Insight into the role of the chemical nature and length of the loop nucleobases in the folding of G-quadruplex by the antimalarial drugs at the DNA interface.

G-quadruplexes (G4) have been proposed as an alternative target for cancer therapy, as the folding of DNA sequences into stabilized G4 in the cancer microenvironment affects key biological functions. The antimalarial drugs, hydroxychloroquine (HCQ) and chloroquine (CQ), are in the clinical trial stage for cancer therapy and have been found to fold DNA sequences into the stabilized G4 even in the absence of KCl salt. In this study, the role of loop nucleobases in terms of chemical nature, number, and location in the HCQ-/CQ-induced folding of DNA sequences into G4 in the absence of KCl has been investigated systematically. The data indicate that both drugs selectively induce the folding of DNA sequences into G-quadruplexes (G4) that contain thymine loop nucleobases. The folding tendency of DNA sequences into stabilized G4 decreases with the increase in the thymine loop nucleobases. Moreover, DNA sequences with fewer thymine loop nucleobases tend to fold into stable G4 when the thymine residues are present at the terminal positions, whereas sequences with more thymine loop nucleobases show higher G4 folding propensity when these bases are located at the central loop. These findings are important in understanding the anticancer effect of antimalarial drugs.