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Phenanthropiperidine Alkaloids: Methodology Development, Synthesis and Biological Evaluation
Niphakis, Micah James
Niphakis, Micah James
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Abstract
This work is directed towards the development of safe phenanthropiperidines for the treatment of cancer. It focuses on synthetic methodologies that facilitate their preparation and biological studies to better understand the neurological side-effects of the only alkaloid within this class to enter clinical trials: tylocrebrine. The preparation of cyclic enaminones in high enantiomeric purity is made possible through a one-flask, two-step protocol that uses mild Boc-deprotection conditions to suppress racemization. Elaboration of the enaminone scaffold was made possible with a direct palladium(II)-catalyzed arylation using aryltrifluoroborates as coupling partners. These methods give access to enantiomerically pure 3-arylpiperidines which were used as precursors of phenanthropiperidine alkaloids. A small phenanthropiperidine library was prepared and studied to elucidate the cause of tylocrebrine's neurological side-effects. Although the causes remain elusive, tylocrebrine and several of its analogs were found to bind to key biogenic amine receptors, disclosing another potential risk factor for their therapeutic use.
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Date
2010-04-08
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Publisher
University of Kansas
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Keywords
Organic chemistry, Pharmaceutical chemistry, Enaminone, Palladium, Phenanthropiperidine, Tylocrebrine, Tylophora indica, Tylophorine