Chemistry Reference
In-Depth Information
THE CHEMISTRY AND BIOLOGY
OF EPOTHILONES—LEAD STRUCTURES
FOR THE DISCOVERY OF IMPROVED
MICROTUBULE INHIBITORS
K
ARL
-H
EINZ
A
LTMANN
Department of Chemistry and Applied BioSciences, Institute of Pharmaceutical Sciences,
Swiss Federal Institute of Technology (ETH), Z
¨
rich, Switzerland
1.1
INTRODUCTION
Cancer represents one of the most severe health problems worldwide, and the devel-
opment of new anticancer drugs and more effective treatment strategies are fields
of utmost importance in drug discovery and clinical therapy. Much of the research
in these areas is currently focused on cancer-specific mechanisms and the corre-
sponding molecular targets (e.g., kinases related to cell cycle progression or signal
transduction),
1
but the search for improved cytotoxic agents (acting on ubiquitous
targets such as DNA or tubulin) still constitutes an important part of modern anti-
cancer drug discovery. As the major types of solid human tumors (breast, lung,
prostate, and colon), which represent most cancer cases today, are multicausal in
nature, there is a growing recognition that the treatment of solid tumors with
''mechanism-based'' agents alone is unlikely to be successful. Instead, improved
treatment strategies are likely to involve combinations of signal transduction inhi-
bitors with new and better cytotoxic drugs.
Microtubule inhibitors are an important class of anticancer agents,
2
with clinical
applications in the treatment of a variety of cancer types, either as single agents or
as part of different combination regimens.
3
Microtubule-interacting agents can be
