7-DrugDiscoveryHLSS08 - Organic Chemistry and Drug...

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Organic Chemistry and Drug Development: Synthesis and Analysis of a Library of Hydrazones 1 Reading Assignment: Review Loudon, G.M. Organic Chemistry , 4 th ed.; Oxford University Press: New York, 2002, pgs 874-876. Introduction You are nearing the end of your year in organic chemistry. By now you have learned countless organic reactions and have a basic understanding of mechanism and synthesis. Organic chemists apply this knowledge every day to design and synthesize molecules that are useful as catalysts, polymers, and medicines. In the area of drug discovery the initial focus is on the discovery of “hits” which are compounds that exhibit potency for a selected target such as an enzyme, receptor, DNA, or RNA. 2 The discovery of hits usually involves screening a large collection of compounds, often referred to as a library of compounds, obtained from natural products or synthesized chemically. Some libraries contain greater than a million compounds 1 and a great diversity of structures are represented. Once a hit is identified medicinal chemists synthesize derivatives to attempt to optimize the potency, selectivity, pharmacokinetic and physiochemical properties and to minimize toxicity 2 . Structure activity relationships (SAR) data is collected which attempts to make a correlation between the structure of a molecule and its biological activity 3 . This information is often coupled with NMR and x- ray crystal data, which supports structure based design. 2 The entire drug discovery process takes 12-15 years, approximately $1 billion and involves a team of scientists from the many areas including medicinal, analytical, and process chemistry, molecular biology, toxicology, pharmacology, cell biology, and biochemistry 3 . Combinatorial chemistry has given the chemists the ability to produce large libraries of compounds for biological testing. This method involves synthesizing and testing mixtures of compounds. Identification of an active compound can be done using fewer reactions and biological tests than synthesizing each molecule individually and therefore can save time and money. Combinatorial synthesis has led to the discovery of some current drugs including indivir, an FDA-approved HIV protease drug.
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In this experiment you will experience drug discovery for yourself! You will first synthesize a small library of compounds (nine) beginning with the six starting materials shown below using combinatorial chemistry. Figure 1. Starting materials for compound library. The product mixtures synthesized will then be tested for their antibiotic activity against Escherichia coli . The biological test will involve infecting an agar plate with the bacteria and positioning discs containing the product mixtures onto the agar. The products will diffuse into the agar. The bacteria will grow unless a compound with antibiotic activity is present on one of the discs. In this case you will observe a circle around the disc in which the growth of the bacteria was inhibited. Once a mixture
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This note was uploaded on 05/13/2010 for the course CHEM 152L taught by Professor Baldwin during the Summer '09 term at Duke.

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7-DrugDiscoveryHLSS08 - Organic Chemistry and Drug...

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