Mono-quinoxaline-induced DNA structural alteration leads to ZBP1/RIP3/MLKL-driven necroptosis in cancer cells

• Published in: European journal of medicinal chemistry 2024-04, Vol.270, p.116377-116377, Article 116377
• Main Authors: Saha, Rimita, Pal, Ritesh, Ganguly, Bhaskar, Majhi, Bhim, Dutta, Sanjay
• Format: Article
• Language: English
• Subjects: Apoptosis; Cytotoxicity; intercalation,5-aza-2′-deoxycytidine; Necroptosis; RIP3/MLKL pathway
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116377

Evading the cellular apoptosis mechanism by modulating multiple pathways poses a sturdy barrier to effective chemotherapy. Cancer cell adeptly resists the apoptosis signaling pathway by regulating anti and pro-apoptotic proteins to escape cell death. Nevertheless, bypassing the apoptotic pathway through necroptosis, an alternative programmed cell death process, maybe a potential therapeutic modality for apoptosis-resistant cells. However, synthetic mono-quinoxaline-based intercalator-induced cellular necroptosis as an anti-cancer perspective remains under-explored. To address this concern, we undertook the design and synthesis of quinoxaline-based small molecules (3a-3l). Our approach involved enhancing the π-surface of the mandatory benzyl moiety to augment its ability to induce DNA structural alteration via intercalation, thereby promoting cytotoxicity across various cancer cell lines (HCT116, HT-29, and HeLa). Notably, the potent compound 3a demonstrated the capacity to induce DNA damage in cancer cells, leading to the induction of ZBP1-mediated necroptosis in the RIP3-expressed cell line (HT-29), where Z-VAD effectively blocked apoptosis-mediated cell death. Interestingly, we observed that 3a induced RIP3-driven necroptosis in combination with DNA hypomethylating agents, even in the RIP3-silenced cell lines (HeLa and HCT116). Overall, our synthesized compound 3a emerged as a promising candidate against various cancers, particularly in apoptosis-compromised cells, through the induction of necroptosis. [Display omitted] •DNA intercalation by 6-nitroquinoxaline scaffold depends on the π-surface of its benzyl moiety.•Potent molecule 3a exhibits cytotoxicity towards various cancer cells.•3a induces in-vitro histone eviction, DNA damage, and ROS generation to trigger apoptosis.•In absence of apoptosis, 3a activates necroptosis through ZBP1/RIP3/MLKL pathway.