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Opioid Tripeptides Hybridized with trans‐1‐Cinnamylpiperazine as Proliferation Inhibitors of Pancreatic Cancer Cells in Two‐ and Three‐Dimensional in vitro Models

According to the World Health Organization, the mortality rate among patients with pancreatic cancer will increase in the upcoming years. Gemcitabine is the first choice for treatment of pancreatic malignancy, but increasing resistance to this drug is decreasing its overall efficacy. Studies on new therapies that target metabolic pathways, growth factor inhibitors, and tumor stroma or tumor stem cells are currently underway in many research groups. Herein we report the bioactive properties (cytotoxicity and hemolytic activity) of synthetic peptidomimetics containing an opioid tripeptide fragment (Tyr‐R1‐R2‐; where R1 is d‐Ala or d‐Thr, and R2 is Phe or Trp) hybridized with trans‐1‐cinnamylpiperazine. These compounds are stable in plasma up to 96 h and exhibit low hemotoxicity and good inhibitory effects on cancer cell growth in two‐ and three‐dimensional in vitro models of pancreatic cancer.