title: pH Sensitive Anticancer Prodrug: Amide of Kemp's Acid

authors: Brooks, Robert Turongo

subjects: Amide hydrolysis kinetics

abstract: Solid tumours are characterised by lower extracellular pH (as low as 5.8 pH) compared to normal healthy cellular pH (actively regulated at pH 7.3). This difference may be exploited with an acid-sensitive anti-tumour prodrug which releases a cytotoxin selectively in tumour tissue.
The research reported in this thesis was aimed at synthesising and performing rate studies on an amide prodrug with pH-sensitive rates of reaction in the pH 5 - 8 region. Amide hydrolysis is catalysed by neighbouring carboxylic acid groups in their fully protonated state but not in its ionised state (shown in the figure below), whereby pH sensitivity around pH 5 - 8 can be exploited. The current study was carried out on an amide of Kemp's acid which, due to enforced stereochemistry of carboxylic acid and amide functional groups, has the type of structure conducive to accelerated amide hydrolysis.
 
The rates for tertiary and secondary aliphatic amides of this Kemp's acid system have shown high reactivity at low pH and a large reduction in rate across pH 5.8 - 7.3, however an aryl amide had not previously been studied. It was thought that an aryl amide of Kemp's acid would provide a faster rate of reaction compared with the alkyl amides, and also aryl amine cytotoxins exist which could be attached as an amide.
A secondary aryl amide of Kemp's acid (58) was obtained via a potassium hydroxide ring-opening reaction on a synthesised imide of Kemp's acid (43).  
 
Aliquots of the ring-opened amide (58) were added to buffered (phosphate and malonate) aqueous solutions (with ionic strength   = 1 mol L-1) and the hydrolysis reaction followed at 30.0 oC across the pH range 0.48 - 8. First order rate constants were calculated from absorbance change with time and the pH-rate profile established. Absorbance changes were shown to be consistent with amide hydrolysis with no evidence of any imide reformation as evident in other studies. The rate data were analysed. There was no evidence from rates for the two successive acid ionisations with only a single rate plateau evident from pH 2 to 5, suggesting that both di- and mono-acid species have very similar hydrolysis rates or that the second ionisation is low due to stabilisation of the mono-ionised molecule by hydrogen bonding interactions. For this reason, the rate profile could be analysed only as if it were a single ionisation in the same way that Menger and Ladika analysed their aliphatic tertiary pyrrolidyl amide in an earlier study. This analysis gave a pKa value of 6.72   0.09 and a limiting rate constant of 7.1 x 10-5 s-1. The studies revealed a three fold rate differential between pH 5.8 (faster) versus 7.3 (slower), a difference which is probably too small a selectivity for possible prodrug application.
Separately, the second order rate coefficient for the reaction of potassium hydroxide solution to open the imide was also established (k2 = 0.00067 L mol-1 s-1 at 30.0 oC,   = 1.00 mol L-1 with KCl).

text: pH Sensitive Anticancer Prodrug: Amide of Kemp's Acid Solid tumours are characterised by lower extracellular pH (as low as 5.8 pH) compared to normal healthy cellular pH (actively regulated at pH 7.3). This difference may be exploited with an acid-sensitive anti-tumour prodrug which releases a cytotoxin selectively in tumour tissue.
The research reported in this thesis was aimed at synthesising and performing rate studies on an amide prodrug with pH-sensitive rates of reaction in the pH 5 - 8 region. Amide hydrolysis is catalysed by neighbouring carboxylic acid groups in their fully protonated state but not in its ionised state (shown in the figure below), whereby pH sensitivity around pH 5 - 8 can be exploited. The current study was carried out on an amide of Kemp's acid which, due to enforced stereochemistry of carboxylic acid and amide functional groups, has the type of structure conducive to accelerated amide hydrolysis.
 
The rates for tertiary and secondary aliphatic amides of this Kemp's acid system have shown high reactivity at low pH and a large reduction in rate across pH 5.8 - 7.3, however an aryl amide had not previously been studied. It was thought that an aryl amide of Kemp's acid would provide a faster rate of reaction compared with the alkyl amides, and also aryl amine cytotoxins exist which could be attached as an amide.
A secondary aryl amide of Kemp's acid (58) was obtained via a potassium hydroxide ring-opening reaction on a synthesised imide of Kemp's acid (43).  
 
Aliquots of the ring-opened amide (58) were added to buffered (phosphate and malonate) aqueous solutions (with ionic strength   = 1 mol L-1) and the hydrolysis reaction followed at 30.0 oC across the pH range 0.48 - 8. First order rate constants were calculated from absorbance change with time and the pH-rate profile established. Absorbance changes were shown to be consistent with amide hydrolysis with no evidence of any imide reformation as evident in other studies. The rate data were analysed. There was no evidence from rates for the two successive acid ionisations with only a single rate plateau evident from pH 2 to 5, suggesting that both di- and mono-acid species have very similar hydrolysis rates or that the second ionisation is low due to stabilisation of the mono-ionised molecule by hydrogen bonding interactions. For this reason, the rate profile could be analysed only as if it were a single ionisation in the same way that Menger and Ladika analysed their aliphatic tertiary pyrrolidyl amide in an earlier study. This analysis gave a pKa value of 6.72   0.09 and a limiting rate constant of 7.1 x 10-5 s-1. The studies revealed a three fold rate differential between pH 5.8 (faster) versus 7.3 (slower), a difference which is probably too small a selectivity for possible prodrug application.
Separately, the second order rate coefficient for the reaction of potassium hydroxide solution to open the imide was also established (k2 = 0.00067 L mol-1 s-1 at 30.0 oC,   = 1.00 mol L-1 with KCl).

