Synthetic Epoxy-Phenanthridine-Triazole Conjugates Induce Dual Redox Imbalance and Metabolic Remodeling in Breast...

Because of resistance and the absence of effective targeted therapies, breast cancer, particularly the hormone receptor-positive (HR+) and triple-negative breast cancer (TNBC) types, presents significant therapeutic problems. One promising therapeutic approach is to target the redox vulnerabilities of cancer cells. In this work, new epoxy-functionalized phenanthridine-triazole conjugates (RM58, RM60, RM61, and RM75) are evaluated as dual redox modulators in models of breast cancer. Using molecular docking and molecular dynamics simulations (100 ns) against a panel of 14 potential protein targets linked to breast cancer, these compounds are shown to have high affinity and stable binding to important redox-regulatory proteins, such as glutathione S-transferase and thioredoxin. Dose-dependent cytotoxicity was demonstrated in vitro in MCF-7 (HR+) and MDA-MB-231 (TNBC) cell lines, with RM75 and RM60 showing the strongest effects. According to mechanistic research, these substances cause oxidative stress overload by causing a considerable buildup of intracellular reactive oxygen species and the depletion of glutathione and thioredoxin. Specifically in the TNBC model, this redox imbalance led to robust caspase-3/7-mediated apoptosis, loss of membrane potential, and mitochondrial dysfunction. Untargeted LC-MS/MS metabolomic profiling revealed clear metabolic reprogramming, with significant changes found in the pathways. These findings show that a sequence of metabolic alterations and cellular apoptosis is induced by the dual disruption of antioxidant defenses. These integrative results suggest that antioxidant disruption by epoxy-phenanthridine conjugates leads to metabolic collapse and apoptosis, highlighting RM75 as a promising redox-active lead. However, in vivo efficacy, pharmacokinetics, and safety studies are needed to advance this scaffold toward clinical evaluation.