Chemistry Reference
In-Depth Information
kinases chk1 and ckh2 and the heat shock protein Hsp90 are also the targets of
some drugs.
The protein tubulin is an interesting and important target. It exists in both
α
and
β
forms, and during a normal cell cycle, these two monomeric proteins
polymerize into microtubules by noncovalent interaction; these microtubules are
then involved in the reorganization of the chromosomes into the nuclei of the
mother and daughter cells. After mitosis, the microtubules dissociate to
β
tubulin monomers. Therapeutic intervention, which controls inhibition of mitosis
and eventual apoptotic cell death, can occur either by inhibition of the assembly
of tubulin monomers into microtubules or by inhibition of the dissociation of
microtubules to
α
and
tubulin monomers. This process is dynamic, and even
very small perturbations in assembly and/or disassembly of the monomers/dimers
may lead to cell death, frequently via the apoptotic cascade(s), but at agent
concentrations that are sometime orders of magnitude lower than those quoted
in the literature to give formal inhibition of tubulin
in vitro
.
The topoisomerases are enzymes that change the topology of DNA. Normal
supercoiled DNA needs to unwind to undergo replication, and this unwinding
requires that the DNA be cleaved and religated. This cleavage can be brought
about by a single-strand break, which is mediated by topoisomerase I, or a double-
strand break, which is brought about by topoisomerase II.
Other mechanisms of action involve inhibitors of the heat shock protein Hsp-
90, of checkpoint kinases, and inhibitors of protein degradation by interaction
with the proteasome.
α
and
β
13.2.1 Compounds that Inhibit Tubulin Assembly
13.2.1.1 The vinca alkaloids
The antitumor alkaloids vinblastine (
1
) and vin-
cristine (
2
) were the first natural products to be used on a large scale as anticancer
agents, and they thus blazed the trail for others that came afterward. Vinblas-
tine (as vincaleukoblastine) was isolated from
Catharanthus roseus
(L.) G. Don,
which was formerly known as
Vinca rosea
L., by two independent teams during
the 1950s (9, 10), and vincristine (as leurocristine) was isolated and structurally
characterized by Svoboda (11) and Neuss et al. (10) in 1961 and early 1962,
respectively. These alkaloids inhibit the polymerization of tubulin to micro-
tubules. Vinblastine is used in combination with other agents for treatment of
Hodgkin's disease and bladder and breast cancers, whereas vincristine is used
for treatment of acute lymphocytic leukemias and lymphomas. The semisynthetic
analogs vindesine (
3
) and vinorelbine (
4
) have been developed more recently.
Vindesine, which was first developed in the 1970s, is in clinical use; it seems to
be more active than vincristine against non-small-cell lung cancer, but it also has
a higher hematological toxicity than vincristine, so its utility is still being eval-
uated (12). Vinorelbine has been approved for treatment of non-small-cell lung
cancer, and the fluorinated analog vinflunine (structure not shown) has entered
clinical trials (13). For a recent general review of the vinca alkaloids and their
analogs, see Reference 14.
