Ferroptosis Induction by a New Pyrrole Derivative in Triple Negative Breast Cancer and Colorectal Cancer

Ferroptosis-inducing agents are an emerging class of nonapoptotic, iron-dependent compounds for anticancer chemotherapy. We describe the synthesis of new aroyl diheterocyclyl pyrrole derivatives 2-21. Compound 12 exhibited the most potent in vitro anticancer activity against breast cancer (BC), triple-negative breast cancer (TNBC), and colorectal cancer (CRC) cell lines, as well as significant efficacy in an HCT116 CRC xenograft model. Compound 12 showed typical hallmarks of ferroptosis in HCT116 cells from tumor tissues both in immunofluorescence and a qPCR gene assay and in the expression of ferroptosis inhibited proteins. Compound 12 significantly lowered GSH, NADP⁺, and NADPH levels. Furthermore, lactoperoxidase, malondialdehyde, and Fe(II) levels significantly increased in 12-treated tissues, whereas superoxide dismutase concentrations decreased. Taken together, these results indicate that the antitumor activity of compound 12 was caused by the strong induction of ferroptosis. Given its high activity, compound 12 represents a promising therapeutic candidate for TNBC and CRC.