Study underlines potential of adding organometallic fragments to established drugs
Attaching a cobalt complex to aspirin significantly changes the molecule’s anti-cancer properties, European researchers have found. Their study underlines the potential for discovering new anti-tumour therapies by adding organometallic fragments to established drugs.
Ingo Ott, at the Free University of Berlin - leading a collaboration of researchers from Germany, Austria and the Netherlands - explains that following the success of the platinum-containing chemotherapy drug cisplatin, much research has gone into investigating other organometallic medications.
Ott’s team have been studying the hexacarbonyldicobalt [Co2(CO)6] species bound to various alkyne ligands, and found that the anti-tumour activity of this cobalt cluster is more potent when attached to aspirin than to other compounds.
’This led to the conclusion that the anti-tumour activity must be related to the presence of aspirin - rather than the cobalt cluster alone,’ says Ott.
’We found that several pathways relevant to the formation of tumours were significantly altered for the cobalt containing compound,’ Ott told Chemistry World.
In particular, the team showed that the bulky cobalt cluster caused aspirin to interact differently with cyclooxygenase (COX) enzymes (which produce prostaglandins and other signalling molecules related to inflammation and blood clotting).
Where ordinary aspirin inhibits COX enzymes by acetylating a serine residue in their active sites, Ott’s team showed that Co-aspirin leaves the serine residue untouched, instead acetylating lysine residues at other locations. This alters biochemical pathways occurring downstream of COX activity, the researchers say.
Investigating further by performing experiments on zebrafish embryos, the researchers found that Co-aspirin could inhibit cell growth and the formation of small blood vessels - two factors crucial for tumour growth.
Medications targeting COX-2 enzymes, such as Merck’s Vioxx, have recently been under scrutiny after it emerged that they could cause cardiovascular side-effects. However, these are unlikely to be a problem with Co-aspirin, Ott says, as it isn’t a selective COX-2 inhibitor. In any case, he adds, the drug is still at a very early stage of development and animal trials are the next step.
’I believe that there is a lot of potential in organometallic enzyme inhibitors,’ says Stefan Knapp at the Structural Genomics Consortium in Oxford. ’This new area of chemical biology offers new exciting possibilities for the design of efficacious compounds - but there is still a lot to learn about how these inhibitors will behave in living systems.’
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et alAngew. Chem. Int. Ed., 2009 (DOI: 10.1002/anie.200803347)