Iron Complex with a Killer Instinct

24-03-2004: German researchers have successfully developed a new class of cytostatics that drive cancer cells to programmed suicide (apoptosis): iron-containing nucleoside analogs. With their discovery, the team led by Hans-Günther Schmalz (University of Cologne), Thomas Wieder (University of Tübingen), and Aram Prokop (Charité, Berlin) has opened a new chapter in bio-organometallic chemistry.

Phosphate-bridged nucleosides are the building blocks that make up our nucleic acids (DNA and RNA), carriers of genetic information. In addition, nucleosides, again linked through one or more phosphate groups, also perform other important tasks, such as energy delivery (adenosine triphosphate, ATP) or as a messenger in signal transmission within cells. Nucleoside analogs, such as the nucleoside antibiotics Carbovir and Tubercidine, are established drugs for fighting viruses, bacteria, and fungi, as well as being cytostatics. Analogs of natural metabolites are under consideration as drugs because they so closely resemble their "models" in structure that they compete with them, inhibiting or misdirecting physiological processes.

Nucleosides are made of one of the nucleotide bases, adenine, cytosine, guanine, and thymine (DNA) or uracil (RNA), bound to a ribose unit. Ribose is a ring-shaped sugar made of five carbon atoms. From previous work, the chemists knew that a specific type of ribose analog can be highly selectively coupled to the right location on a nucleotide base if the ribose analog is bound to an iron-carbonyl complex. The complex stabilizes an intermediate product in the reaction. A carbonyl complex is a coordination complex in which the central metal atom surrounds itself with carbon monoxide molecules (CO) as ligands. Using this technique, the researchers produced a kaleidoscope of different nucleoside analogs. Instead of removing the metal complex after the reaction, however, they decided to test the pharmacological potential of the iron-containing nucleoside analogs. The result: several of the complex-bound nucleoside analogs proved to be distinctly cytotoxic toward tumor cells and degenerate lymphoblasts of the type found in children with acute leukemia. Compounds of the nucleotide base cytosine were especially effective. In contrast, a decomplexed version proved to be considerably less active. "The metal carbonyl fragment is clearly important to the biological activity," says Schmalz, "we are currently researching the precise implications. We are also working on compounds with an improved pharmacological profile."