| A Novel and High Yield Synthesis of the Antimitotic Compound 2-methoxy-5-(2',3',4'-trimethoxyphenyl) tropone(AC) |
| Robert Spitale and Mark Janik |
Microtubules are filamentous intracellular
structures that are responsible for various kinds of structural functions in all
eukaryotic cells. Microtubules are involved in cell division, organization of
intracellular structure, intracellular transport, and provide the framework for
structures such as the mitotic spindle apparatus that appears during cell
division. The microtubule is comprised of tubulin, a heterodimeric protein, made
up of two similar tubulin monomers (a-tubulin and ß-tubulin). The alkoloid drug,
colchicine from the plant Colchicum autumnal is an anti-mitotic agent with the
ability to halt cell division. Colchicine exerts its antimitotic ability by
binding to tubulin, which in turn prevents microtubule formation. The structure
of colchicine is comprised of a trimethoxybenzene ring (A-ring), a seven
membered acetamido ring (B-ring), and an a-methoxytropone ring (C-ring). The B
ring of colchicine locks the A and C rings into a single low energy conformation.
This conformational restriction imposed by the B-ring has proven important in
the drug-tubulin interaction.
The purpose of this research was to synthesize a derivative of colchicine,
2-Methoxy-5-(2,3,4,-trimethoxyphenyl)tropone (AC), that would allow for further
evaluation of the B-ring’s role in drug-tubulin binding. In AC, the B-ring is
deleted and replaced with a carbon-carbon bond that links the A and C rings.
With the B-ring deleted, the A and C rings have free rotation, and should allow
for further elucidation of the role of the B-ring in ligand-protein binding.
The synthesis of AC involved the construction of the A and C ring moieties, and
then the coupling of the rings utilizing a modified Suzuki palladium coupling. |
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