Toyaburgine, a Synthetic <i>N</i>-Biphenyl-Dihydroisoquinoline Inspired by Related <i>N</i>,<i>C</i>-Coupled Naphthylisoquinoline Alkaloids, with High <i>In Vivo</i> 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 <i>N</i>-biphenyl-dihydroisoquinoline, named toyaburgine (<b>4</b>), inspired by naturally occurring <i>N,C</i>-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. <i>In vitro</i>, <b>4</b> 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. <i>In vivo</i>, 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.