目前，人们对通过将铁死亡与其他形式的肿瘤细胞死亡相结合来阻止CRC感兴趣日益增加。然而，铁死亡诱导很少与MMP抑制同时研究。根据机制铁死亡研究强调与MMP相互作用，特别是与CRC转移和不良预后相关的MMP-13，预计这种组合能够增强治疗效果。在此，我们报道了新的杂环三嗪，能够同时抑制MMP-10/13并诱导铁死亡，弥合它们的抗癌潜力之间的差距。该支架的MMP-10/13抑制组分基于非羟酰胺模型抑制剂。s-三嗪被模拟为核心，受到赛曲胺（一种FDA批准的铁死亡诱导剂）的启发。铁死亡药效基团通过三唑基的间隔装入为迈克尔受体。通过并入氰基和/或取代苯基调节亲电活性，影响电子和空间位阻性能，丰富了SAR研究。初步筛选显示，与硝基苄基香豆素5e和带有对氟苯基9b以及对溴苯基9d配基的氰基丙烯酸肼具有杰出的细胞毒性。特别是9d（IC50 = 0.16 μM）超过了MMP-10和-13对NNGH的抑制作用。铁死亡研究证明，9d通过相对折减0.81缩减了HCT-116细胞中的谷胱甘肽，并具有适度的直接GPX4抑制作用，从而相对增加了1.32倍的脂质过氧化，这是铁死亡的标志。对接预测认为，9d可以与MMP-10的S1'口袋和活性位点His221结合，并通过MMP-13的疏水口袋，并与GPX4催化位点硒蛋白共价作用。9d与亚铁氧化物纳米颗粒复合物对HCT-116细胞的细胞毒性比其自由前体高7.5倍。由复合物引起的细胞内铁超载，通过相对折减0.12缩减了谷胱甘肽，从而通过相对增加3.94倍触发了脂质过氧化和铁死亡。总之，9d可以成为调节MMP选择性和铁死亡诱导潜力的引领物，以最大化该组合的效益。版权所有 © 2023 Elsevier Inc. 保留所有权利。

There is an increasing interest in halting CRC by combining ferroptosis with other forms of tumor cell death. However, ferroptosis induction is seldom studied in tandem with inhibiting MMPs. A combination that is expected to enhance the therapeutic outcome based on mechanistic ferroptosis studies highlighting the interplay with MMPs, especially MMP-13 associated with CRC metastasis and poor prognosis. Herein, we report new hybrid triazines capable of simultaneous MMP-10/13 inhibition and ferroptosis induction bridging the gap between their anticancer potentials. The MMP-10/13 inhibitory component of the scaffold was based on the non-hydroxamate model inhibitors. s-Triazine was rationalized as the core inspired by altretamine, an FDA-approved ferroptosis inducer. The ferroptosis pharmacophores were then installed as Michael acceptors via triazole-based spacers. The electrophilic reactivity was tuned by incorporating cyano and/or substituted phenyl groups influencing their electronic and steric properties and enriching the SAR study. Initial screening revealed the outstanding cytotoxicity profiles of the nitrophenyl-tethered chalcone 5e and the cyanoacrylohydrazides bearing p-fluorophenyl 9b and p-bromophenyl 9d appendages. 9b and 9d surpassed NNGH against MMP-10 and -13, especially 9d (IC50 = 0.16 μM). Ferroptosis studies proved that 9d depleted GSH in HCT-116 cells by a relative fold decrement of 0.81 with modest direct GPX4 inhibition, thus inducing lipid peroxidation, the hallmark of ferroptosis, by 1.32 relative fold increment. Docking presumed that 9d could bind to the MMP-10 S1' pocket and active site His221, extend through the MMP-13 hydrophobic pocket, and interact covalently with the GPX4 catalytic selenocysteine. 9d complexed with ferrous oxide nanoparticles was 7.5 folds more cytotoxic than its free precursor against HCT-116 cells. The complex-induced intracellular iron overload, depleted GSH with a relative fold decrement of 0.12, consequently triggering lipid peroxidation and ferroptosis by a 3.94 relative fold increment. Collectively, 9d could be a lead for tuning MMPs selectivity and ferroptosis induction potential to maximize the benefit of such a combination.Copyright © 2023 Elsevier Inc. All rights reserved.