Approaches to the design of catalytic metallodrugs #chempaper 213

Well, we can do catalysis using transition metals. Can we do the same in biological systems? Moreover, can we do biochemical transformations? The answer is yes, we can and here are a few examples of these remarkable processes.

In this brief review, you can read several examples of metal catalyzed cross coupling reactions for fluorescent labelling, deprotection of azides/carbamates, activation of metallodrugs, cleavage of peptides, nucleic acid chains and proteins (HIV1, RNA etc.), using NADH for transfer hydrogenation and many more transformations that are done in biochemical environment. Some of them are their infancy, but there are some in Phase II/III stages and there is even one approved in Russia.

Coordination chemistry and neurodegenerative diseases

I think I've shared at least one paper by Chris Orvig before. This paper is a short review on the role of coordination chemistry in neurodegenerative diseases. As you know, many of these diseases are closely related with certain metal ions and I think inorganic (and bioinorganic) chemists are key people to help us understand more about these diseases. I hope one day an inorganic (or medicinal inorganic/bioinorganic) chemist makes a groundbreaking discovery and will never be forgotten for his contribution to medicine.

"Neurodegenerative diseases are capturing the world's attention as being the next set of diseases we must tackle collectively. Not only are the patients experiencing gradual cognitive and physical decline in most cases, but these diseases are fatal with no prevention currently available. As these diseases are progressive, providing care and symptom treatment for the ageing population is becoming both a medical and a financial challenge. This review discusses how Werner coordination chemistry plays a role in three diseases – those of Alzheimer's, Parkinson's, and prions. Metal ions are considered to be involved in these diseases in part via their propensity to cause toxic aggregation of proteins. First, the coordination of metal ions, with emphasis on copper(II), to metalloproteins that are hallmarks of these diseases – amyloid β, α-synuclein, and prion, respectively – will be discussed. We will present the current understanding of the metal coordination environments created by the amino acids of these proteins, as well as metal binding affinity. Second, a diverse set of examples of rationally designed metal chelators to outcompete this deleterious binding will be examined based on coordination mode and affinity toward bio-relevant metal ions. Overall, this review will give a general overview of protein and metal chelator coordination environments in neurodegenerative diseases. "

http://pubs.rsc.org/en/Content/ArticleLanding/2013/CS/c2cs35236b#!divAbstract

Metals and the Brain I

I have read several papers and books on metal ions in neurodegenerative diseases. So, I decided to start another series of posts as long as I find something to write on the topic.

I just read this article in one of my favorite magazines; The Scientist. I think it is a great review on copper in Alzheimer's disease. I read some of the references long time ago and I think I will read them all as soon as possible. Because, I do not know anything about pharmacology, kinetics of drugs etc., I usually try to understand the structures and read the papers very fast. I do know how to interpret IC50, Ki or other very basic data, graphs or values though. While at it, I should mention that there is a free online medicinal chemistry course on edx.org and it is in the 3rd week I guess.

Although we still know little about the true roles and concentrations of the metal ions, new and more powerful techniques (like X-ray fluorescence as the article mentions)  help the scientists to have better information each day. 

Several transition metals are essential for biological processes. One of the most important ones for brain is copper. Actually, the highest concentration of copper in body, is found in brain [1]. So, it is not surprising to see it as a key in neurodegenerative diseases such as Prion diseases, Wilson's disease and Alzheimer's disease. Recently, a group of scientists suggested that zinc is not a biomarker for Alzheimer's Disease. But, as Nigel Hooper says "these data do not rule out a role for altered zinc in the brain being involved in the disease process." Some of the authors of the research article are also working in the same university with the The Scientist article writer. The writer also mentions something similar :

Although overall zinc and iron levels did not vary significantly between AD and healthy brains in Kirsch’s 2011 meta-analysis, this doesn’t rule out complex subcellular changes to the location of these metals.

Even though one can determine the malfunction of the regulation of the metal, the biggest challenge is to fix the problem. One of the methods is using metal complexes (chelates). Here is a library of them by the same author's publication:

In summary, there is a lot of way to find out the cause and the cure for these diseases and I think this is a great article with beautiful infographics and I strongly suggest reading it.

http://pubs.rsc.org/en/content/articlelanding/2010/mt/c0mt00006j#!divAbstract

1. Hughes, M.N.; The Inorganic Chemistry of Biological Processes ; Wiley and Sons, 1981;  p 298.