Combinatorial Chemistry and Molecular Diversity Course
at the University of Louisville: A Description

Arno F. Spatola

Department of Chemistry
University of Louisville
Louisville, KY 40292



http://www.netsci.org/Science/Combichem/feature10.html

Editors note: The editors found the concept of Dr. Spatola's course to be very interesting given the current emphasis on combinatorial chemistry within the industry. Answers to questions posed by the editors follow Dr. Spatola's description of the course.

A course titled "Combinatorial Chemistry and Molecular Diversity" was offered to senior undergraduate and first year graduate students at the University of Louisville in Spring 1996. The course was devised and implemented by Arno F. Spatola, Professor of Chemistry and Biochemistry at Louisville. Although only a prerequisite of second semester organic chemistry was required, about half of the class has completed physical chemistry and/or introductory biochemistry. The format included two 75 minute lectures per week over a four month period.

Among the unique aspects of this class were seven guest speakers, all involved in some aspect of combinatorial research. The visiting scientists included Mario Geysen (Glaxo), Michal Lebl (Selectide), Jeff Jacobs (Affymax), Sheila DeWitt (Parke- Davis/Diversomers), Phil Andrews (University of Michigan), Baldomero Olivera (University of Utah), and Richard Houghten (Torrey Pines and Houghten Pharmaceuticals). The students also were exposed to Brian Kay (North Carolina) and Robert Armstrong (UCLA) via a videotape of an American Chemical Society sponsored "mini-course" in combinatorial chemistry.

Combinatorial chemistry was contrasted to early "grind and find" methods of drug discovery and also to more popular methods of designing pharmaceuticals based on knowledge of biochemical pathways. Students were challenged to discuss the strengths and weaknesses of each of these approaches and to compare the effectiveness of synthesizing and assaying individual compounds (prepared in parallel fashion using multiple peptide synthesis or diversomer approaches) to the screening of mixtures of thousands or even millions of oligomers, as best represented by Richard Houghten using a positional scan approach. A general conclusion of the course was that combinatorial chemistry should be viewed as a most useful tool, and is perhaps most powerful when combined with known methods of rational drug design where molecular modeling and/or initial leads from hormones or other natural products provide a blueprint for further structural manipulations.

The problems of analysis of complex mixtures were most carefully addressed by Phil Andrews, who is Director of the Protein and Carbohydrate Structure Facility of the University of Michigan. Among examples of mixtures studied were new types of cyclic peptide and pseudopeptide libraries that have been synthesized in Dr. Spatola's group since 1993.

Utah's Baldomero Olivera surprised the class by demonstrating that cone snails, the beautiful but deadly fish-hunters from the South Pacific Ocean, have been making their own versions of peptide combinatorial mixtures for several hundred million years. The venom of each species appears to contain a hundred or more structurally similar cysteine-rich peptides with variable amino acids interspersed among the fixed disulfide-bridged motifs. These peptides exhibit a great diversity of biological activities in mice, thereby demonstrating the potential importance of subtle changes in a basic pharmacophore.

Dr. Spatola has been involved in the synthesis of peptides and backbone-modified peptides (pseudopeptides) for nearly two decades. Interest in cyclic pseudopeptides led the Louisville group to carry out the preparation of soluble cyclic peptide libraries, using a sidechain attachment strategy and cyclization on a solid support, followed by peptide-or pseudopeptide-cleavage using various methods. Part of this research, including its application to such areas as finding new host- guest relationships with metal ions, was also described to the students. This was a perfect illustration of the close relationships that often exist between University research and the teaching activities that represent the major function of University faculty, according to Spatola.

Funding for the Combinatorial Chemistry course was provided by gifts from several companies including Boehringer Ingelheim Pharmaceuticals, Pfizer, Eli Lilly, and Parke-Davis. In addition to travel expenses, these funds helped support a part-time teaching assistant, Mr. Yvon Crozet (Universite de Montpellier), who also helped the students complete a molecular modeling tutorial using the Spartan software from Wavefunction, Inc. Other student assignments included several literature research reports, an oral report, and a final paper in an NIH research proposal format. Students were enthusiastic about the course and the unique opportunity to learn and be part of a growing revolution in chemistry as combinatorial methods become a more fundamental part of modern chemistry. Although Professor Spatola notes that it may be difficult to duplicate the funding and "blue-ribbon" speaker list for a future course offering, he is quite confident that this will certainly not be the last offering at Louisville or elsewhere.

An Interview with Professor Arno Spatola

Network Science: What prompted you to provide the course?

Professor Spatola: I began planning the course in 1994, necessary due to arranging teaching assignments in advance. We began contacting speakers and prospective contributors in early 1995. I had previously taught courses in peptide chemistry and drug design at the same senior/graduate student level. But I felt that the explosive growth in combinatorial chemistry made it a natural umbrella for introducing traditional chemical concepts in a contemporary setting.

