The Hybrid Pyrroloisoindolone-Dehydropyrrolizine Alkaloid (−)-Chlorizidine A Targets Proteins within the Glycolytic Pathway

The cytotoxic activity of (−)‐chlorizidine A, a marine alkaloid containing a unique fusion between a pyrroloisoindolone and dehydropyrrolizine, was explored by using a combination of cellular and molecular methods. Our studies began by applying preliminary SAR evidence gathered from semisynthetic bioactivity evaluations to prepare an active immunoaffinity fluorescent (IAF) probe. This probe was then used to identify two cytosolic proteins, GAPDH and hENO1, as the targets of (−)‐chlorizidine A. Cellular and molecular biological studies have identified that the chlorinated marine alkaloid (−)‐chlorizidine A targets the cytosolic proteins GAPDH and ENO1, two multifunctional proteins associated with the glycolytic pathway and implicated in multiple diseases, including metastatic cancer, autoimmune disorders, neurological disorders, and bacterial infections.