Our research efforts combine synthetic organic
chemistry with computational, biochemical, and
molecular biological tools in an interdisciplinary
approach to designing drugs that specifically target
diseased cells or infectious agents. The
long-term goal of our research is the development of
selective strategies for the treatment of cancer and
infectious diseases. Topics of current interest
include:
Enediyne Analogs:
The enediyne-class of antitumor antibiotics exert
their potent cytotoxic effects through a Bergman
cyclization of an enediyne core to produce a
1,4-didehydrobenzene intermediate, which abstracts
hydrogen atoms from the DNA ribose backbone,
resulting in DNA strand scission. Previous attempts
to harness the DNA cleavage chemistry of these
agents for antitumor drug development have generally
been unsuccessful due to the non-selective
cytotoxicity of these compounds.
We have
undertaken a novel approach to harness the extreme
cytotoxicity of these compounds in order to render
them selectively cytotoxic to cancer cells. Our
approach involves alternate diradical generating
systems based on aza-substituted enediynes. We have
found that the simple substitution of nitrogen for
carbon in the enediyne core has a profound impact on
both the rate of the cycliztion and the reactivity
of the resulting diradicals. We are exploring
modifications of the aza-enediyne core structure in
order to develop molecules that undergo
cycloaromatization, producing diradicals that are
selectively reactive only under the particular
conditions (pH and metal ion concentrations) that
exist in tumor cells.
Metal-Mediated
DNA Binding Agents:
The topoisomerase gyrase
is a bacterial enzyme that is the target of the
fluoroquinolone class of antibacterial drugs. The
quinobenzoxazines, a class of molecules structurally
related to the fluoroquinolones, have been
investigated for their potential as antitumor
agents. We have studied the mechanism of action of
the fluoroquinolones and quinobenzoxazines and find
that both drugs undergo self-association to form 2:2
drug-metal ion dimers in the presence of Mg2+.
The self-association of these drugs occurs both in
solution and when these drugs bind to duplex
DNA. The implication of this self-association
on the metal-mediated DNA binding by these drugs is
being investigated in collaboration with Professor
Jennifer Brodbelt in the Department of
Chemistry.
UK-1 is a novel, bis(benzoxazole)
metabolite of Streptomyces sp. 517-02, which has
been reported to be cytotoxic to a variety of cancer
cell lines, although it displays no antibacterial
effects. We have reported the first total synthesis
of UK-1 and have investigated the metal ion
coordination by UK-1. These studies indicate that
UK-1 may exert its cytotoxic potential by targeting
DNA-processing enzymes in a manner similar to the
Mg2+-dependent DNA-binding antitumor
quinobenzoxazines. These findings are being
exploited in the design of new antibacterial and
antitumor agents with increased selectivity and
potency..
Targeting Telomeres and
G-Quadruplex DNA:
The interaction of small
molecules with nucleic acids continues to be an area
of great interest. Our efforts in this area focus on
targeting the unique structure of specific nucleic
acid sequences as a means for inhibiting nucleic
acid-processing enzymes. We have designed a series
of shape-selective DNA minor groove ligands. We have
also targeted the unique DNA sequences associated
with telomeres and telomerase. Telomerase is a
cancer cell-specific enzyme that catalyzes the
addition of repetitive DNA sequences to the ends of
chromosomes, known as telomeres. Telomeres and other
guanine-rich DNA sequences can form four-stranded
DNA structures known as G-quadruplex DNA.
Using computational techniques, we have
discovered a number of distinct classes of
G-quadruplex interactive agents that inhibit
telomerase, presumably by trapping the G-quadruplex
structure on the enzyme-primer complex. Future work
in this area will explore the utility of these
compounds in cancer treatment and as biophysical
probes for G-quadruplex formation.
Ribosome Inactivating Proteins:
In
collaboration with Professor Jon Robertus in
Biochemistry, we are designing inhibitors of
ribosome inactivating proteins such as ricin and
shiga toxin. These inhibitors may find use as
antidotes to these extremely toxic agents.
