Synthesis of New Triazine-Based Ferroptosis Inducers/MMP-Inhibitors for Halting Colon Cancer

Abstract

Combining ferroptosis with other forms of cancer cell death is new emerging strategy for combating colon cancer. However, ferroptosis induction is seldom studied in tandem with inhibiting MMPs. A combination that is expected to enhance the anticancer therapeutic outcome based on mechanistic studies. The current work introduces hybrid triazines concomitantly inhibit MMP-10/13 and induce ferroptosis bridging their anticancer potentials. The MMPs inhibitory component of the designed scaffold was based on the nonhydroxamate inhibitors model. s-Triazine was rationalized as the scaffold core inspired by the FDA-approved ferroptosis inducer altretamine. The ferroptosis electrophilic warheads were installed as Michael acceptors via triazole-based spacers. Their reactivity was tuned by incorporating cyano and/or substituted phenyl groups. Initial screening elected the cyanoacrylohydrazides bearing p-bromophenyl appendage 9d as the most promising cytotoxic agent. 9d surpassed NNGH against MMP-10 and −13 (IC50 = 0.16 μM). Ferroptosis studies proved that 9d depleted the HCT-116 cells GSH by a relative fold decrement of 0.81 with modest GPX4 inhibition inducing HCT-116 cells lipid peroxidation by 1.32 relative fold increment. Docking presumed binding of 9d to the MMP-10 S1′ pocket and the MMP-13 hydrophobic pocket, as well as covalent interaction with the GPX4 catalytic selenocysteine. 9d complexed with ferrous oxide nanoparticles induced intracellular iron overload, depleted GSH with a relative fold decrement of 0.12, and triggered lipid peroxidation and ferroptosis by a 3.94 relative fold increment. The complex was 7.5 folds more cytotoxic against HCT-116 cells than its free precursor. Collectively, 9d could be a lead for tuning MMPs selectivity and ferroptosis induction potential to maximize the benefit of such a combination.