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Published on: May 15, 2019
Semisynthesis of bersavine and berbamine derivatives that target the CaMKIIγ:cMyc axis for lymphoma therapy
Berkley Lujan1, Mingfeng Zhang2, Yujie Cao1
1Department of Chemistry, University of California, Riverside, California 92507, USA. kevin.kou@ucr.edu.
Abstract:
Berbamine, a bisbenzylisoquinoline alkaloid (bisBIA), is a promising lead for developing novel therapeutics to treat aggressive cancers such as lymphoma, by targeting the CaMKIIγ:cMyc axis. Herein, we report an aza-Friedel-Crafts method for ortho-aminoalkylation of berbamine's phenolic motif, enabling the semisynthesis of the natural product bersavine and analogs that complement current methods focusing on modifying the phenolic oxygen. Several new analogs synthesized by this method exhibit potent cytotoxicity against lymphoma-associated cell line H9 exceeding the naturally occurring berbamine (1) and bersavine (3a). A molecular docking analysis was used to devise a model that rationalizes the structure-activity relationship between the novel bisBIA analogs and CaMKIIγ inhibition.
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