Specific Stabilization of c-MYC and c-KIT G-Quadruplex DNA Structures by Indolylmethyleneindanone Scaffolds
Résumé
Stabilization of Gquadruplex DNA structures by small molecules has emerged as a promising strategy for the development of anticancer drugs. Since G-quadruplex structures can adopt various topologies, attaining specific stabilization of a Gquadruplex topology to halt a particular biological process is daunting. To achieve this, we have designed and synthesized simple structural scaffolds based on indolylmethyleneindanone pharmacophore, which can specifically stabilize the parallel topology of promoter quadruplex DNAs (cMYC, cKIT1 and cKIT2), when compared to various topologies of telomeric DNA and duplex DNAs. The lead ligands (InEt2 and InPr2) are water soluble and meet a number of desirable criteria for a small molecule drug. Highly specific induction and stabilization of the c-MYC and c-KITquadruplex DNAs (ΔT1/2 up to 24 °C) over telomeric and duplex DNAs (ΔT1/2 ~ 3.2 °C) by these ligands were further validated by ITC and ESI-MS experiments (Ka ~ 105106 M−1). Low IC50 (~ 2 µM) values were emerged for these ligands from Taq DNA polymerase stop assay with the c-MYC quadruplex forming template, whereas the telomeric DNA template showed IC50 values >120 µM. Molecular modeling and dynamics studies demonstrated the 5'- and 3'- end stacking modes for these ligands. Overall, these results demonstrate that among the >1000 quadruplex stabilizing ligands reported so far, the indolylmethyleneindanone scaffolds stands out in terms of target specificity and structural simplicity, and therefore offers a new paradigm in topology specific G-quadruplex targeting for potential therapeutic and diagnostic applications.
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