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Dr. Romo
http://www.chem.tamu.edu/rgroup/romo/ A major focus of our group is to
develop new strategies and methods for the total synthesis of natural
products that display potent physiological effects with the ultimate goal of
coupling these natural products to their putative cellular receptors. A
representative set of current natural product targets in the Romo group are
provided in
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Figure 5 (above) showing a few strategic retrosynthetic
disconnections and reported bioactivities for these natural products. In one
approach, new methods (e.g. the nucleophile catalyzed aldol-lactonization (NCAL)
and tandem Mukaiyama aldol-lactonization (TMAL) for b-lactone synthesis) and
efficient, convergent synthetic strategies (e.g. Dubois C-H insertion
strategy) are developed that allow access to the natural product as well as
designed derivatives that will ultimately enable isolation of putative
protein receptors by affinity chromatography. The identification of protein
receptors for these natural products enable subsequent detailed cell biology
studies of the precise mechanism of action of these natural products at the
molecular level. For example,
following the total synthesis of the marine
isolate pateamine A, we prepared a biotin conjugate which enabled isolation
of it’s cellular receptor, the elongation initiationfactor
4A (eIF4A), an integral protein for the initiation phase of protein
synthesis in eukaryotic cells (mechanism depicted at right). Pateamine A and
a simplified, equipotent derivative des-methyl-des-amino pateamine A are now
serving as highly useful biological probes for further elucidation of
eukaryotic protein translation initiation. We have also initiated an
interdisciplinary effort to more rapidly correlate a natural product with
its cellular protein target(s) as a potential inhibitor or activator. We
seek to develop a systematized and streamlined approach for mining the rich
potential and tradition of natural products as: 1) cellular probes to
elucidate fundamental mechanisms in cell biology by identifying new protein
targets 2) small molecule leads for drug development.