US researchers improve the biological activity of compounds from sponges.

US researchers improve the biological activity of compounds from sponges.

Marine sponges are sources of unusual biomolecules, some of which act as highly potent drugs against many different diseases, including cancer and malaria. Due to the scarcity of the substance in the natural source, however, total synthesis, though challenging, is often the only viable route to medical applications. Recently, researchers succeeded in re-making the powerful anticancer substance dictyostatin from Corallistidae deep sea sponges 1,2. Now, chemists in New York, US, have managed not only to recreate another powerful substance from marine sponges but also to improve on its medical activity by replacing a single atom.

The glycolipid KRN7000, a synthetic analogue of the class of potent antitumour substances from the sponge Agelas mauritianus, collectively known as agelasphins, already has an unusually high activity as a stimulator of the immune system in animal models of many different diseases including malaria, type 1 diabetes, and several kinds of cancer. Nevertheless, Richard Franck’s group at the City University of New York (CUNY), US, tried to enhance this activity further. Their reasoning was that the O-glycoside link that connects a galactosyl ring to the rest of the molecule might be degraded by enzymes (galactosidases) and thus limit the survival time of the substance in the body. Having recently developed a new strategy to replace O-glycoside links by C-glycosides, Franck and his co-workers chose KRN7000 to test-drive their method.

In many other examples, the replacement of O with C has resulted in equal or reduced activity, but this time the altered molecule has between 100- and 1000-fold increased activity in many of the disease models where the original was already highly active 3. Ironically, the stability increase which provided the original motivation to make the molecule may turn out not to be the crucial point. Although the issue is not yet resolved, the researchers favour the interpretation that an alteration of the molecular recognition site is responsible for most of the activity boost.

Michael Gross

Reference

1. I Paterson et al, Angew. Chem. Int. Ed., 2004, 43 (DOI: 10.1002/anie.200460589)

2. Y Shin et al, Angew. Chem. Int. Ed., 2004, 43 (DOI: 10.1002/anie.200460593)

3. G Yang et al, Angew. Chem. Int. Ed., 2004, 43, 3818