Deciphering BindingPotential of Naphthalimide–CoumarinConjugate with c‑MYC G‑Quadruplex for Developing AnticancerAgents: A Spectroscopic and Molecular Modeling Approach

It has been well accumulated that G-quadruplex (G4-DNA) has great anticancer relevance, and various heterocyclic moieties have been synthesized and examined as potent G4-DNA binders with promising anticancer activity. Here, we have synthesized a series of naphthalimide-triazole-coumarin conjugates by substituting various amines and further examine their anticancer activity against 60 human cancer cell lines at 10 μM. One and five dose concentration results reveal low values of MG-MID GI₅₀ for compounds including <b>8a</b> (3.18 μM), <b>8b</b> (13.11 μM), <b>8e</b> (7.68 μM) and <b>8f</b> (1.75 μM). Further cell apoptosis manifests that all compounds can induce cell apoptosis in cancer cells by stabilizing the c-MYC promoter G-quadruplex. Therefore, the G-quadruplex-mediated pathway may be responsible for the apoptosis that these naphthalimide-coumarin compounds caused in cancer cells. Therefore, multispectroscopic techniques are employed to evaluate the binding of molecules with c-MYC G4-DNA where all four molecules readily bind to G4-DNA and stabilize it with a high binding constant, leading to inhibition of cancer cells and apoptosis of cancer cells. Binding studies toward ct-DNA disclose that these compounds do not interact with ds-DNA and thus selectively target G4-DNA to exert their anticancer activity. All the active compounds have greater affinity toward Human Serum Albumin (HSA) and can readily bind with HSA with a binding constant of 12 × 10⁴ M^–1 (<b>8a</b>), 13.0 × 10⁴ M^–1 (<b>8b</b>), 14.2 × 10⁴ M^–1 (<b>8e</b>), 16.3 × 10⁴ M^–1 (<b>8f</b>). Thus, the results disclose that inhibition and killing of cancer cells by these derivatives feasibly occur due to their ability to interact with c-MYC G-quadruplex forming promoters and their high affinity toward HSA unfold potent anticancer agents and can be taken further for clinical trials.