Novel Approaches for Controlling Target Selectivity and Pharmacological Properties of Platinum-intercalator-based Anticancer Agents

Released on by Amanda Jayne Pickard
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  • Novel Approaches for Controlling Target Selectivity and Pharmacological Properties of Platinum-intercalator-based Anticancer Agents Book Detail

  • Author : Amanda Jayne Pickard
  • Release Date : 2014
  • Publisher :
  • Genre :
  • Pages : 235
  • ISBN 13 :
  • File Size : 83,83 MB
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Novel Approaches for Controlling Target Selectivity and Pharmacological Properties of Platinum-intercalator-based Anticancer Agents by Amanda Jayne Pickard PDF Summary

Book Description: Traditional DNA-targeted anticancer agents, such as platinum-based therapies, have been a mainstay in the treatment of aggressive solid malignancies in the clinical setting. Unfortunately, due to multifactorial drug resistance and systemic toxicity the clinical efficacy of these drugs is severely limited. Platinum–acridine hybrid agents have proven to overcome multifactorial drug resistance in some of the most aggressive forms of cancer, in particular non-small-cell lung cancer (NSCLC). The remaining challenges with this generation of anticancer agents revolve around overcoming the dose-limiting toxicities caused by indiscriminate chromatin damage (genotoxicity) in malignant and healthy cells and improving the unfavorable pharmacokinetics (PK) caused by the poor drug-like properties of these agents. The goal of this dissertation was to devise a structurally minimalistic approach by which platinum–acridines can be tuned to simultaneously achieve both of these goals. In particular, a design was desired that minimizes platinum adduct formation in the double-stranded portion of genomic DNA but enhances the reactivity with G-quadruplex DNA, a preclinically validated anticancer target. Density functional theory (DFT) calculations were used to study the reactivity of the monofunctional platinum moieties toward nucleobases in relevant target structures. Computational pre-screens were also used to identify DNA-targeted chromophores that show decreased basicity of the endocyclic nitrogen (proton affinities, [triangle]DG[subscript proton].) and an increased planar aromatic surface area to promote G-quadruplex binding. From these pre-screens, quinoline (Q1), acridine (A1), and three benz[c]acridines (B1, B2, B3) were selected and synthesized for a structure–activity relationship (SAR) study. Using microscale reactions, a modular library of 20 hybrid agents was assembled from the 5 chromophores and 4 platinum modules (P1–P4) and evaluated in two aggressive NSCLC cancer cell lines (NCI-H460, NCI-H520) using a cell proliferation assay. From the combinatorial pre-screen, two molecules of interest ("hits") emerged, P1-B1 and P1-B2, which both contained a core benz[c]acridine chromophore. In an extended panel of NSCLC cell lines (NCI-H522, NCI-1435, A549), P1-B1 maintained submicromolar IC50 values. In addition, when compared to the acridine prototype P1-A1, the new benz[c]acridine chromophore showed significantly decreased basicity (pK[subscript a(P1-B1)] = 7.6 vs. pK[subscript a(P1-A1)] = 9.4) (pH-dependent absorbance spectra). The combination of structural and electronic tuning achieved in derivative P1-B1 proved to have a major effect on the subcellular distribution of the hybrid agent and its ability to accumulate in cellular DNA and RNA (confocal fluorescence microscopy, inductively-coupled plasma mass spectrometry, ICP-MS). Although P1-A1 and P1-B1 undergo efficient trafficking from the lysosomes to the nucleus, the latter derivative did not show significant adduct formation in DNA after 6 h of incubation with NCI-H460 cells. All tested hybrids, P1-A1, P1-B1, and P1-B2, as well as their platinum-free carrier ligand modules A1, B1, and B2 were shown to interact favorably with relevant G-quadruplex forming sequences, including the human telomeric repeat and three sequences identified in the genes encoding ribosomal RNA (rRNA) (CD spectroscopy, highresolution mass spectrometry, HRMS). In particular, the benz[c]acridine derivative B1 appears to promote a highly specific interaction with the human telomeric repeat. To validate the approach pursued in this research, a dose escalation study was performed with the new "lead" compound P1-B1 in mice. When administered by intraperitoneal injection for five consecutive days, the new derivative proved to be significantly less toxic to the test animals than the prototype, P1-A1, resulting in an approximately 32-fold higher maximum tolerated dose (MTD). Together with the SAR established in this study, these results attest to the successful design strategy and encourage further preclinical development of P1-B1 and related molecules.

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Platinum-Based Drugs in Cancer Therapy

Platinum-Based Drugs in Cancer Therapy

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Leading international experts comprehensively review all aspects of platinum anticancer drugs and their current use in treatment, as well as examining their fut