title: Specific Stabilization of c-MYC and c-KIT G-Quadruplex DNA Structures by Indolylmethyleneindanone Scaffolds.
abstract: Stabilization of G-quadruplex 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 G-quadruplex topology to halt a particular biological process is daunting. To achieve this, we have designed and synthesized simple structural scaffolds based on an indolylmethyleneindanone pharmacophore, which can specifically stabilize the parallel topology of promoter quadruplex DNAs (c-MYC, c-KIT1, and c-KIT2), when compared to various topologies of telomeric 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-KIT quadruplex DNAs (ΔT1/2 up to 24 °C) over telomeric and duplex DNAs (ΔT1/2 ∼ 3.2 °C) by these ligands were further validated by isothermal titration calorimetry and electrospray ionization mass spectrometry experiments (Ka ∼ 10(5) to 10(6) M(-1)). Low IC50 (∼2 μM) values were emerged for these ligands from a 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 stand out in terms of target specificity and structural simplicity and therefore offer a new paradigm in topology specific G-quadruplex targeting for potential therapeutic and diagnostic applications.
authors.affiliation: Department of Chemistry, Indian Institute of Technology Bombay , Mumbai 400076, India.
authors.forename: K V
authors.initials: KV
authors.lastname: Diveshkumar
authors.affiliation: Department of Chemistry, Indian Institute of Technology Bombay , Mumbai 400076, India.
authors.forename: Saaz
authors.initials: S
authors.lastname: Sakrikar
authors.affiliation: CNRS, UMS3033/US001, Institut Européen de Chimie et Biologie, 33607 Pessac, France.|Université de Bordeaux, U869 ARNA Laboratory, 33600 Pessac, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rosu
authors.affiliation: Department of Chemistry, Indian Institute of Technology Bombay , Mumbai 400076, India.
authors.forename: S
authors.initials: S
authors.lastname: Harikrishna
authors.affiliation: Université de Bordeaux, U869 ARNA Laboratory, 33600 Pessac, France.|Inserm, U869 ARNA Laboratory, 33000 Bordeaux, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gabelica
authors.affiliation: Department of Chemistry, Indian Institute of Technology Bombay , Mumbai 400076, India.
authors.forename: P I
authors.initials: PI
authors.lastname: Pradeepkumar
mesh_terms: D004247:DNA / Q000737:chemistry*; D054856:G-Quadruplexes; D006801:Humans; D007189:Indans / Q000737:chemistry*; D007211:Indoles / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011401:Promoter Regions, Genetic; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry*; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry*
chemical_list: D007189:Indans; D007211:Indoles; D016271:Proto-Oncogene Proteins c-myc; D004247:DNA; D019009:Proto-Oncogene Proteins c-kit