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Modular Synthesis of Annonaceous Acetogenins and Their Activity Against H-116 Human Solid Colon Tumor Cells

Paige, Mikell Atkin
Thesis/Dissertation; Online
Paige, Mikell Atkin
Marshall, James
A 4-pronged approach enabling the syntheses of all 256 possible stereoisomers of bis- THF Annonaceous acetogenins is described. In this approach, the acetogenins are divided into 4 major segments, an aliphatic terminus, a core sub-unit, a spacer sub-unit, and a butenolide terminus. The aliphatic terminus and the spacer sub-unit are joined to the core sub-unit utilizing well-precedented α-oxygenated allylic stannane chemistry, which also serves to set key stereocenters. The final butenolide fragment is attached by Sonogashira coupling. Completion of the synthesis involves reduction of multiple bonds and deprotection of hydroxyl groups. The generality of the 4-pronged approach is illustrated by the syntheses of three acetogenins: (30S)-bullanin, (10R)-asimin, and an unnatural acetogenin, (4S)-asimicin. The efficiency of the 4-pronged approach is further exemplified in the synthesis of (30S)-hydroxybullatacin in 3 steps from a previously synthesized intermediate. The four aforementioned acetogenins were found to be highly cytotoxic toward H-116 human solid tumor cells with IC50 values in the 10-3 to 10-4 μM range. Differential cytotoxicity studies against CFU-GM human bone marrow cell lines were also performed to determine the best candidate for in vivo studies. A summary and comparison of structure-activity relationships from the literature and bioactivity data of our synthesized acetogenins is given.
University of Virginia, Department of Chemistry, PHD (Doctor of Philosophy), 2003
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PHD (Doctor of Philosophy)
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