Taxanes made using new method

A Scripps research team led by chemist Phil Baran recently synthesized the largest amount of pure taxadiene to date. Taxanes, a family of compounds that includes Taxol, one of the most important cancer drugs discovered, have been difficult to isolate in the past due to their complexity. These findings suggest the possibility of researching previously unavailable potential drugs.

Paclitaxel, commonly known as Taxol, has been used to treat ovarian, breast, lung, liver and other cancers with high degrees of success. Since its discovery in 1967, seven different research teams have designed methods to synthetically produce the drug. However, due to the complexity and inefficiency of these methods, researchers have synthesized less than 30 milligrams of Taxol.

Therefore, it is unsurprising that finding an efficient way to produce large quantities of Taxol in the laboratory is one of the most sought-after goals in organic chemistry. Accomplishing this feat would allow for the production of many other taxanes that are inaccessible from nature.

In the past, researchers attempted to synthesize Taxol by making progressively complex molecules until they reached their target. This method was inefficient and often required taking extra precautions to avoid unwanted side reactions or chemical complications. According to Baran, it was like trying to convert a Toyota Corolla into a Ferrari instead of just building a Ferrari.

In 2009, Baran's team proposed an unconventional scheme that they could use to produce a simpler relative of Taxol, eudesmane. The team then analyzed this target and created a retrosynthesis pyramid, a diagram with the target compound at the apex and lower levels filled with molecules that could be modified to ascend to the level above them. This pyramid showed that a variety of paths could be open to chemical exploration.

There are two main phases in producing taxanes and related compounds, the cyclase and oxidase phases. During the cyclase phase, the researchers construct a chemical scaffolding that Baran likens to a Christmas tree. The ornaments are reactive oxygen molecules, and it is this oxidation phase that is the most challenging.

In a paper published in Nature Chemistry, Baran's group reported that their method involved just 10 steps to produce many more times of Taxol than has been previously synthesized. A conventional taxadiene synthesis, in contrast, takes 26 steps.

Baran's group specifically chose to synthesize a molecule called taxadiene, as this molecule can be modified to create a wide range of taxanes or varying complexity. This choice is important, as the research is not only intended for finding a better way to produce Taxol. The current method of commercially producing Taxol involves culturing cells from its natural source, the yew tree. It is more economical than any new synthesis will probably be.

Instead, Baran and his team aim to understand the natural processes used to produce the compound, which is much more efficient than any synthesis technique to date. According to Baran, there is a huge discrepancy between the efficiency of nature and humans, and that leaves room for innovation.

Baran believes that, while developing an efficient way to synthesize Taxol, the group will gain a fundamentally improved understanding of the chemistry involved and develop more widely applicable techniques. These innovations could allow for the production of a wide variety of taxanes that are currently inaccessible for research due to the difficulty of producing sufficient quantities of the drugs.

Baran estimates that it will take years to establish the remaining steps between taxadiene and Taxol or other complex taxanes. However, if the taxane oxidation process is controlled, then new and important drugs, perhaps drugs that are better at fighting cancers than Taxol, could be discovered.