Date of Award

2013

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr Celine Marmion

Second Supervisor

Dr Marc Devocelle

Third Supervisor

Dr Maria Morgan

Keywords

Chemistry, Pharmaceutical.

Abstract

The search for metallodrugs (Pt or non-Pt based) which (i) target cancer cells and/or (ii) have a different mode of action to Pt drugs currently in clinical use remains the subject of intense investigation. The recent correlation between the inhibition of enzymes that regulate chromatin structure/function and tumour growth suppression has, for example, validated chromatin control as a promising new molecular target in contemporary medical oncology for example, through histone deacetylase (HDAC) inhibition. In addition to the use of HD AC inhibitors (HDACi) for novel avenues of cancer chemotherapeutics, targeting the cancer cells based on their unique and unanimous membrane properties is another avenue of investigation. Cationic antimicrobial peptides (CAPs) have emerged as drug candidates that may overcome the drawbacks associated with classical chemotherapeutics. Their therapeutic potential stems from their ability to selectivity attack cancer cells over healthy cells at new molecular targets, their activity against both proliferating and dormant cells, their ability to act synergistically with existing chemotherapies and their low propensity to select for resistant mutants. Tumour cell killing by CAPs is usually by a cell membrane-lytic effect, although some CAPs can trigger apoptosis in cancer cells via mitochondrial membrane disruption while others can inhibit angiogenesis that is associated with tumour progression.

Classical Pt drugs react indiscriminately in the body giving rise to many of the drawbacks associated with their use. We believe that by tethering a HDAC inhibitor or CAP to a Pt complex that a synergistic (or at least an additive) effect would result. The presence of the HDACi/CAP, with its known affinity for both dormant and proliferating cancer cells, would (i) confer selectivity to the bifunctional drug for its target, thereby reducing toxicity and (ii) deliver the complex containing two potent chemotherapeutics i.e. the Pt complex as a DNA binding agent and the HDACi/CAP with anti-proliferative or anti-angiogenic properties to its biological target (i.e. cancer cells). These compounds may have a mechanism of action and a lower toxicity profile from those of classical Pt drugs and might therefore be active against (i) a broader spectrum of human cancer cells relative to classical Pt drugs and (ii) human malignancies that have acquired or intrinsic resistance to conventional Ptbased therapies.

The question that this thesis addresses is: can we form novel Pt-CAP/HDACi conjugates in which the CAP/HDACi will act as a 'homing device', conferring selectivity to the conjugate while also delivering the complex containing two potent anti-cancer entities (Pt-DNA binding agent and peptide with anti-proliferative or antiangiogenic properties) to its cancer target?

Chapter 1 provides an introduction to the role of inorganic chemistry in cancer chemotherapeutics and an overview of the current trend that aims at delivering a known cytotoxic Pt drug selectively to cancer cells and introduce new modes of activity through the tethering agents to afford an alternative or enhanced antiproliferative effect. The remaining three chapters detail experimental work and a discussion of the obtained results.

Chapters 2 and 3 focus on the derivatisation of the potent HDACi belinostat and SAHA respectively and the subsequent complexation of the derivative to various platinum scaffolds. Chapter 2 details the derivatisation of belinostat with the aid of molecular modelling to construct cw-[Pt(NH3)2(mal-/?-bel_2H)L where mal is a malonic acid linker connecting the HDACi to Pt via a short alkyl chain without affecting the activity of the HDACi. The novel complex has the capacity to dissociate within cancer cells releasing a highly reactive and cytotoxic Pt species and the cytotoxic HDACi. The success with the synthesis of the Pt-belinostat complex directed our investigations into the in vitro cytotoxic evaluation of the novel dual functioning Pt drug candidate. Chapter 3 explores the derivatisation of SAHA and its successful complexation to Pt(II) to form a complex that contains two HDACi to one Pt moiety capable of binding DNA.

Chapter 4 details the derivatisation of CAPs for the coordination to Pt. Specifically, chapter 4 focuses on two platinum-peptide conjugates, namely (i) cis- [Pt(NH3)2(malBuf.2H)], where mal is a malonate linker adjoining the Pt complex to the peptide via a short alky chain and (ii) c/.v-[Pt(dap-P 18-leu)Cl2] where dap is a diammine linker connecting the Pt unit to the peptide via a short alkyl chain. It is envisaged that c/s-[Pt(NH3)2(malBuf.2H)] with a labile malonate linker system affording a dual functioning drug conjugate that has the capacity, like cis[Pt(NH3)2(nial-/?-bel.2n)], to dissociate within cancer cells releasing a highly reactive and cytotoxic Pt species and the cytotoxic CAP. In contrast, c/.y-[Pt(dap-P18-leu)Cl2] with the permanently tethered Pt-peptide complex may display a different mechanism of action based on the stronger affinity of the peptide-Pt linker for Pt. An in vitro antiproliferative activity of the novel complex c/s-[Pt(NH3)2(mal-/?-bel.2n)] is also reported against a small panel of cell lines. Furthermore, chapter 4 presents work detailing complexation of a different CAP to Pt via a permanent linker to afford cis- [Pt(dap-P18-leu)Cl2)] and establishes the in vitro cytotoxicity of the parent peptide PI 8-leu on various cancerous cell lines.

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Comments

Submitted for the Award of Doctor of Philosophy (PhD) to the Royal College of Surgeons, 2013.

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