A potent hybrid of two anticancer natural products has been designed and synthesised by UK chemists.

Developing analogues of natural products with improved biological activity is an area of great current interest. Ian Paterson and colleagues at the University of Cambridge, have now made a natural product analogue with anticancer activity using a combination of rational design and state-of-the-art synthesis. 

Discodermolide is a natural product from marine sponges with high activity against cancer cells. It is currently in clinical trials, but the search is always on for more active analogues. Paterson compared the structure of discodermolide with that of dictyostatin, a more potent but less studied natural product. Using knowledge of the protein binding site involved in the anticancer activity of both molecules, they improved the potency of discodermolide by replacing a part of its structure with a fragment from dictyostatin. 

Both natural products are only available in minute quantities, so the group made their hybrid from scratch. Paterson says that this proved challenging, but that they were able to exploit boron aldol methodology and other synthetic methods to develop 'an efficient and scalable route' to the hybrid.

The hybrid was then tested on four cancer cell lines, and was found to be more potent than discodermolide for all of them. The group also found that deactivating the two hydroxyl groups at the bottom left of the molecule, by tying them up in a ring, resulted in a large drop in activity. This indicates, says Paterson, that one or both of these hydroxyls 'play a key role' in the activity of dictyostatin and discodermolide. 

Dennis Curran, from the University of Pittsburgh, US, finds the work very exciting: 'the Paterson group has a flair for analogue design and efficient synthesis, and it looks like they have hit gold with the testing results on this one.' Future work, says Paterson, will involve 'further probing the pharmacophore and anticancer profiles of these fascinating marine natural products and their hybrids'.

David Barden