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.

Figure optionsDownload as PowerPoint slide