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Dual functional dinuclear platinum complex with selective reactivity towards c-myc G-quadruplex.

ABSTRACT: G-quadruplexes (GQ) folded by the oncogenic G-rich sequences are the promising targets for developing anticancer therapeutic molecules. However, the current drug development mainly focused on non-covalent dynamic binders to stabilize GQ structures, while the covalent targeting from inorganic complexes via chelating principles, as a potent therapeutic strategy was surprisingly lack of exploration. Herein, a series of dinuclear platinum complexes, [(Pt(Dip)Cl)2(?-diamine)](NO3)2 (Dip: 4,7-diphenyl-1,10-phenanthroline), were designed to contain two dual-functional Pt cores connected by an alkyl linkage. Pt3 with nonanediamine linkage optimized the specific binding towards c-myc G-quadruplex via dual functional clamp on GQ as 1) non-covalently ?-stacking of aromatic ligands, and 2) two Pt(II) cores covalently chelated to guanines at both 3'- and 5'-ends.

SUBMITTER: He L

PROVIDER: S-EPMC5768759 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Dual functional dinuclear platinum complex with selective reactivity towards c-myc G-quadruplex.

He Lei L Meng Zhenyu Z Xu Dechen D Shao Fangwei F

Scientific reports 20180115 1

G-quadruplexes (GQ) folded by the oncogenic G-rich sequences are the promising targets for developing anticancer therapeutic molecules. However, the current drug development mainly focused on non-covalent dynamic binders to stabilize GQ structures, while the covalent targeting from inorganic complexes via chelating principles, as a potent therapeutic strategy was surprisingly lack of exploration. Herein, a series of dinuclear platinum complexes, [(Pt(Dip)Cl)<sub>2</sub>(μ-diamine)](NO<sub>3</sub ...[more]

PMID: 29335501

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Project description:The transcription factor MYC plays a pivotal role in cancer initiation, progression, and maintenance. However, it has proven difficult to develop small molecule inhibitors of MYC. One attractive route to pharmacological inhibition of MYC has been the prevention of its expression through small molecule-mediated stabilization of the G-quadruplex (G4) present in its promoter. Although molecules that bind globally to quadruplex DNA and influence gene expression are well-known, the identification of new chemical scaffolds that selectively modulate G4-driven genes remains a challenge. Here, we report an approach for the identification of G4-binding small molecules using small molecule microarrays (SMMs). We use the SMM screening platform to identify a novel G4-binding small molecule that inhibits MYC expression in cell models, with minimal impact on the expression of other G4-associated genes. Surface plasmon resonance (SPR) and thermal melt assays demonstrated that this molecule binds reversibly to the MYC G4 with single digit micromolar affinity, and with weaker or no measurable binding to other G4s. Biochemical and cell-based assays demonstrated that the compound effectively silenced MYC transcription and translation via a G4-dependent mechanism of action. The compound induced G1 arrest and was selectively toxic to MYC-driven cancer cell lines containing the G4 in the promoter but had minimal effects in peripheral blood mononucleocytes or a cell line lacking the G4 in its MYC promoter. As a measure of selectivity, gene expression analysis and qPCR experiments demonstrated that MYC and several MYC target genes were downregulated upon treatment with this compound, while the expression of several other G4-driven genes was not affected. In addition to providing a novel chemical scaffold that modulates MYC expression through G4 binding, this work suggests that the SMM screening approach may be broadly useful as an approach for the identification of new G4-binding small molecules.

Dataset Information

Dual functional dinuclear platinum complex with selective reactivity towards c-myc G-quadruplex.

Publications

Dual functional dinuclear platinum complex with selective reactivity towards c-myc G-quadruplex.

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