|
(page 2 of 2)
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.
Diels–Alder
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.
1 | 2 |
|
