From catalyst to cancer drug

C&I Issue 6, 2008

Irish chemists have successfully converted a compound normally used in plastic manufacture into what could prove to a powerful anti-cancer drug. If all goes to plan, this compound, titanocene Y, could be the first successful chemotherapy agent against advanced renal-cell carcinoma for which there is currently no treatment.

The new compound is based on titanocene dichloride, a catalyst used in polystyrene polymerisation. Trials in the 1990s on titanocene dichloride, which is cytotoxic, meaning that it selectively targets cancer cells, revealed that it was not cytotoxic enough to justify further trials. But a team led by Matthias Tacke at the school of chemistry and chemical biology at University College Dublin, found that by making simple substitutions, they could make molecules that are more soluble and more easily delivered to cancer cells.

The most recent tests in mice have revealed that the lead compound titanocene Y can shrink breast cancer tumours by up to a third (Anti-Cancer Drugs 2007, 18, 311). ‘This is the first time we have seen shrinkage and in that regard, it is a bit of a breakthrough,’ said Tacke. ‘Although breast cancer is not our target application, the fact that there are such good animal models and that breast cancer is a slower growing tumour meant that we could do more comprehensive testing over longer periods of time,’ said Tacke. ‘And it is an important proof of concept,’ he added. Like kidney tumours, breast tumours are solid.

Tests also show that even at the maximum tolerated dose of 40mg/kg/day, titanocene Y exhibits limited toxicity. ‘The mice do lose about 15% of their weight, but this is not life-threatening and is reversible,’ said Tacke. By contrast, commonly used chemotherapy agents like Cisplatin cannot be given to patients with advanced kidney cancer because they are toxic to the diseased kidney and likely to kill the patient.

In earlier tests, titanocene Y merely slowed tumour growth. Shrinkage was achieved by using a new treatment regime, which involved decreasing the dose from 40 to 30 mg/kg/day and increasing the treatment time from five to 21 days.

The original compounds have been used for years in catalyst chemistry. ‘Basically, we took a compound used for one purpose and found that there was more to it,’ said Tacke. The compound is therefore well known to the industry, but in order to be used therapeutically, it would have to go through the same regulatory and registration procedures as any other candidate compound, according to the Association of the British Pharmaceutical Industry.

Tacke’s team produced the improved titanocene molecule in a few simple steps, including an organosynthesis and an organometallic step, using cheap readily available  materials. A polypentadiene is condensed with benzaldehyde to produce a fullvene with a substitutent in the 6 position and a lithium hydride is added across the oxocyclic carbon-carbon double bond (see Figure).

About 100,000 people die from advanced kidney cancer every year. A chemotherapy agent designed for this application would therefore not be a blockbuster. But at about E5000 per treatment, the market would still be significant, Tacke said. These compounds are basically conventional small molecules and as such still represent significant value over monoclonal antibodies being developed for this application. ‘Antibodies are so expensive, you basically would have to sell your house and if you’re lucky you’ll only survive a few more months in any event,’ Tacke said.

A successor to titanocene Y, oxali-titanocene Y, which is 13 times more cytotoxic, has already been produced. Tests using this compound are expected to be complete by the end of this month. Tacke is currently in talks with two companies potentially interested in developing the drug.

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