James M. Cook
Organic Chemistry
University Distinguished Professor
PhD, University of Michigan
(414) 229-5856
e-mail: capncook@uwm.edu
Cook's Group Page
Recent Publications
Professor Cook's group is working in several related fields including Natural Products, Medicinal Chemistry, and Organic Synthesis. More specifically, he is interested in the enantiospecific synthesis of natural products with biological activity and the construction of related heterocycles with enhanced activity. Research of this type has led him into the indole, benzylisoquinoline, and isoquinoline alkaloid areas, as well as the chemistry of the important alkaloids quinine, quinidine and reserpine. His group is also currently involved in the study of ligand-receptor interactions at the molecular level.
Figure 1. Macralstonine. |
Over seventy macroline/sarpagine/ajmaline related alkaloids have been isolated from species of Alstonia. A stereospecific Pictet Spengler reaction developed at Milwaukee is currently being employed to execute an enantiospecific total synthesis of the bisindoles macralstonine (figure 1) and villalstonine (figure 2) which have been shown to demonstrate antihypertensive and antimalarial activity, respectively.
Figure 2. Villalstonine. |
A general approach for the synthesis of polyquinenes via the Weiss reaction continues in his laboratory. The construction of the [5.5.5.5]fenestrane hexaene (figure 3) and the related heptaene (figure 4) are being pursued in regard to the bonding character of molecules formerly proposed to house a planar tetracoordinate carbon atom, a three-center, two electron bond at carbon. Other annulenes such as cyclopentapentalene (figure 5) are being prepared to examine homoconjugation as well as Hüuckel pi stability.
![Figure 3. [5.5.5.5] Fenestrane hexaene](http://alchemy.chem.uwm.edu/research/cook/fenestr.gif)
Figure 3. [5.5.5.5] Fenestrane hexaene. |
Figure 4. Heptaene. |
Figure 5. Cyclopentapentalene. |
The synthesis of beta-carbolines, 2,7-dihydropyridodiindoles, isoquinolines, indolo-pyridoimidazoles and imidazobenzodiazepines, when combined with molecular modeling, has resulted in the pharmacophores for agonist and inverse agonist activity at benzodiazepine receptors. The inverse agonists are being evaluated for cognitive enhancement, while the more potent agents in this series will be tested for treatment of hepatic encephalopathy and to reverse the effects of barbiturate-alcohol overdose.
The agonists at BzR, especially partial agonists, are being evaluated for anxiolytic and anticonvulsant activity, as well as ataxic activity. Lead compounds in this series are devoid of the muscle relaxant effects of Valium. The aim is to provide new drugs with anxiolytic and anticonvulsant activity which are devoid of the deleterious side effects of the classical benzodiazepines including abuse potential. This will result in more selective agents to treat a number of serious anxiety disorders.
In a related area of indole chemistry, ligands have been developed that competitively inhibit the enzyme, indoleamine 2,3-dioxygenase. This enzyme is induced to high levels during the immune response and seriously alters the metabolism of tryptophan in inflammatory diseases. This results in increased biosynthesis of kynurenic acid and quinolinic acid followed by cell death. This condition has been implicated in over twenty inflammatory diseases, including acquired immune deficiency syndrome (AIDS), hepatic encephalopathy and polio virus. The inhibitors of this enzyme are designed to reverse the aberrant metabolism of tryptophan in the CNS and return levels of quinolinic acid, etc. to normal.
