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  • Book
    Nathan Benjamin Cardin.
    In this work, a function-oriented array of simplified analogs of the daphnane diterpene orthoester class of natural products bearing palmitate, phenyl, or phenylacetyl orthoesters was synthesized starting from commerically available starting materials via a key late stage common diversification intermediate. These families of novel compounds were evaluated for both selective PKC activation and growth inhibition of K562 (myleogenous leukemia) cancer cells. While these analogs showed no growth inhibitory activity in K562 cells up to concentrations of 10 micromolar, they did display varying profiles of PKC activation. One analog in particular demonstrated the ability to activate and cause translocation of conventional PKC b1 and novel PKC d to the same extent as resiniferonol, a potent natural resiniferonoid. A second analog, however, was found to activate novel PKC d selectively over conventional PKC b1; surprisingly, resiniferonol did not share this selectivity profile. Because the simplified, functional analogs synthesized in this study were shown to activate PKC while having no growth inhibitory activity, these compounds should be further investigated for their potential as therapeutic leads for the treatment of diseases like Alzheimer's or Parkinson's, in which (selective) activation of PKC could serve a therapeutic purpose without being plagued by growth inhibitory pathways.