Design, synthesis and bioactivity evaluation of parthenolide-chalcone hybrids as potential anti-lung cancer agents

Natural products are valuable resources in drug discovery. To improve the activity of parthenolide, 49 parthenolide-chalcone hybrids were designed and synthesized. The activity evaluation suggested compound 10d exhibited the most potent anticancer activity with an IC₅₀ of 0.11 μM, 40.9-fold improvement compared with parthenolide. Besides that, compound 10d induced apoptosis, inhibited cell migration and proliferation. The mechanistic studies revealed that 10d may directly bind to Cys416 of ALOX5 (Arachidonate 5-lipoxygenase) and enhance its protein stability, then inhibited β-catenin protein levels and eventually suppressed STAT3 (Signal Transducer and Activator of Transcription 3) signal pathway. Moreover, water-soluble prodrug of 10d significantly inhibited tumor growth in lung cancer patient-derived xenograft (PDX) model without notable toxicity. These findings suggested that 10d could be considered as a promising ALOX5-targeting anticancer candidate worthy of further development.