51 Platinum(II) phenanthroimidazoles with “clicked” side chains as selective G-quadruplex DNA binders

Abstract

G-quadruplexes (noncanonical secondary structures), have gained recognition as viable targets for chemotherapeutic drug design based on their ability to interfere with cancer cell proliferation. These DNA structures, held together by Hoogsteen hydrogen bonds, result from the folding of guanine (G)-rich DNA sequences in the presence of potassium or sodium cations.(Lane et al., 2008) G-quadruplex (G4)-forming sequences have been identified throughout the human genome, and depending on the sequence, different monomeric topologies prevail. These varying topologies present a means of specific targeting of one polymorph rather than all polymorphs. Two regions that have been highly investigated as G4 targets for small molecule drugs are the telomeres and the promoters of oncogenes. To date, both organic and inorganic compounds with varying degrees of efficacy in their targeting of G4 structures have been reported.(Georgiades et al., 2010; Monchaud & Teulade-Fichou, 2008) We have previously shown that Pt(II) phenanthroimidazole binders are good stabilizers of both intermolecular and intramolecular human-telomere-derived G4 motifs.(Castor et al., 2012; Kieltyka et al., 2008) Now, we focus on broadening our target to include those G4s derived from the c-myc and c-kit oncogene promoters due to their apparent ability in controlling gene expression through regulating transcription and translation. We hypothesized that the addition of side chains to our existing phenanthroimidazole core will enable our complexes to discriminate between different groove environments presented by topologically distinct G4s. Thus, we have taken our core and have appended “clicked”-amine containing side chains from the phenyl moiety of the phenylphenanthroimidazole. Through a high-throughput fluorescence intercalator displacement assay, circular dichroism, surface plasmon resonance, and molecular modeling, we have evaluated three complexes with G4s derived from human telomere, c-myc, and c-kit sequences and have shown enhanced binding of the complexes with the c-kit sequence and an unprecedented kinetic profile from SPR. We hope that this kinetic profile results in a long residence time while interacting with the c-kit promoter G-quadruplex, resulting in lower levels of c-kit mRNA in human glioblastoma cells and subsequent down-regulation of the gene expression.