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Phorbol esters and their derivatives, such as TPA, have been reported as potential natural antitumor products, with some derivatives entering clinical research for leukemia treatment. In this study, 16 phorbol derivatives were synthesized from phorbol, and their anti-leukemia activity against Jurkat, HL-60, and K562 were tested. The results showed that several derivatives had anti-leukemia activity, with 5B demonstrating the strongest cytotoxic activity against the K562 cell line (IC50 = 0.24 ± 0.04 μM). Based on the IC50 values, a structure-activity relationship was established. When the substituent contained an aromatic group, phorbol derivatives esterified with long-chain organic acids at three reactive hydroxyl groups (C12-OH, C13-OH, and C20-OH) had better activity. When aryl groups were absent from the substituent groups, phorbol derivatives esterified with short-chain organic acids at two hydroxyl groups had better activity. Derivatives esterified with heterocyclic acids, either tri-substituted or di-substituted, showed a significant decrease in cytotoxicity. The mechanism of anti-leukemia activity was explored through flow cytometry, which indicated that phorbol esters inhibited the growth of leukemia cells by inducing apoptosis, leading to cell death. Molecular docking data of compound 5B docking to PKC δ C1B suggested that substituent groups should not be too large, and caution should be taken when substituting C20-OH. Overall, these findings provide valuable insights into the design of more effective phorbol esters as anti-leukemia agents, but further research is needed to confirm their safety and efficacy in clinical settings. [ABSTRACT FROM AUTHOR]