Network Science: How did you determine the format?

Professor Spatola: The format with guests from both industry and academia was intended to provide diversity (pun intended), interest, and to insure inclusion of the latest developments in this rapidly evolving field. The heavy emphasis on oral and written reports was in response to numerous calls, especially from industrial sources, for college graduates with improved communication skills.

Network Science: Once you received sponsorship, did the companies have any specific requirements they expected to be met?

Professor Spatola: Virtually all the companies I contacted provided speakers or funding or both. A few companies requested copies of the syllabus or of the bound, lightly annotated collection of combinatorial "classics" that the students purchased as their text for the course.

Network Science: Was the pre-req at the appropriate level?

Professor Spatola: The only pre-requisite was organic chemistry and this was appropriate since I introduced the basics of solid phase synthesis, protecting groups, stereochemistry, and other topics required to appreciate the guest speakers. I also tried to prepare the students for each of the visitors by assigning journal articles and by my pre-lectures on the relevant topics.

Network Science: How much of your time was spent scheduling the speakers and how far ahead did you start in order to make the course available in spring 1996?

Professor Spatola: A fair amount of time was spent both by me and by my administrative assistant, Julia Payne, in arranging for travel, lodging, airport pick-ups, lunch and dinner, and other on-site scheduling activities. We also videotaped all but one of the guest lectures. But I did gain about five pounds over the semester so it wasn't totally curricular!

Network Science: Combinatorial chemistry is obviously an area of significant current interest. Do you feel students signed up for the course because combichem is a "hot" area for employment opportunities now?

Professor Spatola: Some of the students took the course as a pre-requisite for their majors such as chemical engineering. Others, such as some of my graduate students, are doing research in combinatorial chemistry and they clearly recognize that experience in this field will be helpful as they enter the job market.

Network Science: Protein chemists are familiar with the concept of solid phase synthesis. How difficult was it to get traditional synthetic organic chemists used to thinking in these terms?

Professor Spatola: I don't think organic chemists have any problems with the concept of solid phase synthesis. But you have to remember that peptide chemists have been optimizing their reactions for 30 years A.M. (After Merrifield). The big "catch" with solid phase chemistry is the requirement for "100%" yields at every step. The experiences achieved by solid phase peptide chemists over the past 30 years are not necessarily assimilated or appreciated immediately.

Network Science: How large is the library of reactions available for solid phase organic synthesis? How fast is it growing?

Professor Spatola: The library of reactions is growing dramatically. But for the reasons noted above, organic solid phase reactions seldom exceed three steps, unless they are oligomeric.

Network Science: Did you and the students draw conclusions about future developments in combinatorial chemistry?

Professor Spatola: The major take-home message was that combinatorial chemistry is another research tool, albeit a potentially very powerful one. And it will not, in my opinion, replace "rational" drug design. I made every effort to compare and contrast these two approaches in this course. But the students discovered, through their own readings, additional examples of more efficient problem solving paradigms using combinatorial chemistry.

Network Science: Would you consider (or be interested in) using additional software in future offerings? If so, what areas do you feel could be covered through the use of software?

Professor Spatola: If time permitted (7 guest lectures out of 28 classes - 75 minutes each - a large component) I would have liked to invite a representative from a software company specializing in data bases for combinatorial chemistry. The amount of structures, characterization, and bioassay data that is typically generated is enormous. Future classes should be exposed to possible solutions. Some of the student presentations (7 more days at 3 per day) did touch on these problems but tended to lack a real world perspective.

Network Science: How did you arrive at the idea of having the students write the final paper in NIH format? How long did it take them to complete the paper and how did you feel about the quality of their work?

Professor Spatola: The NIH format encourages you to frame the problem concisely (specific aims), place it in perspective (background) and to be specific about your solutions (methods). I also asked the students to propose the synthesis of a heretofore unreported organic library and to draw or provide a color printout of any one member of the library in an energy minimized form. For various, mostly silly, technical reasons, the last component could not be completed.

Network Science In retrospect, is there anything you would change, add or delete?

Professor Spatola: In any future course offering I would love to have a text. I'm not sure who would write one since it would almost immediately be dated. The reference compilation was useful but I did learn that some journals require as much as $6 per article per student in copyright fees! Ironically, the highest cost, Nature, was reduced to no fee after a number of phone calls and faxes. As a result, students were able to purchase a bound set of 14 articles (80 pages) for about $12 including about $4 in fees.

A biochemistry pre-requisite would be useful to reduce the amino acid, carbohydrate, and protein structure review lectures. I would also try to spend more time on new solid phase organic synthesis since this provides a fun way to review or learn many classic organic "name" reactions, especially those involving carbon-carbon bond formation.



Editors note: During 2003, Professor Spatola died after suffering a heart attack while running. His contributions to organic chemistry and his willingness to help his students develop a passion for science are missed by the entire community.



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