Synthesis of pleiogenone A and 2,3-dihydropleiogenone A: Identification of the pleiogenone pharmacophore

Abstract

Pleiogenone A was identified in 2015 from organic extracts of the bark of Pleiogynium timoriense and shown to exhibit sub-micromolar antiproliferative activity against the A2780 ovarian tumor cell line. A central structural feature of pleiogenone A is a hydroxylated cyclohexenone. As a potential electrophilic site this group may represent the pharmacophore of pleiogenone A. To evaluate the relevance of the enone functionality to the antitumor activity of pleiogenone A, the saturated analog (2,3-dihydropleiogenone A) was prepared by chemical synthesis and compared to pleiogenone A in a cell proliferation assay. As 2,3-dihydropleiogenone A was inactive in the proliferation assay we conclude the cyclohexenone core represents the pharmacophore of pleiogenones A-C and a likely site of protein adduction.