Coordination Chemistry of Novel Drug Candidates for the Treatment of Iron Overload

• Main Author: Norin, Anneli
• Format: Others
• Language: English
• Published: Mälardalens högskola, Institutionen för biologi och kemiteknik 2007
• Subjects: Chemical engineering; Kemiteknik
• Online Access: http://urn.kb.se/resolve?urn=urn:nbn:se:mdh:diva-227

Iron overload is a serious clinical condition caused by excessive iron in the body, which can be largely prevented by the use of iron-specific chelating agents. At the moment there are only a few chelators in clinical use for the treatment of Fe overload. One of them, and so far the best working one, is desferrioxamine (DFO). This iron chelator has a major disadvantage of being orally inactive and is given by long and frequent subcutaneous infusions (12-24 hours/5-6 days/week) to patients. 1 Consequently, the design of an orally active, nontoxic, selective iron chelator has become a high priority. To design an iron chelator for clinical use, the important factors to consider are metal selectivity and affinity, ligand-metal complex stability, bioavailability and toxicity. The best iron chelator should be highly selective for iron(III) in order to minimize chelation of other biological essential metal ions which could lead to deficiency with prolonged usage. Favouring the Fe (III) oxidation state avoids Fenton chemistry and the production of toxic free radicals. This report deals with complexes of aroylpicolylhydrazines. Chemical and biological testing has established that these molecules function extremely well as iron chelators in vivo. The most effective candidates are more efficient at promoting iron efflux (release of iron) from cells than the existing drug DFO. Although the ligands discussed in this report, are selective for iron, there is no record of how they interact with other essential metal ions (Mn, Co, Ni, Cu and Zn) in our body and it is this that is the topic of this report. It was found that the complexes with H2PPH (N,N’-bis(α-picolinoyl)hydrazine) probably built polymeric complexes and therefore they were almost totally insoluble in all common solvents. The complexes of H2BPH (N-(benzoyl)-N’-(picolinoyl)hydrazine)) were also problematic in terms of insolubility. Another problem was decomposition of the complexes in solution, with resultant precipitation of the ligand and that happened with all of the ligands. The ligand H2TPH formed complexes with Ni and Co, [MII(HL)2] and [MIII(L)2]-, and crystals were grown suitable for x-ray structure studies. The cobalt complex is the first one reported of its kind. There was also crystals grown suitable for x-ray work of a protonated picolylhydrazide and that is also the first crystal structure reported.