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Duocarmycins—A Classic Example

Many of the compounds that Boger and his group study and synthesize have some tumor supressor activity or are derived from anti-tumor agents.

One family of compounds that stands out in particular are the powerful cytotoxic molecules known as the duocarmycins. Naturally derived duocarmycin SA, which is produced by bacteria of the Streptomyces family, alkylates DNA and prevents replication, leading to apoptosis of the cells.

In 1982, when Boger began to synthesize a closely-related natural product, CC-1065, not much was known about the molecule, other than it had anti-tumor activity and possibly interacted with DNA. He completed its total synthesis in 1987, and has spent many years since studying the selective mechanism of the agent, looking at how it alkylates DNA through structural studies.

These structural studies have involved modifying certain atoms or moieties on the agent and its structural analogues and testing the modified molecules against the same DNA substrates that bind the original compound. In this way, the molecules can be "diced up" and their different pieces examined.

Any chemical changes to a molecule will change its structure, altering electron distributions and bond lengths. After many years of this, says Boger, you can predict to an extent how structural changes will affect the reactivity, though there are always unexpected results.

Subtle changes—even a single atom—may not look like much on paper, but can induce a million-fold difference in activity.

Florescence quenching or similar chemical assays can quantitate how much of an effect these changes will have on the molecule’s reactivity—how much and how quickly they bind to DNA, for example. Cell culture assays can be used to probe how the chemical changes affect the molecules’ biological activities—their cytotoxic efficiency, for example. And high-resolution nuclear magnetic resonance and x-ray crystal structures of the agents bound to their substrates allow unambiguous correlations between chemical, structural, and biological changes.

Structural changes can be introduced into the compound in order to probe how the compound itself exerts its biological effect. This insight, in turn, can help Boger’s group design simpler structures that have the same properties or to increase the potency or sensitivity of the natural structure.


A synthesis will yield more than just a final product. It will yield precursors, analogues, substructures, and useful chemistry along the way. Antibiotic analogues, like those of the vancomycin aglycon molecule, for instance, may be useful for treating infections with bacteria that are resistant to standard vancomycin. Other novel chemicals generated by a synthesis can be used for combinatorial chemistry screening to find compounds with biological activities against particular targets.

Also, new chemistry may be a by-product of Boger’s efforts. New synthetic methodologies and strategies can often be extended and generalized beyond any particular synthesis.

One of Boger’s well-known success stories has been his use of the hetero Diels–Alder reaction, powerful synthetic methodology which he has studied in detail for many years.

The reaction takes a compound containing a diene—conjugated four carbon chains with two doubly bonded carbons connected by a single bond—and combines them 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 the all-carbon Diels–Alder reaction.

"Until we systematically explored it, the hetero Diels–Alder reaction, which contains hetero atoms in the diene, had not been applied in organic synthesis to any large extent," says Boger.

Boger has extended the scope of the reaction by using certain heterocyclic structures that naturally contain dienes, such as heteroaromatic azadienes and acyclic azadienes.

And like any good chemist, Boger spends time and energy perfecting his reactions and publishing the methodologies so that others can use it as a tool in cases where it applies.

"We do get a lot of enjoyment out of that," he says.

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The Boger laboratory has made extensive use of the Diels–Alder reaction, which is shown in its simplest form above: the gas phase cycloaddition of Ethene and 1,3-butadiene to produce cyclohexene, for which Otto Diels and Kurt Alder shared the 1950 Nobel Prize in Chemistry.