5.9 Limitations of cisplatin
Now watch the following video which summarises the limitations of cisplatin from a chemical viewpoint and looks at strategies for the development of new drugs. It starts by mentioning the drug carboplatin.
Transcript: Video 11 The cisplatin story: Part 6. (2:26 min)
NARRATOR: As well as understanding the mechanism, the drive is also on to improve existing drugs.
LLOYD KELLAND: It was realised very early on that the problem with cisplatin was one of chemical reactivity – the rate at which those chloride ligands leave the molecule. And the whole idea behind carboplatin was to tone down that reactivity. And, in fact, what is present in carboplatin, instead of the chlorides, is a cyclobutane dicarboxylato group, which laboratory experiments have shown slows down the rate of aquation – the rate at which those ligands leave – by about tenfold in carboplatin.
And that has had a dramatic clinical effect in patients in that the kidney toxicity seen with cisplatin is almost totally absent with carboplatin. And indeed, the nausea and vomiting seen with cisplatin, which is also a severe problem, is much less with carboplatin as well.
NARRATOR: Research now continues to make new platinum-containing drugs. One method is to employ so-called combinatorial methods. This is like one-pot cooking, where all the ingredients are put into the pot together and then heated. In the set-up here, it is possible to synthesise 96 new compounds at a time by simply adding different combinations of ligands to a platinum-containing starting material.
The reactions can take place under inert atmospheres, such as argon or nitrogen, or in the air. They can also take place at different temperatures, in a range from minus 80 to 150 degrees Celsius. The reactants are mixed. And after a suitable reaction time, the products in each part are filtered off, dried and then tested for anticancer activity.
STEPHEN LIPPARD: We’ve been developing new methodologies that would allow us to test large families, or libraries, of platinum compounds prepared in a combinatorial way, meaning that we would take mixtures of ligands, including amines, but extending it way beyond amines, to examine thousands, or maybe even millions, of molecules, for their ability to damage DNA and to produce altered structures which would lead to the binding of these HMG domain proteins and/or the specific blocking of gene function.
What aspect of the chemistry of the cisplatin molecule motivated the search for alternative platinum-based drugs?
The reactivity of the molecule – in particular, the rate at which chloride ligands leave the complex.
What are combinatorial methods?
A synthetic approach designed to produce a large number of related compounds in a single process – in this case, different combinations or permutations of ligands. The video referred to the technique as ‘one-pot cooking’.