Lorraine M. Deck - US grants

Dr. Lorraine W. Deck and other members of the Chemistry Department of the University of New Mexico are being supported to continue a Research Experiences for Undergraduates (REU) site in Chemistry. For the period 1993-5, ten undergraduate students will spend ten weeks each summer actively engaged in a variety of research projects. Projects cover the traditional areas of chemistry- analytical, inorganic, organic, physical and biochemistry. A unique feature of this program is the recruiting of most of the students from other institutions where research programs are limited, particularly the many small ones in the southwestern U.S. which lack comprehensive research programs and facilities.

Dr. Lorraine Deck and other members of the Chemistry Department at the University of New Mexico are being supported to continue a Research Experiences for Undergraduates (REU) site in chemistry. For the period 1996-98, ten undergraduate students will spend ten weeks each summer actively engaged in basic research projects drawn from the traditional areas of chemistry and biochemistry. The site encourages participants from small institutions in the southwestern United States, particularly minority students from the Native American and Hispanic communities.

This award is Career Advancement Award in the Organic Dynamics Program of the Chemistry Division. With these funds, Dr. Loraine Deck of the University of New Mexico will synthesize haloenol lactones, potential inhibitors of pancreatic cholesterol esterase, which are expected to bind covalently to the active site and cause permament inactivation of the enzyme. Bioassays will be conducted to verify the expected inhibition. The understanding of intermolecular interactions in biochemical processes is necessary before any clinical utility based upon them can rationally be developed. This work will study ways to understand, predict, and control enzyme-inhibitor interaction of a series of potential inhibitors of activity of a particular enzyme.

This award from the Chemistry Research Instrumentation and Facilities (CRIF) Program and the Office of Multidisciplinary Activities (OMA) will assist the Department of Chemistry at University of New Mexico purchase of a 500 MHz NMR. This equipment will enhance research in a number of areas including the following: (1) synthesais of biologically active compounds, (2) mechanism of enzyme catalysis, (3) molecular routes to inorganic materials, (4) organic photochemistry and mechanistic enzymology, and (5) novel main group ring and cage chemistry. Nuclear Magnetic Resonance (NMR) spectroscopy is the most powerful tool available to chemists for the elucidation of the structure of molecules. It is used to identify unknown substances, characterize specific arrangements of atoms within molecules, and to study the dynamics of interactions between molecules in solution. Access to state-of-the-art NMR spectrometry is essential to chemists who are carrying out frontier research. The results from these NMR studies are useful in the areas such as polymers, catalysis, and in biology.

This proposal seeks matching funds from the NSF to support modification of a 250 MHz Fourier transform nuclear magnetic resonance spectrometer for use in the undergraduate chemistry laboratories at UNM. At the present time there is no NMR instrument available for use by undergraduates in the department of chemistry. The addition of an NMR instrument will impact the educational experience of approximately 350 students per year at the sophomore, junior and senior levels. The four major laboratory courses targeted for immediate introduction to NMR experimentation include organic chemistry, chemistry lab III, synthesis and structure determination and instrumental analysis. The acquisition of an NMR spectrometer for these undergraduate laboratories will benefit students by improving and augmenting existing experiments in the curriculum and by allowing them hands-on experience with a modern, computer based instrument similar to research-grade instrumentation. It will also permit the addition of interesting and challenging experiments that are not implemented because their success and educational value relies heavily on the availability of an NMR.

Pancreatic cholesterol esterase (CE) has a dual function in the absorption of dietary cholesterol. First, CE catalyzes the hydrolysis of cholesterol esters to liberate cholesterol for absorption; second, CE transports cholesterol from micelles to the surface of the enterocyte where absorption takes place. There is also evidence that CE functions within the enterocyte to re-esterify cholesterol in the pathway leading to the formation of chylomicrons. It is our hypothesis that inhibition of any of these functions of CE would provide a new approach to the treatment of hypercholesterolemia through limiting the bioavailability of dietary cholesterol. This proposal will focus on the development of irreversible inhibitors of CE for prevention of the hydrolysis of cholesterol ester. CE is a serine esterase with a catalytic mechanism that is similar to that of serine proteases. We propose to develop selective irreversible inhibitors of CE. Our specific aims are: (1) to develop versatile schemes for the synthesis of haloenol lactones such as substituted 6-chloropyrones as potential irreversible inhibitors of cholesterol esterase, and (2) to use molecular modeling and kinetic studies to reduce structure-activity relationships for the development of selective inhibitors of CE. Our preliminary work demonstrates the versatility of the synthetic schemes that we have developed. Selectivity will be determined at the enzyme level by screening compounds for their rates of inactivation of CE compared with the proteases chymotrypsin, trypsin and elastase, all of which are serine proteases that function within the intestine.