ILIMAQUINONE AND NORRISOLIDE
Researchers - Rebecca Casaubon,
basis of my graduate research has been the use of organic
synthesis to study biological interactions. Ilimaquinone
(1) is a marine sponge metabolite with a
wide range of biological activities including antiviral, antiinflammatory,
antimicrobial, and antimitotic effects. In 1993,
Malhotra et al. showed that 1 impedes cellular
protein trafficking events by reversibly breaking up the Golgi
apparatus into vesicles. This
activity gives us an opportunity to use ilimaquinone and analogs
as probes of intracellular vesicle-mediated protein trafficking,
which could lead to the development of specific inhibitors
of these processes and may even have implications in antiviral
and anticancer treatments. Affinity
chromatography, photoaffinity, and fluorescence microscopy
studies using active ilimaquinone analogs (e.g. 2-4)
have implicated enzymes of the cellular activated methyl cycle,
particularly S-adenosylhomocysteine hydrolase, as targets
In conjunction with the ilimaquinone study,
and to gather more information about the mechanisms behind
these biological activities, we have begun studies toward
the total synthesis of norrisolide (5). Norrisolide
was isolated in 1983 by Faulkner, Clardy and coworkers in
a study of the chemical defense system of nudibranch molluscs
and has also been reported to vesiculate the Golgi apparatus.
However, unlike the case of ilimaquinone, vesiculation
by 5 is irreversible. A convergent
synthetic route will allow for synthesis of analogs that can
be used to determine the biological interactions of the natural
product. It will be particularly interesting to determine
if 1 and 5 share the same
or related biological targets.
of (-)-Ilimaquinone with Methylation Enzymes: Implications
for Vesicular-Mediated Secretion.” Radeke, H.
S.; Digits, C. A.; Casaubon, R. L.; Snapper, M. L. Chem.
Biol., 1999, 6, 639.
(b) “ S-Adenosylmethionine Reverses Ilimaquinone’s
Vesiculation of the Golgi Apparatus: A Fluorescence Study
on the Cellular Interactions of Ilimaquinone.” Casaubon,
R. L.; Snapper, M. L. Bioorg. Med. Chem. Lett.,
2001, 11, 133.