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Natural Product Libraries

Roecker has also participated in several combinatorial chemistry projects, developing solid phase chemistry and producing natural product libraries for biological screening purposes.

"This is the kind of science that serves as the foundation to the drug discovery process," says Nicolaou.

The advantage of using libraries of natural products to screen for drug candidates is that these natural products inhabit that part of the chemical universe that may be the most practical place to look for drugs. Nature has designed these chemicals with many of the correct properties already—they are generally small, soluble, and have already been designed by nature to do certain things, like stop bacteria from growing.

Roecker worked on a natural product-like library using a motif common in a lot of drugs called a 2,2-dimethylbenzopyran. His work included designing chemistry to put the benzylpyran onto a solid phase in order to make a library of the 10,000 compounds. And recently, he has been looking for biological applications for the library.

"He and his teammates invented numerous enabling technologies for combinatorial chemistry," says Nicolaou. "Screening of the libraries led to the discovery of a number of antibacterial agents, enzyme inhibitors, and receptor agonists and antagonists."

"It's fun to work with a lot of good chemists," says Roecker. "My peers, the other graduate students and postdocs in the laboratory, have a lot of different experiences. I try to keep my eyes and my ears open and gain as much knowledge as I can from reading the literature and listening to other people."

Combinatorial Chemistry for the Masses

Wolkenberg has some experience with combinatorial chemistry of a different sort.

With Andrew Su, another student in the chemistry program, Wolkenberg became involved in the summer outreach program at TSRI, which brings local high school science teachers, mainly of biology, to TSRI where they get hands-on laboratory experience.

"We were thinking, 'what could we possibly bring that is going to be useful for them?'" says Wolkenberg, who taught these teachers for the past two years. "We ended up thinking about drug discovery."

Wolkenberg and Su came up with an exercise for high school classrooms that involves discovering a drug using the techniques of combinatorial chemistry. The students make a mixture of compounds and then screen for biological activity against bacteria. Then, from those that work, the students deconvolute the mixtures to determine which compound has the active ingredient. And thus students discover a drug; simple, fun, and brilliant.

"It ended up being a huge success," says Wolkenberg, who published, with Su, an article on the laboratory and the experience in the Journal of Chemical Education. "It was a great experience."

One Award to Rule Them All...

The fellowships offer one year of support plus money for expenses, including a trip to next year's National Organic Symposium (sponsored by the ACS Division of Organic Chemistry), at which the fellows will present a poster on their work.

"It's a great fellowship program," says Boger. "One that, through the years, quite a few people at Scripps have been successful at competing for."

For their applications, both fellows had to write a mini-review of a subject not necessarily related to their own research.

Roecker chose to write about organic catalysis, following this field from its roots in the laboratories of the 1970s to its practice in the labs of today—including several in his department in rooms right down the hall. "It's very interesting to use chiral organic molecules to induce selectivity in reactions," he says.

Wolkenberg wrote about the in situ activation of anti-cancer alkylating agents. This involves compounds that are inert but are modified into some active form, becoming reactive, when they reach their target.

After Wolkenberg was done with the mini-review, he kept going, turning it into a full-fledged review he submitted with Boger to Chemical Reviews last month.


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