The Scripps Research laboratory of Professor Phil Baran has created the largest amount of pure taxadiene isolated or prepared to date. Image: Photo courtesy of the Scripps Research Institute |
Taxanes
are a family of compounds that includes one of the most important
cancer drugs ever discovered, Taxol, among other cancer treatments. But
the difficulty producing these complex molecules in the lab has hampered
or blocked exploration of the family for further drug leads. Now, a
group of Scripps Research Institute scientists has successfully achieved
a major step toward the goal of synthetically producing Taxol and other
complex taxanes on a quest to harness chemical reactions that could
enable research on previously unavailable potential drugs.
The
project, led by Scripps Research chemist Phil Baran, is described
November 6, 2011 in an advance, online issue of the journal Nature Chemistry.
Taxol,
the trade name for a chemical called paclitaxel first discovered in
1967 in the bark of a yew tree, is a highly successful drug used to
treat ovarian, breast, lung, liver, and other cancer types. No less than
seven different research groups have designed several ways to produce
Taxol synthetically, beginning in the 1990s with a team led by K.C.
Nicolaou, chair of the Scripps Research Department of Chemistry.
While
each synthesis was a significant accomplishment, each has also been
exceedingly complex and inefficient. Using all these methods
collectively, researchers have produced less than 30 milligrams of
synthetic Taxol. Producing other chemicals from the same promising
taxanes chemical group is nearly as challenging, vastly limiting access
to them for research.
Building Ferraris
Finding
an efficient way to produce Taxol in sizable quantity in the laboratory
remains one of the most sought-after and elusive goals in organic
chemistry. If accomplished, it would open the door to producing
countless other taxanes that are not accessible from nature. Past
methods were devised using conventional schemes where researchers plot a
linear path of increasingly complex molecules leading to a target
compound. Creating each increasingly complex molecule along that line is
an inefficient process that often requires numerous extra steps to
prevent unwanted reactions or to correct other chemical complications.
“It’s like trying to convert a Toyota Corolla into a Ferrari instead of
just building a Ferrari,” said Baran.
To
build the Ferrari, Baran and his team are taking a different route. In
2009, the researchers showed that by using an unconventional scheme they
could produce a simpler relative of Taxol called eudesmane. They
analyzed this target and then created what Baran calls a retrosynthesis
pyramid. This is a diagram with the target compound at the top and lower
levels filled with molecules that could theoretically be modified to
reach the level above them. Such a pyramid reveals not a set linear
path, but a variety of path options open to chemical exploration.
With
taxanes and related compounds there are two main phases in production,
the cyclase phase and oxidase phase. Working up the bottom half of the
pyramid involves mostly well-understood chemistry. During this cyclase
phase, researchers construct a chemical scaffolding that Baran likens to
a Christmas tree to which ornaments must then be attached. The
ornaments are primarily reactive oxygen molecules and this “decoration,”
or oxidation, phase is the most challenging.
The
eudesmane synthesis was something like decorating the Charlie Brown
Christmas tree, while a completed Taxol production could be compared to
the lighting of the famous multi-story Rockefeller Center tree.
In
the new paper, Baran’s group reports erecting that Rockefeller tree and
adding the first few ornaments—a molecule called taxadiene. “It’s a
Herculean task,” said Baran of Taxol synthesis, “What we’re doing here
is merely part one.”
A
conventional taxadiene synthesis is inefficient and involves 26 steps
to produce. The Baran group’s method involves just 10 steps to produce
many times what has been previously synthesized—more than sufficient for
planned research to find a way to efficiently produce Taxol.
Innovation leads to access
The
taxadiene synthesis is more than just a midway stop on the way to
Taxol. The researchers chose this molecule intentionally because, like a
Christmas tree that can be decorated in any number of ways, this
molecule can be modified to create a wide range of taxanes of varying
complexities.
This
is key, because at its heart the research isn’t only about finding a
better way to produce Taxol, even though the group is working toward
that goal. The current commercial Taxol production method, which
involves culturing cells from the yew tree, is more economical than any
new synthesis is likely to be.
Instead,
Baran and his team are aiming to understand the processes used in
nature to produce the compound, which are many times more efficient than
those used by scientists to date. “It’s my opinion that when there’s a
huge discrepancy between the efficiency of nature and humans, in the
space between, there’s innovation.”
More
specifically, Baran believes that while developing an efficient
synthesis for Taxol, they will gain a fundamentally improved
understanding of the chemistry involved and develop more widely
applicable techniques. Such innovation could allow production of a whole
range of taxanes currently inaccessible for drug discovery research
either because the quantities researchers can produce are vanishingly
small, or because they can’t produce them at all. Control of the taxane
oxidation process therefore offers the potential for discovering new and
important drugs, perhaps even one or more that is better at fighting
specific cancers than Taxol.
Establishing
the remaining steps between taxadiene and Taxol or other more complex
taxanes remains a challenging task that Baran estimates will take years.
“Nature has a choreography in the way she decorates the tree,” he said.
“It’s a precise dance she has worked out over millennia. We have to
figure out a way to bring that efficiency to the laboratory setting.”
This
research was supported by the National Institutes of Health, the
Fulbright Scholar Program, the National Sciences and Engineering
Research Council of Canada, and Bristol-Myers Squibb.
In
addition to Baran, authors on the paper, entitled, “Scalable,
enantioselective taxane total synthesis,” were co-first authors Abraham
Mendoza and Yoshihiro Ishihara, both of Scripps Research.
Filed Under: Drug Discovery