Selective Recognition of Oncogene Promoter C-Myc G-Quadruplex: Design, Synthesis, and In Vitro Evaluation of Naphthalimide and Imidazo[1,2-]pyrazines for Their Anticancer Activity.

c-Myc is a transcription factor that is overexpressed in most human cancers. Despite its challenging nature, we have developed a series of naphthalimide-imidazopyrazine conjugates to target c-Myc. The library of synthesized derivatives was tested for their anticancer activity against a nine-panel of cancer cell lines. Compound showed excellent cytotoxicity against all the tested cancer cell lines, with the range of growth inhibition from -98.79% to 96.62% at a single-dose concentration of 10 M. Further, was employed for a 5-dose assay against the same cancer cell lines, which showed efficacy at varying concentrations with an MG-MID GI value of 2.61 μM. Biophysical studies were performed to explore the interaction of with c-Myc 27 over ct-DNA, oncogene promotor 22, and human telomere, with a binding constant value of 1.3 × 10 M. Additionally, experiments were performed to get insights into the interaction mechanism between and the c-Myc oncogene promoter. A molecular docking study unveiled the stacking of the compound with G4 DNA through groove binding, where very few reports are available, with a favorable binding energy of -9.2 kcal/mol. Moreover, the pharmacokinetic study and HOMO-LUMO energy gap analysis underscored the potency of the active candidate. The compound's binding ability toward HSA was also assessed, where results suggested effective binding of the compound to HSA, revealing its potential for easy delivery to the target site. The above findings suggested that these newly synthesized candidates with potent anticancer activity offer a promising avenue as G4 DNA c-Myc stabilizers.