The formation and stabilization of G-quadruplex nucleic acid structures has potential applications in the development of more selective cancer chemotherapeutics with decreased systemic toxicity.  These non-classical nucleic acid structures are found in many regions of the human genome and transcriptome, including sequences that have been linked to aberrant cancer cell proliferation, such as the telomeres and ribosomal RNA genes (rDNA). G-quadruplexes in guanine-rich nucleolar rDNA have recently attracted attention as targets of new chemotherapeutic agents aiming to exploit the unique morphological differences between normal and malignant cells.  Toward this goal we are pursuing novel platinum-intercalator conjugates capable of inducing irreversible damage in form of monofunctional adducts with nucleobases in the loop regions of the G-quadruplexes.  This form of damage has the ability to elicit a rapid damage signal in treated cells potentially leading to apoptotic or autophagic cell death.  Novel hybrid agents have been rationally designed and synthesized exhibiting unique geometry and electronic properties.  The goal of the design was to minimize the dose-limiting genotoxicity of the parent compounds by minimizing their reactivity with dsDNA and by hijacking them into cellular structures harboring targetable G-quadruplexes.  To identify potential �leads�, a small library of analogues was tested for biological activity in solid tumor cell lines using a modular combinatorial approach.  Selected derivatives were re-synthesized and studied for uptake and subcellular localization using confocal fluorescence microscopy and inductively-coupled plasma mass spectrometry (ICP-MS).  In addition, their binding properties with telomeric and nucleolar G-quadruplex sequences have been studied using CD spectroscopy, ESI-HRMS, and various biochemical assays. Potential structure-activity and structure-target selectivity relationships will be discussed.

Tuning the subcellular distribution and target selectivity of cytotoxic platinum-intercalator conjugates

247th National Meeting (2014)

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