Synthesis and biological evaluation of glaucocalyxin A derivatives as potential anticancer agents

•Sixteen Glaucocalyxin (GLA) derivatives were prepared through Michael addition reaction between GLA and amines.•MTT assay revealed that the resulting GLA derivatives retained antiproliferative effects against six cancer cell lines.•These GLA derivatives were shown to exhibit reduced cytotoxicity against normal cell.•The plasma incubation analysis confirmed the prodrug property of these GLA derivatives.•These prodrugs exhibited markedly enhanced plasma stability.

A series of Mannich base type derivatives of Glaucocalyxin A (GLA) were designed and prepared. The cytotoxicity of these compounds was evaluated against six tumor cell lines (SMMC-7721, B16, SGC-7901, A549, KB, HL-60). Most compounds exhibited potent antiproliferative effects with low micromolar IC50 values. Compound 1 with para methyl benzyl amine moiety and compound 16 with cyclohexylamine moiety displayed the highest inhibition efficacy. Significantly, the cytotoxicity of compound 1 was much lower than GLA against the normal human liver cell (HL-7702). The in vitro stability assay revealed that transformation of GLA to Mannich base type derivatives improved the compound stability in rat plasma. Finally, decomposition product analysis supported that compound 1 could act as a prodrug and release GLA in the intracellular environment.

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