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PhD - Science / Methotrexate (MTX) is a highly potent drug against leukemia and other neoplasias. The drug is notorious, however, for exerting toxic side effects and inducing drug resistance in the target cells as a result of deficiencies in the active carrier-mediated membrane-crossing mechanism. The bioreversible binding to a water-soluble and biocompatible carrier polymer is an advanced technology designed to circumvent critical pharmacological hurdles the drug must clear for efficacious biological action. The present project aimed at the anchoring of MTX and other drugs to various primary amine-functionalized polymeric carriers and the evaluation of the cytotoxic performance of the resulting conjugates in cell culture tests. The polymeric carriers used were polyaspartamides, prepared by an aminolytic ring-opening process of polysuccinimide, and poly(amidoamines), on the other hand, obtained by the copolymerization of methylenebisacrylamide with mono-N- tert-butoxycarbonyl-protected primary diamine and bifunctional amines. The anchoring was achieved through formation of biofissionable amide bonds. The in vitro biological evaluation against various human cell lines revealed the polymer-MTX conjugates to be more active than the clinically used parent drug. In order to demonstrate the multidrug-binding capacity of the polyaspartamidetype carriers, and at the same time ensuring target-specific drug delivery, folic acid, a potential cell entry facilitator, was co-conjugated to selected polymeric conjugates containing MTX or ferrocene. The in vitro inhibition of cell growth by the folate-drug co-conjugates was also evaluated against the same human cell lines.

The discovery and development of effective chemotherapeutic agents in the past few decades have immensely enhanced the treatment and management of human cancer. However, because these drugs are associated with adverse side effects, high genotoxicity, risk for secondary cancers and devastating effects on the patients’ immune system; the need for developing more effective anticancer agents remains. A priority Research shows that 9-aminoacridine (9AA) derivatives have substantial anticancer properties. The pharmacological properties of this agent are well characterized and this scaffold has been widely used to treat different diseases for decades. Quinacrine is a 9AA derivative, which was first discovered as an antimalarial compound in 1930’s and since then had been widely used in treating a variety of parasitic infections and demonstrated potential for cancer treatment. Importantly, the polypharmacology of Quinacrine makes it an attractive drug to treat a variety of cancers. Quinacrine acts by specifically targeting cellular signaling pathways that play an important role in cell survival. Given the distinctive cancer treating abilities of Quinacrine by specifically targeting cellular signaling pathways, it was the objective of this study to develop a compound that has similar properties as Quinacrine but has better efficacy and selectivity in targeting tumor cells. Therefore, for this project we created derivatives of 9AA compound using hybrid pharmapore approach and examined one of the derivatives of Quinacrine compound named VR118. After performing a series of experiments to test the efficacy and selectivity of the Quinacrine derivative VR118, I came to the conclusion that VR118 is highly effective in treating cancer cells and have the potential to selectively target cancer cells without causing severe harm to normal cells at concentrations applicable for malignant cell lines. This report discusses the efficacy and selectivity of VR118 compound in targeting cellular signaling pathways and the mechanisms through which VR118 kills cancer cells.

Although cis-PtCl2(NH3)2 (cisplatin) has been widely used as a chemotherapeutic agent, its use can be accompanied by toxic side effects and the development of drug resistance. Consequently, much research has been focused on the discovery of novel transition metal compounds which elicit elevated cytotoxicities coupled with reduced toxic side effects and non-cross resistance. Recently, research in this lab has focused on preparing derivatives of titanocene dichloride (TDC), a highly active chemotherapeutic agent, with pendant alkylammonium groups on one or both rings. Earlier results have demonstrated that derivatives containing either cyclic or chiral alkylammonium groups had increased cytotoxic activities. This research therefore investigated a new series of TDC complexes focusing specifically on derivatives bearing cyclic and chiral alkylammonium groups. A library of ten cyclic derivatives and six chiral derivatives were synthesized and fully characterized. These derivatives have undergone in vitro testing as anti-tumour agents using human lung, ovarian, and cervical carcinoma cell lines (A549, H209, H69, H69/CP, A2780, A2780/CP and HeLa). These standard cell lines represent solid tumour types for which new drugs are urgently needed. The potencies of all of the Ti (IV) derivatives varied greatly (range from 10.8 μM - >1000 μM), although some trends were observed. In general, the dicationic analogues exhibited greater potency than the corresponding monocationic derivatives. Additionally, the cyclic analogues bearing 1,3- and 1,4-substituted pyridines displayed potent cytotoxic activities (IC50> 20 μM). It was also found at concentrations of ~30 μM that the derivatives bearing an ephedrine derived substituent were cytotoxic. Conversely, analogues substituted with piperidinyl, morpholinyl or primary alkylammonium groups were inactive (>200 μM) against the cancer cell lines assayed. / Thesis (Ph.D, Chemistry) -- Queen's University, 2008-05-14 13:18:28.141

