Synthesis and pharmacological evaluation of polyamine-diarylidenyl piperidone derivatives as potent antitumor agents

Two polyamine-diarylidenyl piperidone (DAP) derivatives, dimer polyamine-H-4073 and tetrameric polyamine-H-4073, were designed and synthesized as antitumor agents by coupling the bifluoro-substituted DAP STAT3 inhibitor H-4073 to two different polyamines through the binary fatty acid chains, respectively. MTT assay and a SW480 xenograft model identified dimer polyamine-H-4073 as good candidate antitumor agent with good efficacy, limited toxicity, and low resistance, in comparison with H-4073, cisplatin, and doxorubicin. Western blot analysis results indicated that dimer polyamine-H-4073 exhibited effectively inhibition on signal transducer and activator of transcription 3 (STAT3), indicating that it may be a STAT3 inhibitor.