Binding of G-quadruplex DNA and serum albumins by synthetic non-proteinogenic amino acids: Implications for c-Myc-related anticancer activity and drug delivery

This study delves into the impact of two synthetic non-natural amino acids, <b>7</b> and <b>8</b>, on the structural dynamics of serum albumin and their potential significance in anticancer drug delivery systems. Crucially, the dihydrofuran-containing compound <b>7</b> has been identified to bind to the G-quadruplex (G4) DNA sequence 22-mer Pu22, a mimic of the proto-oncogene c-Myc, as ascertained by circular dichroism (CD) and UV spectroscopy. Our docking studies suggest that <b>7</b> binds to the G4 structure from the side of the G-quartet in a quasi-parallel manner, engaging in ten intermolecular interactions, including hydrogen bonds, π-lone pair and π-alkyl interactions. Notably, one interaction involves the heterocyclic ring of the compound. Compound <b>7</b> emerges as a notable structure modulator, showcasing a significant enhancement in protein α helix formation, as observed in a serum albumin binding CD experiment, and the capability to form supramolecular networks, as evidenced by dynamic light scattering (DLS) and Scanning Electron Microscopy (SEM), with the added benefit of encapsulating the natural anticancer drug curcumin within its self-assemblies. Toxicity assessments on human fibroblast cell lines demonstrate that both compounds are non-toxic, highlighting their biocompatibility and potential for safe biomedical applications. Interestingly, the triazole-based compound <b>8</b> induces distinctive structural changes in serum albumins, elucidated through CD and UV spectra using bovine serum albumin (BSA) as a model albumin target.