Anticancer Drugs Targeting Tubulin and Microtubules
Contents 1. Introduction 229
2. Drugs That Inhibit Microtubule Polymerization at High Concentrations 231
2.1. Compounds binding at the Vinca site 231
2.2. Compounds binding at the colchicine site 236
3. Microtubule-Stabilizing Agents: Compounds Binding at the
Taxane Site 237
3.1. Taxanes 237
3.2. Epothilones 241
3.3. Miscellaneous marine compounds that bind to the taxane site 243
4. Miscellaneous Anticancer Drugs Acting on Novel Sites on Tubuline 245
5. Antivascular Effects of Microtubule-Targeted Agents 245
6. Mitotic Kinesin Inhibitors 246 References 247
1. INTRODUCTION
Microtubules are filamentous intracellular structures that are responsible for several aspects of the cell morphology since they form the cytoskeleton in eukary-otic cells and are also responsible for various kinds of cell movements because they are part of the cilia and flagella.
Microtubules are hollow structures formed by 13 parallel protofilaments that grow and shorten by the reversible, noncovalent addition of tubulin dimers at their ends. Tubulin is a protein that contains two subunits called a and p in a head to tail arrangement. Microtubules and free tubulin dimers are involved in a highly dynamic equilibrium, which is very sensitive to external factors (Fig. 8.1).
Medicinal Chemistry of Anticancer Drugs © 2008 Elsevier B. V.
DOI: 10.1016/B978-0-444-52824-7.00008-1 All rights reserved.
Free tubulin dimers »
Polymerization -----
Depolymerization
Microtubule
FIGURE 8.1 Dynamic equilibrium between microtubules and tubulin dimers.
A very important structure generated from microtubules is the mitotic spindle, used by eukaryotic cells to segregate their chromosomes correctly during cell division and allow the transfer of the chromosomes of the original cell to the daughter cells. During cell division, microtubules in the cytoplasmic network depolymerize, and the tubulin thus liberated is again polymerized to give the mitotic spindle.
Several important antitumor drugs exert their action by disrupting these equilibria, either by binding to tubulin and inhibiting polymerization or by binding to the microtubules and inhibiting depolymerization by stabilizing them.1'2 This leads to inhibition of the formation of the mitotic spindle and therefore these compounds behave as antimitotic agents.
Microtubules are the main target of cytotoxic natural products, and most of the drugs discussed in this chapter have been discovered in large-scale screens of natural materials. These compounds are highly successful in cancer treatment,3 and it has been argued that microtubules represent the best known cancer target.
Drugs acting on microtubules bind to several sites of tubulin and at different positions of the microtubules but they all suppress microtubule dynamics, thereby blocking mitosis at the metaphase/anaphase transition and inducing cell death. The spindle microtubules are much more dynamic than the cytoskeletal ones, and exchange their tubulin units with the soluble pools with half-times of about 15 s, explaining why drugs that interfere with microtubule dynamics are so effective against dividing cells.
Based on their behavior at high concentrations, antitumor drugs acting on microtubules have been traditionally classified into two groups: (1) drugs that inhibit microtubule polymerization (microtubule-destabilizing agents) and (2) drugs that stimulate microtubule polymerization (microtubule-stabilizing agents). Although we will adopt this time-sanctioned classification for organizing this chapter, it is probably overly simplistic as it has been recently shown that at low concentrations both types of drugs act similarly by stabilizing spindle microtubule dynamics.4,5
An interesting feature of drugs acting on microtubules is the synergistic effects that can often be found among them that potentially allow their combination, avoiding high doses of any individual drug.
2. DRUGS THAT INHIBIT MICROTUBULE POLYMERIZATION AT HIGH CONCENTRATIONS
There are three main binding sites of drugs to tubulin, which are designed according to their best known ligands as the Vinca, colchicine, and taxol sites. For some of them, further research has uncovered the existence of different subsites corresponding to different ligand-structural families.
2.1. Compounds binding at the Vinca site 2.1.1. Vinca alkaloids and their synthetic analogs
Vincristine and vinblastine are complex molecules produced by the leaves of the rosy periwinkle plant Catharanthus roseus (Vinca rosea), whose potent cytotoxicity was discovered in 1958. They were introduced in cancer chemotherapy in the late 1960s and remain in widespread clinical usage to this day. Despite their very similar structures and common mechanism of action, they have widely different toxicological properties and antitumor spectra. Thus, vinblastine is currently used in the treatment of Hodgkin's disease and metastatic testicular tumors, where it is combined with bleomycin and cisplatin, while vincristine is used in the treatment of leukemia and lymphomas.
Several semisynthetic analogs of these alkaloids6 are also in clinical use, most notably vindesine, used mainly to treat melanoma and lung carcinomas and, associated with other drugs, to treat uterine cancers, and the nor-derivative vinorelbine, used for non-small cell lung cancer, metastatic breast cancer, and ovarian cancer. The fluorinated analog vinflunine is in clinical development.7
R = CHO Vincristine R = CH3 Vinblastine
Vindesine
R = CHO Vincristine R = CH3 Vinblastine
Vindesine
Vinorelbine
Vinflunine
N" >T ^OCOCH3 H3CHO 'CO2CH3
Vinorelbine
Vinflunine
The Vinca alkaloids specifically block cells in mitosis with metaphase arrest, and hence are antimitotic drugs. Their biological activity is explained by their specific binding to the p subunit of tubulin dimers, in a region called the Vinca domain. Binding is fast and reversible, but it induces a conformational change in tubulin, increasing its affinity for itself and leading to the formation of paracrystal-line aggregates. This decreases the pool of free tubulin dimers available for microtubule assembly, resulting in a shift of the equilibrium toward disassembly and microtubule shrinkage. These phenomena result in microtubule depolymeri-zation and destruction of the mitotic spindles, as verified in HeLa cells at high (10-100 nM) concentrations (Fig. 8.2). As a consequence, dividing cells are blocked in mitosis with condensed chromosomes.
The mechanism described above led to the Vinca alkaloids being thought for many years to act solely as microtubule-depolymerizing agents. However, recent observations have shown that, at concentrations that are low but clinically relevant (0.8 nM in HeLa cells), the spindle microtubules are not depolymerized but mitosis is still blocked and cells die by apoptosis. This suggests that the block is due to suppression of microtubule dynamics rather than to microtubule depolymerization.
One of the drawbacks of Vinca alkaloids and their analogs is their neurotoxic-ity, which is probably related to the fact that microtubules are a key component of neurons. Another problem associated with the use of Vinca alkaloids is the easy development of resistance, normally mediated by the overexpression of the Pgp-170 transport protein (see Chapter 12).
- Mitotic spindle
Microtubule
Free tubulin dimers dimers a u a %
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