Despite considerable progress in modern chemotherapy, there remains a large
demand for innovative anti-tumor agents. A new approach involves modeling the
pharmacological properties of established drugs with organometallic fragments.
As a team of scientists from Berlin and Bochum (Germany), Innsbruck (Austria),
and Leiden (The Netherlands) report in the journal Angewandte
Chemie, cobalt–aspirin complexes have potential as cytostatics.
Most drugs used today are purely organic compounds. Stimulated by the enormous
success of the inorganic complex cisplatin in tumor treatment, interest in metal
complexes has grown. Within cells, metal complexes can participate in reactions
that are not possible with conventional organic substances.
Aspirin (acetylsalicylic acid) belongs to the family of nonsteroidal antirheumatics
(NSAR), which have anti-inflammatory and pain-relieving effects. The pharmacological
effects of NSARs stem from the inhibition of enzymes in the cyclooxygenase family
(COX). These enzymes not only play a central role in inflammatory processes,
they also seem to be involved in tumor growth. NSARs have thus come into focus
as potential cytostatics. It may be possible to improve anti-tumor activity
in the case of aspirin by binding it to an organometallic fragment.
Within the scope of the “Biological Function of Organometallic Compounds”
research group funded by the Deutsche Forschungsgemeinshaft (German Research
Foundation, DFG), the team determined that “Co-Aspirin”, a hexacarbonyldicoboalt–aspirin
complex, inhibits COX activity differently to aspirin. Whereas the effect of
aspirin stems from the acetylation of a serine residue in the active center
of COX, Co-Asprin does not attack this side chain, instead acetylating several
other sites. This may block access to the active center of the enzyme, resulting
in a different activity spectrum for the drug.
Experiments with zebra fish embryos showed that in contrast to aspirin, Co-Aspirin
inhibits both cell growth and the formation of small blood vessels (angiogenesis).
Tumors are dependent on newly formed blood vessels for their nutrients and can
be starved out by the inhibition of angiogenesis. In addition, Co-Aspirin modulates
other tumor-relevant metabolic pathways. For example, it activates the enzyme
caspase, which is involved in processes that lead to apoptosis (programmed cell
death).
Posted January 13th, 2009
