Synthesis and structure–activity relationships study of cytotoxic bufalin 3-nitrogen-containing-ester derivatives

A series of bufalin 3-nitrogen-containing-ester derivatives (2–6) were designed, synthesized, and evaluated for their proliferation inhibition activities against human cervical epithelial adenocarcinoma (HeLa) and non-small-cell lung cancer (A549) cell lines. The structure–activity relationships (SARs) of this new series were described in this paper. Cytotoxicity data revealed that C3 moiety had important influence on cytotoxic activity. On two cell lines, the bufalin-3-piperidinyl-4-carboxylate compound 2 (IC50 values on HeLa and A549 cell lines were 0.76 nM and 0.34 nM, respectively) displayed a significant cytotoxic potency compared to the parent compound bufalin.

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► Two-step and highly efficient method to synthesize bufalin-3-ester derivatives.
► Bufalin 3-nitrogen-containing-ester derivatives show significant cytotoxicity.
► The cytotoxicity is correlated with the C3 moiety of bufalin.