Apoisonous plant’s value is in the eye of the beholder and Thapsia garganica has become highly prized by cancer specialists. In the wake of a recently published development by investigators at Queen’s University, many cancer patients could become downright fond of these noxious yellow Mediterranean perennials.
Thapsia has long been known as the “deadly carrot” for its ability to kill animals. Ancient Greek physicians are believed to have successfully employed it as a pain reliever and purgative in people. Modern oncologists have set their sights even higher, hoping to stop malignant tumours with an extract from the plant’s roots, a complex molecule called thapsigargin that was identified almost 40 years ago.
Thapsigargin is too toxic for straightforward use as a drug. It inhibits a key calcium channel found in each of our cells, which then activates the fatal biochemical cascade known as apoptosis, or cellular death.
Pharmacologists neutralized this property by attaching a small peptide to create a prodrug called Mipsagargin, which responds to enzymes released by some types of cancer cells. This interaction strips off the peptide and allows the thapsigargin analog to dispatch the tumour cells.
Inspyr Therapeutics, a Texas-based biotechnology firm, is heading toward Phase III trials of Mipsagargin. If successful, it could create an annual demand for as much as one tonne of the material. Until recently, that would have been a tall order, as Thapsia does not cultivate well and the only known means of synthesizing the molecule called for 42 steps with a yield of 0.61 percent. Earlier this year, the research group led by Andrew Evans at Queen’s developed a 12-step synthesis with a yield of 5.8 percent, which is a more than 40-fold increase in output. Even more significantly, Chen constructed the pharmacological core of thapsigargin, its sesquiterpene lactone skeleton, in just five steps. “That’s incredible because it allows you to do meaningful medicinal chemistry on this agent,” says Evans, who acknowledges that this work began with a different, unsuccessful approach. Dezhi Chen, a graduate student working in his research group, suggested a bio-inspired strategy that called for the disconnection of carbon-carbon bonds to minimize the number of necessary functional group transformations. Nine months later, Chen translated the idea into a practical and efficient total synthesis of this material.
Prior to publishing their results in the Journal of the American Chemical Society, Evans and Chen filed a patent on the technique.
Chen has prepared more molecules in the thapsigargin family, including structural analogs, which should open the door for a drug production platform to deliver the necessary quantities and allow for chemical manipulation to achieve the necessary qualities demanded by specific cancer therapies. “You can get significant amounts of material through this route,” says Evans, noting that pharmaceutical companies prefer the reliability of synthesis over the agricultural vagaries of plant-based manufacture. “We don’t have to make the natural product, we can manipulate our chemical route to make the prodrug. We’re hoping to make simple analogues that are as potent as thapsigargin or better, then work with others to get these to target certain cells.”