MotW12 – potential prodrugs for Alzheimer’s disease
The molecule for this week comes from research out of the Medicinal Inorganic Chemistry Group at the University of British Columbia in Vancouver and concerns altering pyridinone N-substituents to optimize activity as potential prodrugs for Alzheimer’s disease (Lauren E. Scott, Brent D. G. Page, Brian O. Patrick and Chris Orvig. Dalton Trans., 2008, 6364 – 6367). The research focuses on using metal-binding pyridinone prodrugs for Alzheimer’s disease treatment because of their brain targeting abilities as well as their antioxidant characteristics. Pyridinones are already approved for therapeutic purposes in some areas of the world and, since hydroxypridinones are good at binding to metals, the N-substituent can be modified which in turn alters the structure without changing metal binding capabilities.
In previous research, it was found that molecules that contain a glucose moiety can easily target the brain. Based on this, the researchers aimed to attach a glucose moiety at the 3-hydroxyl oxygen. This glucose moiety can then be enzymatically removed once the molecule reaches the target leaving the metal binding agent. The copper complexes 3-Hydroxy-2-methyl-1-phenyl-4(1H)-pyridinone (Hppp) and 3-hydroxy-2-methyl-4(1H)-pyridinone (Hnbp) were synthesized. Copper was used as it is one of the redox active metals involved in Alzheimer’s disease and because it has a higher affinity for amerliorate toxic beta-amyloid deposits, which are found in the brains of affected patients. It was found that the Hppp and Hnbp significantly reduced the amount of amerliorate toxic beta-amyloid deposits and there was no significant difference between the Hppp copper complex and the Hnbp copper complex in efficiency.
I found this research both interesting and important as there is currently no cure for Alzheimer’s disease. It is also interesting to see how inorganic chemistry can be applied to solving problems in medical and biological settings . I am hopeful that in a few years we will see a similar drug or concept that will help cure Alzheimer’s disease.