Synthesising a cancer cure

British chemists are poised to complete synthesis of a molecule they predict could make a significant impact on the treatment of prostate cancer. Some 25 000 new cases of this disease are diagnosed in the UK each year, says Steven Ley, professor of organic chemistry at the University of Cambridge, and the current mortality rate is about 50 per cent.

It is a slow-growing cancer and often not identified until men reach their 50s, by which point it may have spread. Ley’s group is focusing on a molecule - thapsigargin - that has shown promise as a putative pro-drug for prostate cancer treatment in in vitro and animal studies.

Thapsigargin was identified in the umbelliferous plant Thapsia garganica in the 1970s although an extract of the plant had been used as a counter-irritant for centuries. It is still used to treat inflammatory disorders, such as rheumatoid arthritis, and is known to stimulate the release of histamine and to inhibit the sarco-endoplasmic reticulum Ca ²⁺ ATP dependent (SERCA) pump, which regulates intracellular Ca ²⁺ levels. Blocking these pumps causes a massive build up of Ca ²⁺ inside cells, which in turn triggers programmed cell death - apoptosis - making thapsigargin an attractive candidate for cancer therapy.

But there’s a problem with thapsigargin extraction, says Ley. ’It is not easy to get out, it’s pretty unpleasant to do and it often requires a lot of HPLC work to be done . You can’t get large quantities of it and it’s not a compound that people would ideally like to get from the natural source.’

Synthesising thapsigargin would be the ideal solution, he says, but that also presents problems. ’What complicates the whole story is it’s not alone as a single molecule,’ said Ley. The biologically active components of the Thapsia plant include thapsigargin and 15 closely related sesquiterpene lactones collectively termed the ’thapsigargins’. All these analogues, together with the fact that the thapsigargins have a highly oxygenated tricyclic framework containing seven or eight stereogenic centres functionalised with a range of different acyl groups, provides a unique challenge to chemists.

Ley’s team reported last year the total synthesis of one subfamily of the thapsigargins, the trilobilides, comprising three molecules that lack the acyloxy substituent at C2. These are about three to five times less active than other thapsigargins in terms of binding to the SERCA pump, and Ley’s team is hard at work building on this to incorporate the most biologically active features of the thapsigargins into one molecule, while removing features not involved in activity.

He presented his latest data in June at a meeting on organic synthesis in Riga, Latvia (see Chemistry World, July 2004, p8) and had hoped to have completed the project by then. ’We’re not quite there yet,’ he told delegates. ’It’s been a synthesis that took some time, some false starts, but it gives us great opportunities to build scaffolds that we could use to make analogues from.’

Ley was awarded the Society of Chemical Industry’s Messel Medal in July for research on the discovery and development of new synthetic methods and their application to biologically active systems.

Bea Perks