Uracil-BX: A New Class of Cyclic Hypervalent Iodine Reagents for Unraveling Approach Towards Umpolung Functionalization and VEGF G-Quadruplex DNA Identification

Herein we report a straight forward synthetic protocol to afford a series of novel uracil based cyclic hypervalent iodine reagent Uracil-benzoiodaoxol (Uracil-BX). The 3c-4e week bond of these hitherto unreported hypervalent iodine reagents were synthetically exploited for sulfenylation and amination at C-5 position of Uracil via umpolung strategy. After exploration of metal-free base promoted functionalization in wide range of substrate scopes, we focused on biological importance of novel Uracil-BX. G-quadruplex (GQ) DNA is recognized as a key target for anticancer therapies, highlighting the importance of studying its interactions with our sulfenylated compound and different forms of Uracil-BX. Given the polymorphic variability of GQ-DNA, it is vital to identify ligands that can selectively bind to specific quadruplex sequences. Various biophysical studies, were employed to explore ligand’s interaction with quadruplex and duplex DNAs. The compound 1,3-dimethyl-5-(3-oxo-1l3-benzo[d][1,2]iodaoxol-1(3H)-yl)pyrimidine-2,4(1H,3H)-dione (UBX 3a), preferentially interacts with VEGF (vascular endothelial growth factor)-GQ DNA, potentially regulating gene expression in cancer cells. This finding also opens the door for more GQ biology research by highlighting the possibility of creating medications to comprehend the molecular elements of GQ-DNA recognition and signaling for hypervalent iodine reagent.