Metal-free synthesis of N-fused quinazolino-quinazoline-diones as a <i>MALAT1</i> RNA triple helix intercalator

The development of chemical scaffolds that target highly conserved <i>MALAT1</i> RNA received attention due to its significance in splicing, nuclear organization, and gene expression in disease progression pathways. Here, we synthesized a series of N-fused quinazolino-quinazoline-diones <i>via</i> a PIDA-induced C-N coupling methodology to target <i>MALAT1</i>. Interestingly, compound 2z binds to the UUG pocket of a <i>MALAT1</i> RNA triple-helix through intercalation, evidenced from molecular docking studies, fluorescence-based assay and CD experiments. 2z exhibited cytotoxicity towards <i>MALAT1</i> overexpressing cancer cells (SKOV-3, IC₅₀ of 8.0 ± 0.4 μM). These findings demonstrated 2z as a <i>MALAT1</i> RNA triple-helix intercalator with therapeutic potential, offering an important chemical scaffold to understand <i>MALAT1</i> activity in disease development pathways.