Spirooxindol‐1,3‐oxazine Alkaloids: Highly Potent and Selective Antitumor Agents Evolved from Iterative Structure Optimization

Spirooxindole‐1,3‐oxazines are a small and structurally unique class of spirooxindole alkaloids. To date, only four of these compounds have been isolated from natural sources, and their biological properties remained unknown thus far. Dioxyreserpine is a synthetic spirooxindole‐1,3‐oxazine, that can readily be prepared from the Rauvolfia alkaloid (–)‐reserpine by catalytic photooxygenation. While dioxyreserpine itself was now identified as a moderately effective antitumoral agent, structurally modified analogs of it emerged as a new class of highly potent and selective growth inhibitors of various human cancers, including pancreatic cancers. Systematic structural optimization ultimately led to an inhibitor displaying low‐micromolar IC50‐values against six cancer cell lines as well as selective apoptosis induction in vitro. Six birds with one stone: A highly effective and selective inhibitor of six human cancer cell lines, including pancreatic cancer, evolved after the systematic structural optimization of alkaloids that possess the unusual spirooxindol‐1,3‐oxazine core structure.