Toyaburgine, a Synthetic N-Biphenyl-Dihydroisoquinoline Inspired by Related N,C-Coupled Naphthylisoquinoline Alkaloids, with High In Vivo Efficacy in Preclinical Pancreatic Cancer Models

Pancreatic cancer is a highly aggressive and lethal malignancy, with a 5-year survival rate below 10%. Traditional chemotherapy, including gemcitabine, has limited efficacy due to chemoresistance and a unique tumor microenvironment characterized by hypovascularity and nutrient deprivation. This study reports on the discovery of a new N-biphenyl-dihydroisoquinoline, named toyaburgine (4), inspired by naturally occurring N,C-coupled naphthylisoquinoline alkaloids. Developed through systematic structural optimization, toyaburgine is a potent anticancer agent, showing promise for pancreatic cancer treatment. It exhibits strong antiausterity activity with low nanomolar PC₅₀ values, effectively inhibiting pancreatic cancer cell viability under nutrient-deprived conditions. In vitro, 4 causes significant morphological changes and cancer cell death in MIA PaCa-2 cells while also inhibiting cell migration and colony formation, which indicates its antimetastatic potential. Mechanistically, toyaburgine disrupts the PI3K/Akt/mTOR pathway, essential for pancreatic cancer cell survival in a stressful microenvironment, and inhibits MIA PaCa-2 spheroid formation. In vivo, toyaburgine, alone or combined with gemcitabine, shows effective tumor suppression in subcutaneous xenograft and clinically relevant orthotopic models, where it also reduces cachexia. These results highlight the potential of toyaburgine as a new therapeutic drug for pancreatic cancer. Its combination with gemcitabine presents a promising treatment approach by targeting both proliferating and gemcitabine-resistant cancer cells.