- School of Pharmacy
- University of Wisconsin
- 777 Highland Ave.
- Madison, WI 53705-2222
- Curriculum Vitae
Jeanette C Roberts, Ph.D., MPH
No longer accepting graduate students or postdoctoral fellows.
1126B Rennebohm Hall
- B.S. 1979 - Albright College
- Ph.D. 1986 Medicinal Chemistry - University of Minnesota
- M.P.H. 2001 - University of Utah
Medicinal/Pharmaceutical Chemistry. Biological aspects of drug/isotope/toxin
targeting using prodrugs; monoclonal antibodies and/or liposomes; thiols and
selenols as chemoprotective and chemopreventive agents.
- A major emphasis in my laboratory is the design, synthesis, and preliminary
evaluation of prodrugs of L-cysteine. We construct the prodrugs by the chemical
condensation of the amino acid with a variety of carbonyl donors to produce
thiazolidine rings with various structural features. 2-Oxothiazolidine derivatives
require enzymatic biotransformation to release the cysteine, while 2-alkyl
analogs spontaneously undergo ring opening and hydrolysis to liberate the
desired agent. Once freed from the prodrug, the L-cysteine is available for
direct effects, such as free radical scavenging via the thiol functionality,
or indirect effects, such as providing the required precursor for glutathione
biosynthesis. Prodrug forms are necessary because the free amino acid itself
possesses unwanted side effects at protective doses.
- The overarching goal is to protect the body against a variety of toxic agents
or situations. We've used the hepatotoxin acetaminophen for several
years as a model toxin that requires glutathione for detoxication. In a related
area, a new HPLC method was recently completed that allows us to quantitate
several thiols of biological interest simultaneously.
- There is growing evidence that effects on the transcription of important
genes is an underlying mechanism of action of redox active agents such as
cysteine. The upregulation of Phase II drug metabolizing genes (many of which
use glutathione as a cofactor) looks like a very promising way to go. We're
also particularly interested in exploring effects at the transcriptional level
of the enzyme gamma-glutamylcysteine synthetase, the rate-limiting step in
glutathione biosynthesis. Our hypothesis is that there must be a coordinate
upregulation of glutathione-producing and glutathione-utilizing systems for
protection to be optimized.
- Because glutathione is important in so many diseases and toxicities, this
approach should be useful against all sorts of things, including solvent exposures,
radiation, the side effects associated with many anticancer therapies, environmental
pollutants, AIDS, cancer, cataracts, etc.
- In related work, we are attempting to explore structural modifications to
the cysteine prodrugs to optimize their ability to enter the cell and provide
the amino acid. As a first step, thiazolidine prodrugs are being synthesized
in which the free carboxylate group is being replaced by ester or amide functionalities.
In this way, the lipophilicity of the compound is increased, hopefully leading
to increased residence time in the body, increased cell penetration, and increased
- Our newest project grew out of the thiazolidine prodrug of cysteine work.
In this case, however, we are starting with selenocysteine and hence producing
Selenazolidine ring forms. Selenium is enjoying growing prominence as a cancer
chemopreventive agent and is also of great interest in the AIDS arena. Unfortunately,
it gets toxic at levels not terribly far above those required for nutritional
uses, and rather high amounts appear to be required, at least for cancer prevention.
Therefore, supplementing the body with selenium is a rather tricky business.
- Our hypothesis is that selenocysteine represents the biochemically superior
form in which to supply selenium, primarily due to how various selenium-containing
compounds are metabolized by the body. [See Figure 1 Below] Unfortunately,
selenocysteine is difficult to handle chemically, which has probably deterred
its extensive study and use. Applying our prodrug approach [See Figure 2 Below],
however, should produce a chemically superior form, greatly facilitating the
use of selenium as a cancer chemopreventive or AIDS therapeutic agent. Synthesis
of a handful of prototype Selenazolidines is in progress.