G-Quadruplex-targeting Anticancer Metal Complexes

Project Number
RI 4/13 YYK

Project Duration
May 2014 - May 2018

Status
In-Progress

Abstract
The investigation of metal complexes as G-quadruplex (GQ) binders is an interdisciplinary area of emerging interest. Such complexes are promising candidates for potent and target-specific drugs which exert anticancer activity with minimal toxicity. The G-quadruplex is a peculiar DNA structure that can be formed at the guanine-rich sequences found at the end of telomeric DNA. Small molecules binding to these GQs can sequester the telomeric ends and inhibit the enzyme telomerase, which is selectively expressed in cancer cells. Molecules that stabilize GQ DNA have been observed to induce transcriptional inhibition of oncogenes and growth inhibition of cancer cells. Metal complexes have a very broad range of structural and electronic properties that can be successfully exploited when designing quadruplex DNA binders. Incorporating transition metals into organic scaffolds provides the opportunity to generate GQ binders of multiple geometries beyond those that organic compounds can access. In addition to their structural features, the electron-withdrawing properties of metal centers can reduce the electron density on coordinated aromatic ligands. This affords electron-poor systems, which are expected to display stronger π interactions with GQs. We have recently completed an exploratory study on the GQ-binding ability of a series of anticancer Cu(II) complexes of salicylaldehyde semicarbazones. Some of the complexes were found to show affinity and specificity for human telomeric GQ DNA (versus duplex DNA). In this project, we aim to synthesise new transition-metal semicarbazone complexes for the targeting of GQs. The strength of binding and the specificity of these complexes with G-quadruplex and duplex DNA will be investigated using the Fluorescent Intercalator Displacement Assay, UV-VIS Spectroscopy, Circular Dichroism spectroscopy and Fluorescence Resonance Energy Transfer (FRET) experiments. Systematic structural modifications will be conducted on the metal complexes (with the help of molecular modeling and QSAR techniques) to identify the design features of the complexes that will optimize G-quadruplex binding. All new complexes will be screened for cancer cell cytotoxicities. Various biochemical assays will be applied to study the modes of cell death caused by the complexes. An attempt will be made to correlate quadruplex binding ability with cytotoxicity and mode of cell death, so as to gain insights into the molecular consequences of GQ binding.

Funding Source
NIE

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