On-line Course In Pharmaceutical Chemistry Taught by Dr. Givens

Pharmaceutical Chemistry 744 (PHCH 744): Organic Chemistry for Pharmaceutical Scientists (2010- present)

A consideration of the structural features and driving forces that control the course of chemical reactions in organic chemistry.  Topics will include functional group chemistry; electronic structure (from Lewis structures to LCAO-derived molecular orbital approaches); acid/base properties (Bronsted and Lewis acidity concepts); molecular structure and properties (dipole, strain, and steric effects, inductive and resonance electronic effects); dynamics of reactions  including more common, major organic reaction mechanisms; kinetics; free energy profiles; isotope effects; linear free energy relationships; solvent effects; stereochemistry and conformational analysis; an introduction to orbital symmetry control; basic thermodynamic and kinetic concepts; and an overview of other important classes of organic reaction mechanisms.

Three lecture periods per week will be devoted to the topics listed.  Addition­al material will be covered through problem sets and assignments.  These are intended to develop and test your understanding of the concepts and material.  The answers will be posted in a timely manner on Blackboard as will course information, problem sets, and the keys for the examinations, problems sets, quizzes and the final examination.

The course performance is measured by the results on three examinations, each cumulative and comprehensive tests of the students knowledge in mastering the material presented in the lectures, from the text, and from material drawn from literature references.  Problem sets, quizzes, and examinations will be drawn from the primary literature, typically from the Journal of Pharmaceutical Sciences, Journal of the American Chemical Society, the Journal of Organic Chemistry and Organic Letters and others.

This is a begining one-semester course for graduate studies in Pharmaceutical Chemistry.  The course is designed to review and enhance your knowledge of the “structural features and driving forces that control the course of chemical reactions”.  As noted in the Course Description, the topics include acid-base properties of functional groups, effects of strain, steric effects, electronic inductive and resonance effects, and solvent effects as well as combinations of these factors for understanding chemical reactivity.  Effects of molecular conformation and stereochemistry, kinetic isotope effects, and the influence of solvent properties on chemical reactions will be introduced.  Developing an ability to devise electron-pushing reaction mechanisms and construct pictorial representations of energy profiles based on the basic thermodynamic and kinetic concepts necessary for understanding driving forces for reactivity will be major objectives of this course.  The course will also include an introduction to molecular orbital theory and orbital symmetry control of reactions. Throughout the discussions of the topics listed below, we will integrate the important classes of reaction mechanisms in organic chemistry and biochemistry.

Undergraduate Research in Photochemistry (2010 - present)

Synthesis and Rapid, Controlled Release of Glutamate and pro-Drugs: A Study on Their Effect on Dopamine release1,2.  

 

            Currently we are extending our search for the controlled release of pharmaceuticals (i.e., drug delivery).  Prof. Johnson’s group at KU is probing the influence of glutamate on intracellular stimulated dopamine release as part of his NIH sponsored Huntington’s disease project.3 I am a collaborator on his project, advising his group on pHP photochemistry.1

We not only provide Professor Johnson’s group with caged glutamate but also have begun developing models for caged pro-drugs that will probe effects of agonists/antagonists on glutamate and dopamine release in tissue samples. We will synthesize model pHP protected phenols (3a c), which are relatively new functional groups for our studies1,2 including some phenols known to alter the release of dopamine (an example, 3c) is shown in Scheme 1).

 

Using the synthetic strategy in Scheme 2, we will make the bromoketone 1 and then react it with methyl chlorosalicylates 2a or 2b under basic conditions to give the phenyl ethers 3a or 3b.

 

    

The release photochemistry (Scheme 3) will be then be explored as was done with esters 5a – c shown in Scheme 2.  Tom is caging Raclopride (3c), a phenolic D-2 dopamine receptor inhibitor,3 and he will carry out the photoreaction of caged 3c.   Julie, has progressed through the steps of the synthesis with a model phenol (p-cyanophenol) and is about to test it photochemistry for release.  We will continue her project this summer, if necessary, as well as further work on synthesis of 3a and 3b from phenols 2a and 2b, respectively. 

 

Johnson group has explored the effect of released glutamate from pHP Glu and its effect on dopamine concentrations in “Huntington’s disease” rat brain tissue samples.  They have discovered that both dopamine and the photoproduct 3 (pHAA) are electrochemically active.  Cyclic voltammetry (CV) measurements of dopamine (DA) and pHAA are clearly distinguishable (Figure 1) and can be analyzed during photolysis, thus permitting simultaneous, quantitative time-resolved measurement of the photoreaction while it is in progress using the same electrode.   This fortuitously good fortune will aid in exploring the mechanism for changes in agonist and dopamine concentrations simultaneously. 

      Glutamate concentrations are known to be a causative vector in dysregulation of dopamine. This approach will also be examined using the D-3 receptor antagonist like 3c.  A study of the interactions between photoactivated neurotransmitter release and the effects of added pharmacological agents can be melded into this study by simultaneously measuring the release of both electro active neurotransmitters and neuromodulators.  The approach could be potentially very useful for determination of photoactivatable agonists and antagonists of dopamine on the D2-family receptors and for screening candidate drugs for their efficacy.     

                     

  Figure 1.  a) Cyclic voltammetry response of pHP Glutamate in solution up to a 200 ms exposure.  Response is linear up to 400 ms. b) Dopamine release from uncaging pHP glutamate. DA = dopamine; pHPAA is p-hydroxyphenylacetic acid (7).

1a. Givens, R. S.; Rubina, M.; Wirz, J. Photochem. Photobiol. Sci. 2012, 11, 472, b. Goeldner, M.; Givens, R. S. Dynamic Studies in Biology; Wiley-VCH: Weinheim, Germany, 2006,

2. A comprehensive review of PPG chemistry, see: Klán, P.; Givens, R.; Rubina, M.; Wirz, J.; et al. Photoremovable Protecting Groups in Chemistry and Biology: Release Rates, Mechanisms, and Efficacy” Chem. Rev. 2013, 113, 119.

3.  Johnson, M.; Givens, R.; Kaplan, S.; Field, T.; Peterson, J. in progress, unpublished results (KU).

 

 

 

 


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