Synthesis of New Triazine-Based Ferroptosis Inducers/MMP-Inhibitors for Halting Colon Cancer | ||
| Alexandria Journal of Science and Technology | ||
| Editor-in-Chief Lecture, Volume 3, Issue 2, September 2025, Pages 130-130 | ||
| DOI: 10.21608/ajst.2025.452268 | ||
| Authors | ||
| Christine A. Morcos1; Mohamed Teleb* 2; Nesreen S. Haiba3; Rafik W. Bassily1; Marwa M. Abu-Serie4; Sherine N. Khattab1 | ||
| 1Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt. | ||
| 2Department 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. | ||
| 3Department of Physics and Chemistry, Faculty of Education, Alexandria University, Egypt. | ||
| 4Medical 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. | ||
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