NMR and EM models
are, however, able to explain a consistent set of SAR data. The authors of the two
chapters discuss critically the advantages and limitations of each methodology.
The sixth chapter reviews the structural studies of complexes of tubulin with
microtubules destabilizing agents performed by X-ray crystallography. The intel-
ligent use of a complex of two tubulin dimers and the stathmin-like domain of the
RB3 protein allows crystallization of the proteins in presence of microtubules
destabilizing agents. A mechanistic model for the activity of microtubules destabi-
lizing agents is provided on the basis of the structural results.
The last chapter is a comprehensive overview of the efforts made to understand
the pharmacophore of both microtubules stabilizing and destabilizing agents by
molecular modelling techniques. In the absence of converging structural informa-
tion, modelling is a viable technique to study the feasibility of ligand bound con-
formations and pharmacophore models, bearing in mind the intrinsic problems
associated with the structural flexibility of the binding site(s).
The broad range of techniques used by the authors of the book to investigate the
mechanisms of the conformational control exerted on tubulin by small organic
molecules is representative of the complexity of the problem. I hope that you will
enjoy reading this book: those of you who are actively working in the field of
tubulin-binding agents may find useful insights into the mechanisms of tubulin-
binding drugs and inspiration for new experiments; those of you who are not con-
cerned about tubulin-binding agents will appreciate this survey of the joined effort
of many scientists with different expertise around the world to address the intrigu-
ing and difficult problem of conformational control in tubulin.
Spring 2009 Teresa Carlomagno
