Metal-free synthesis of N-fused quinazolino-quinazoline-diones as a MALAT1 RNA triple helix intercalator.

Abstract

The development of chemical scaffolds that target highly conserved MALAT1 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 via a PIDA-induced C-N coupling methodology to target MALAT1. Interestingly, compound 2z binds to the UUG pocket of a MALAT1 RNA triple-helix through intercalation, evidenced from molecular docking studies, fluorescence-based assay and CD experiments. 2z exhibited cytotoxicity towards MALAT1 overexpressing cancer cells (SKOV-3, IC50 of 8.0 ± 0.4 μM). These findings demonstrated 2z as a MALAT1 RNA triple-helix intercalator with therapeutic potential, offering an important chemical scaffold to understand MALAT1 activity in disease development pathways.