Two Students, Two Prizes, Two Promising Futures

By Jason Socrates Bardi


"If I have seen further... it is by standing upon the shoulders of Giants."

—Sir Isaac Newton, Letter to Robert Hooke, 1675


Last summer, Scott Wolkenberg and Anthony Jon Roecker, two students in The Scripps Research Institute (TSRI) Department of Chemistry, applied for fellowships in organic chemistry sponsored by the American Chemical Society (ACS). After a nationwide competition, the ACS chose them both to receive these prestigious fellowships.

From Upstate New York to Southern California

Scott Wolkenberg came to Professor Dale Boger's group in the summer of 1998, driving west from Ithaca, New York, soon after he completed undergraduate work at Cornell University. In the years since he joined the laboratory, he has become an important part of the group, even helping with day-to-day duties as a de facto manager.

"Each person has responsibilities that they take on for the group as a whole, and Scott assigns them to people," says Boger.

But Wolkenberg's primary work is in the science he is doing at TSRI. One of his research projects is the total synthesis of the molecule cytostatin, a linear molecule with a polyene portion and several asymmetric centers with an alcohol unit and a ring on one side.

Some targets for total synthesis are interesting because of the inherent beauty and complexity of their chemical structure, and some are interesting because of what they do. "We are really interested in [the molecule] because of its biological activity," says Wolkenberg.

This target has anti-cancer properties through an unknown mechanism. Most likely, Boger and Wolkenberg believe, cytostatin inhibits an enzyme that is linked to cancer, a protein phosphatase called 2B, which removes the phosphate groups from other proteins involved in cell cycle signaling and adhesion. If the phosphatase removes the phosphates from adhesion molecules, then cells can pick up and move, and this is exactly what you don't want if the cells are cancerous—like criminals who suddenly find the prison doors flung wide open.

That cytostatin discourages this sort of behavior is exactly what makes the molecule such an alluring target. If you can use cytostatin to disrupt the cell adhesion process, perhaps you can prevent metastasis. The target is particularly promising because it is rare for protein phosphatase inhibitors to be specific, which is one of the properties of cytostatin.

Wolkenberg is also asking basic questions about the underlying biology, such as "what is responsible for protein phosphatase inhibition?" and "how does the inhibitor interact with the enzyme?" He is also looking for structural analogues to the natural product in the hopes of improving its activity against the enzyme, its potency as an anti-tumor agent, and its stability.

Stability is of particular concern. The inhibitor is part of a class of molecules that includes another structure completed by Boger's group a few years ago—pursued as an anti-tumor agent by the National Cancer Institute until recently when trials were halted due to doubts about the stability of the sample.

From the Midwest to the West Coast

Anthony Jon Roecker, or "A.J." as he is affectionately known, is in his third year in the laboratory of Department of Chemistry chair K.C. Nicolaou, whom he joined after completing his undergraduate work at Ohio State University. He got the idea to apply for the fellowship from Nicolaou himself, who brought him the application.

"A.J. impressed me from the very beginning. It was only a matter of time, I thought, before his successes will bring him recognition," says Nicolaou. "So when I was invited to nominate a student for an ACS fellowship, his name came to mind."

At the moment, Roecker is working on studies leading towards the total synthesis of azadirachtin, a potent insect pesticide that comes from the plant Azadirichta indica, commonly known as the neem tree. This natural product is a popular insecticide because it only attacks molting insects and does not affect mammals, making it a tantalizing target for chemists.

Taking the substance from the source trees is problematic because of the difficulty and expense of separating this chemical from the rest of the components of the tree's seed kernel. Yet, despite years of attempts, chemists have never been able to synthesize the chemical because it has a central bond between two quaternary carbons, one of the hardest bonds to form in organic synthesis.

"Its demonic molecular architecture has been challenging synthetic chemists for decades," says Nicolaou. "A.J.'s contributions address the thorniest problem posed by this structure: he found a way to construct the crowed bond connecting the two domains of the molecule."

This approach differs from the fruitless path that has been followed by many other synthetic chemists who have tried to synthesize the molecule in the last 20 years. Most of them attempted to make two highly advanced portions of the molecule and then bring them together at a later stage in the synthesis to form the quaternary center.

"[The difficulty] inspires you to become creative and go to the literature and find ways that haven't been explored," says Roecker.

Roecker, Nicolaou, and other laboratory members working on the project are trying to generate the bond in advance and utilize the resulting compound as a precursor upon which the outside of the molecule can be built.

"We're trying some novel chemistry to try to generate systems that contain this quaternary center," says Roecker. "We've had some success that hopefully [the work] will be coming out soon."

The New Diels

Another project that Wolkenberg is involved with is working out the details for a type of synthetic methodology, a technique that, once established, can become a tool for synthetic chemists everywhere.

The particular methodology Wolkenberg is working on arises out of the long-standing interest of the group, the heterocyclic Diels–Alder reaction.

An ordinary Diels–Alder reaction takes a compound containing a diene—conjugated four carbon chains with two doubly bonded carbons connected by a single bond—and combines it with a molecule containing a two-carbon doubly bound "–ene." Under suitable conditions, the six pi-orbital electrons in the two molecules react in such a way that the two molecules join and form a new, cyclic compound.

This type of reaction, which is called a cycloaddition, is a powerful tool for organic synthesis, since ring structures are a common feature in many target molecules and dienes are required motifs within precursor molecules. The Diels–Alder reaction can simplify certain synthetic problems and help shortcut synthetic pathways, allowing sometimes complicated ring structures to be built in a single step.

For many years, though, the reaction was limited to carbon, but the reaction becomes an even more powerful tool of organic synthesis when it is expanded to include other, "hetero" atoms like nitrogen and oxygen.

The heterocyclic Diels–Alder reaction, a powerful synthetic methodology Boger has studied in detail for many years, does just that, using as a precursor a compound containing a ring of heteroatoms. The heteroatoms are important because the non-carbons act as local electrophiles and draw electron density from the ring, leaving it less electron-rich than the corresponding all-carbon ring.

The cyclic system with which Wolkenberg works is a 5-membered ring with two carbons, two nitrogens, and an oxygen. The work, like many chemistry projects, is highly collaborative, and Wolkenberg is working with graduate students Gordon Wilkie and Danielle Soenen and research associates Greg Elliott, Brian Blagg, Michael Miller.

"We're first defining its scope, and then we have in mind a couple applications for that methodology in natural products' total synthesis," says Boger.

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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Fourth year TSRI chemistry graduate student Scott Wolkenberg conducts research in the Laboratory of Professor Dale Boger. Photo by Jason S. Bardi.





















Third year TSRI chemistry graduate student A.J. Roecker conducts research in the laboratory of Professor K.C. Nicolaou
. Photo by Jason S. Bardi.