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

Editor-in-Chief Lecture

Authors

1 Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.

2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt. Department of Medicinal Chemistry, Faculty of Pharmacy, Alamein International University (AIU), Alamein City, Alamein City 5060310, Egypt.

3 Department of Physics and Chemistry, Faculty of Education, Alexandria University, Egypt.

4 Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Egypt.

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.

Main Subjects

Alexandria Journal of Science and Technology
Volume 3, Issue 2 - Serial Number 2
Special Issue (Conference Presentations): The Role of Organic, Medicinal, and Pharmaceutical Chemistry in Small Molecule Discovery for Biomedical Applications
September 2025
Pages 130-130

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