title: Benzothiazole hydrazones of furylbenzamides preferentially stabilize c-MYC and c-KIT1 promoter G-quadruplex DNAs.
abstract: The stabilization of G-quadruplex DNA structures by using small molecule ligands having simple structural scaffolds has the potential to be harnessed for developing next generation anticancer agents. Because of the structural diversity of G-quadruplexes, it is challenging to design stabilizing ligands, which can specifically bind to a particular quadruplex topology. To address this, herein, we report the design and synthesis of three benzothiazole hydrazones of furylbenzamides having different side chains (ligands 1, 2 and 3), which show preferential stabilization of promoter quadruplex DNAs (c-MYC and c-KIT1) having parallel topologies over telomeric and duplex DNAs. The CD melting study revealed that all the ligands, in particular ligand 2, exhibit higher stabilization toward parallel promoter quadruplexes (ΔTm = 10-15 °C) as compared to antiparallel promoter quadruplex (h-RAS1), telomeric quadruplex and duplex DNAs (ΔTm = 0-3 °C). FID assay and fluorimetric titration results also reveal the preferential binding of ligands toward c-MYC and c-KIT1 promoter quadruplex DNAs over telomeric and duplex DNAs. Validating these results further, Taq DNA polymerase stop assay showed IC50∼ 6.4 μM for ligand 2 with the c-MYC DNA template, whereas the same for the telomeric DNA template was found to be >200 μM. Molecular modeling and dynamics studies demonstrated a 1 : 1 binding stoichiometry in which stacking and electrostatic interactions play important roles in stabilizing the c-MYC G-quadruplex structure. Taken together, the results presented here provide new insights into the design of structurally simple scaffolds for the preferential stabilization of a particular G-quadruplex topology.
authors.affiliation: Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai-400076, India. pradeep@chem.iitb.ac.in.
authors.forename: Sushree Prangya Priyadarshinee
authors.initials: SP
authors.lastname: Pany
authors.forename: Praneeth
authors.initials: P
authors.lastname: Bommisetti
authors.forename: K V
authors.initials: KV
authors.lastname: Diveshkumar
authors.forename: P I
authors.initials: PI
authors.lastname: Pradeepkumar
mesh_terms: D001483:Base Sequence; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000737:chemistry*; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D015195:Drug Design; D054856:G-Quadruplexes / Q000187:drug effects*; D006835:Hydrazones / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011401:Promoter Regions, Genetic / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*
chemical_list: D001549:Benzamides; D052160:Benzothiazoles; D006835:Hydrazones; D016271:Proto-Oncogene Proteins c-myc; C037689:benzamide; D004247:DNA; D019009:Proto-Oncogene Proteins c-kit; C005465:benzothiazole