Due to our continually increasing life expectancy and
exposure to environmental toxins, we are constantly facing new health problems.
Among these, chronic diseases represent the main cause of mortality globally,
and account for more than 63% of deaths 1, a number that is likely
to increase in the next decades according to the WHO 2. Cancer is
one of the most prevalent chronic diseases, and is the second leading cause of
death 3. The most commonly diagnosed cancers are lung and breast
cancer with a cumulative risk to age 75 of 2.7% and 4.6%, respectively 4.
Given population growth, these figures will continue to grow.
Many different biological targets have been pursued in
efforts to treat cancer and prevent metastasis 5. One of the most
promising targets identified thus far are microtubules due to the key role they
play in mitosis. Mitosis is the process of duplication of a single cell into two
daughter cells, and is one of the fundamental process underlying cancer cell
proliferation. In clinic and in practice, it has been shown that inhibition of
this process can result in the selective killing of cancer cells and prevent
their uncontrolled spread to other organs and tissues. Thus, there is an urgent
need for new inhibitors of microtubule formation that have improved properties
over those presently in use 6.
Currently, one of the most common chemotherapeutic
agents used to treat cancer is taxol. Since it was granted FDA approval in
1992, taxol has been used to treat millions of patients affected by lung,
breast and ovarian cancers 7. Taxol was originally extracted from
the Pacific yew tree, however there was a limited supply of this material and
the process required the sacrifice of a large number of slow growing trees to
provide the drug in very low yield 8. To address the lack of
supply as well as unfavorable properties of taxol that include high toxicity 9,
low solubility 10, drug resistance 11 and high cost 12,
much effort has been expended in the search for suitable alternatives with
similar properties that can be produced in higher quantities through total synthesis.
One such lead is eleutherobin 13 Figure 1.
was originally isolated in 1997 from a rare alcyonacea coral located near
Bennett’s Shoal in Western Australia 13. After testing eleutherobin
on different cancer cell lines, it was found to be surprisingly potent (IC50
= 10-15 nM). Moreover, it showed significant cytotoxicity and seemed
effective on taxol resistant carcinoma cells 14. It was eventually
shown that this compound’s effect on cancer cell proliferation derives from its
interaction with tubulin protein (the building block of microtubules) and
stabilization of microtubules, which leads to mitotic arrest, apoptosis and
cell death 15.
Despite eleutherobin’s promising features, its use as
a cancer therapeutic has stalled due to the scarcity of material from the
natural source. To address this impasse, eleutherobin total synthesis has been
the subject of remarkable efforts from some of the top research groups in the
world. Though numerous questions have yet to be answered regarding eleutherobin’s
toxicity, its mechanism of resistance and its metabolic stability, more than 50
publications have described efforts to develop a robust and practical synthesis
of this natural product. Out of those, only 2 total syntheses 16-20
and 1 formal synthesis 21-22 have been completed. Despite important
contributions to our understanding of this molecules properties and activity, the
large number of steps together with the poor overall yield have unfortunately
failed to adequately address the problem of supply, and consequently eleutherobin’s
biological potential has yet to be fully realized.
This project has been active since 2005 at Simon
Fraser University. A synthesis strategy has been established that allowed
researchers in the Britton group to access a key intermediate Figure 3. However,
translation of these results into a synthesis of eleutherobin has not been
successful and thus, a new synthetic route is required Figure 3.