Cork’s international trade during the first industrial revolution

This thesis explores the impact international trade and commercial agreements had on the economic and industrial development of Cork during the first industrial revolution. From the Act of Union onwards Cork moved from a region where trade became increasingly reliant on Britain at the expense of trade that had been cultivated over the eighteenth century with the Americas and Europe. The legislative underpinnings of Cork’s trade is the focus of this research and how this changed after the Act of Union. It begins by examining the transatlantic trade of Cork city and the issues faced in the West Indies trade due to the growth of the United States. It will also consider the impact of the Napoleonic Wars on Cork’s trade with both the Americas and continental Europe. The conclusion of the Napoleonic Wars saw the United Kingdom negotiate treaties and agreements that would have a direct impact upon Cork’s merchants. This thesis will address the degree to which the mercantile community in Cork were able to influence policy that directly impacted upon their trade networks. It will then examine the trade between Cork and the United Kingdom and assess the impact of the Union on the ability of Cork’s merchants to affect political change. The operation of the Committee of Merchants in Cork is detailed and their responses to the changing nature of international trade. The thesis finishes by examining the underdevelopment of Cork’s transportation networks. This work will place Cork’s international trade in both its national and international context and argues that Cork’s mercantile community were overly reliant on protectionist legislation to further Cork’s trade as opposed to investment in industrial development. Volumetric data on the trade of Cork city has been transcribed and made available in a relational database to support the arguments made in this thesis and to facilitate future research on this subject. This database is accessible at http://modernirishvenice.com/.

Synthesis and evaluation of novel azaindolocarbazole derivatives as cancer chemotherapeutics

This thesis details the design and implementation of novel chemical routes towards a series of highly propitious 7-azaindolyl derivatives of the indolocarbazole (ICZ) and bisindolylmaleimide (BIM) families, with subsequent evaluation for use as cancer chemotherapeutic agents. A robust synthetic strategy was devised to allow the introduction of a 7-azaindolyl moiety into our molecular template. This approach allowed access to a wide range of β-keto ester and β-keto nitrile intermediates. Critical analysis identified F-ring modulation as a major theme towards the advancement of ICZ and BIM derivatives in drug therapy. Thus, the employment of cyclocondensation methodology furnished a number of novel aminopyrazole, isoxazolone, pyrazolone and pyrimidinone analogues, considerably widening the scope of the prevalent maleimide functionality. Photochemical cyclisation provided for the first reported aza ICZ containing a six-membered F-ring. Another method towards achieving the aza ICZ core involved use of a Perkin-type condensation approach, with chemical elaboration of the headgroup instigated post-aromatisation. Subsequent use of a modified Lossen rearrangement allowed access to further analogues containing a six-membered F-ring. Extensive screening of the novel aza ICZ and BIM derivatives was carried out against the NCI-60 cancer cell array, with nine prospective candidates selected for continued biological evaluation. From these assays, a number of compounds were shown to inhibit cancer cell growth at concentrations of below 10 nM. Indeed, the most active aza ICZ tested is currently under assessment by the Biological Evaluation Committee of the NCI due to excellent antiproliferative activity demonstrated across the panel of cell lines, with a mean GI50 of 34 nM, a mean total growth inhibition (TGI) of 4.6 μM and a mean cytotoxicity (LC50) of 63.1 μM. Correlation to known topoisomerase I (topo I) inhibitors was revealed by COMPARE analysis, and subsequent topo I-mediated DNA cleavage assays showed inhibitory activity below 1 μM for several derivatives.