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Since Bortezomib®, a proteasome inhibitor, was approved by US FDA for the treatment of multiple myeloma in 2003, proteasome is recognized as one of the most promising targets for cancer therapeutics. The proteasomes play a critical role in regulating the level of cellular proteins and recycling damaged and misfolded proteins. Although the activity of the proteasome is essential for normal cells, it is especially critical for the proliferation and survival of cancer cells. In an attempt to develop effective and safe proteasome inhibitor-based anticancer drugs, the Lee laboratory created a chemical library by a hybrid approach using a 4-piperazinylquinoline scaffold and a sulfonyl phamarcophore. It is known that the chloroquine scaffold possesses a weak proteasome inhibition activity, and chloroquine itself preferentially kills malignant cells over non-cancer cells, alone or in combination with other therapeutics. To identify compounds with desirable anticancer activities, I have screened the aforementioned chemical library. The screening yielded several hits with substantial efficacy and selectivity against malignant cells. In this thesis, I describe the functional mechanism of VR23, one of the most promising compounds identified from my screening, as it kills cancer cells up to 17 fold more effectively than non-cancer cells. Molecular docking and substrate competition studies revealed that VR23 binds to the β2 peptide of the 20S proteasome catalytic subunit. The IC50 value of VR23 in inhibiting trypsin-like proteasome activity is 1.0 nM. VR23 is also substantially effective in inhibiting chymotrypsin-like proteasome activity (IC50, 50-100 nM). The inhibition of proteasome activity by VR23 led to the accumulation of ubiquitinated cyclin E at centrosomes. This, in turn, induces abnormal centrosome amplification by a de novo centrosome synthesis pathway in cancer cells, but not in non-cancer cells. The presence of multiple centrosomes in single cancer cells results in cell cycle arrest at prometaphase and, eventually, cell death by apoptosis. Thus, VR23 possesses a very desirable property as a safe anticancer drug.

Yes / In the past decade, libraries of iridium organometallic arene compounds have expanded rapidly, with the majority of their applications aimed towards effective catalysts and potential anti-cancer drug candidates. Researchers have begun to adapt the traditional “piano-stool” structures to include different bidentate ligands, ancillary ligands and extend the aromaticity and functionality of the arene substituent, all in the hope to optimize their activities and allow the determination of structure activity relationships. Many of the complexes incorporate N- and O-donor ligands, but more recently, these structures have been expanded to include C-donor ligands such as cyclometalated bidentate ligands and N-heterocyclic carbenes. This mini-review highlights the recent and ongoing research in C-donor iridium arene complexes, and discusses their importance as potential anticancer drugs.

Yes / Two approaches for the prediction of which of two vehicles will result in lower toxicity for anticancer agents are presented. Machine-learning models are developed using decision tree, random forest and partial least squares methodologies and statistical evidence is presented to demonstrate that they represent valid models. Separately, a clustering method is presented that allows the ordering of vehicles by the toxicity they show for chemically-related compounds.

Mitomycin C (MMC), obtained from Streptomyces caespitosus, a clinically useful antitumour antibiotic, is the archetypical quinone bioreductive alkylating agent. The reductive activation mechanism of MMC, involves quinone reduction sequentially activating electrophilic sites in the drug molecule (C-l and C-lO for MMC). This research project was designed to investigate the role of the C-lO in alkylation processes by preparing compounds in which the electrophilicity at C-l is much reduced by substituting a cyclopropane for the aziridine ring. The resulting pyrrolo[I,2-a]indole, cyclopropamitosenes, could on reductive activation, by either 1- or 2-electron processes, followed by elimination of the carbamate, generate a powerful electrophile capable of alkylating DNA (or other nucleophiles) at C-lO .. A range of compounds was prepared utilising the azidocinnamate decomposition route to substituted indoles and an intramolecular [3 + 2] cycloaddition strategy was employed to synthesise the pyrrolo[I,2-a]indole nucleus. The rapid ring opening of cyclopropylcarbinyl radicals is briefly outlined. The reduction-initiated ring opening of the cyclopropane ring is investigated, thereby establishing its relevance to the potent bioreductive anticancer action of the cyclopropamitosenes, novel analogues of MMC. The design and synthesis of fused [I,2-a]indoles without the cyclopropane ring, is examined for comparative purposes. The key step in the synthesis is the formation of the [I,2-a ]indole nucleus via a radical cyclisation. Biological data were recorded for the cyclopropamitosenes and correlated with their structures.