year: 2009

title: Sustainable energy transition toward renewable energies in the New Zealand dairy industry: An environmental life cycle assessment

authors: Tarighaleslami, Amir Hossein

abstract: The dairy processing industry is considered as energy-intensive processes between New Zealand industries that use fossil fuels as a primary energy source which results in greenhouse gas emissions as well as raising other environmental impacts. To mitigate the environmental impacts of fossil fuels that are used in dairy processing plants, it is essential to design a pathway moving from fossil-based energies towards renewable energy sources in a transition period. To do so, Life Cycle Assessment (LCA), as a standardised approach, has been implemented to quantify the environmental profile of different products by evaluating the environmental impacts of product systems. In this paper, three impact categories are considered adopting accessible inventory databases that match the regional and local data along with ReCiPe as the life cycle impact assessment method. These impact categories are 1) human health; 2) ecosystem; and 3) resources. Each category contains subcategories; seven different-statistically discernible energy mix scenarios (moving from coal through natural gas towards biomass) assisted by Monte Carlo simulation are defined to assess environmental impacts. Furthermore, Cumulative Exergy Demand (CExD) as an aggregated criterion has been exploited to indicate the sustainability of the whole system. Results show that for a cheese production process a biomass based scenario has the lowest environmental burden impact in 13 impact categories out of 14 studied impacts. Indeed, it has the lowest CExD with 1.05x10-5 MJ-Eq while surprisingly natural gas based scenario has the highest environmental burden with CExD of 3.85x10-1 MJ-Eq followed by coal with 4.73x10-4 MJ-Eq.

text: Sustainable energy transition toward renewable energies in the New Zealand dairy industry: An environmental life cycle assessment The dairy processing industry is considered as energy-intensive processes between New Zealand industries that use fossil fuels as a primary energy source which results in greenhouse gas emissions as well as raising other environmental impacts. To mitigate the environmental impacts of fossil fuels that are used in dairy processing plants, it is essential to design a pathway moving from fossil-based energies towards renewable energy sources in a transition period. To do so, Life Cycle Assessment (LCA), as a standardised approach, has been implemented to quantify the environmental profile of different products by evaluating the environmental impacts of product systems. In this paper, three impact categories are considered adopting accessible inventory databases that match the regional and local data along with ReCiPe as the life cycle impact assessment method. These impact categories are 1) human health; 2) ecosystem; and 3) resources. Each category contains subcategories; seven different-statistically discernible energy mix scenarios (moving from coal through natural gas towards biomass) assisted by Monte Carlo simulation are defined to assess environmental impacts. Furthermore, Cumulative Exergy Demand (CExD) as an aggregated criterion has been exploited to indicate the sustainability of the whole system. Results show that for a cheese production process a biomass based scenario has the lowest environmental burden impact in 13 impact categories out of 14 studied impacts. Indeed, it has the lowest CExD with 1.05x10-5 MJ-Eq while surprisingly natural gas based scenario has the highest environmental burden with CExD of 3.85x10-1 MJ-Eq followed by coal with 4.73x10-4 MJ-Eq.

year: 2019

title: New Zealand history is Maori history: Tikanga as the ethical foundation of historical scholarship In Aotearoa New Zealand

authors: Mahuika, Nepia

subjects: Arts & Humanities

abstract: IT SHOULD COME AS NO SURPRISE TO FIND that New Zealand history is Māori history. In 1987 when Tipene O’Regan stated that the ‘the past belongs to all New Zealanders, but first it is ours’, he was drawing attention to New Zealand history’s foundation in Māori history.1 Thinking about New Zealand history as Māori history does not mean denying the histories of European, Asian and Pasifika immigrants, but draws attention to the notion that ‘settler’ aspirations to claim ‘Aotearoa’ as home occur within a much broader narrative of indigenous occupation and struggle.2 Indeed, how can New Zealand history be the story of ‘here’ when it has ‘othered’ indigenous narratives that speak to the heart of what it is to belong in the land of the long white cloud? Yes, New Zealand history is Māori history – and that presents a problem for tangata whenua self-determination. Likewise, for Pākehā, it is an issue because until New Zealand history recognizes and enables the centrality of Māori history it will always fail to articulate the collective ‘us’ that is so often assumed in the discourse of ‘full and final settlement’.3 In its current form it will never be able to ethically or adequately account for the shaping of a New Zealand identity that finds ‘composure’ in the story of how Pākehā became ‘native’ New Zealanders.4 For Māori, these issues are keenly felt, because while New Zealand history has always been about us, it has predominantly been articulated on the colonizers’ terms. In the ‘discursive constructions’ that are New Zealand histories, the indigenous have regularly been culturally appropriated, dislocated and misrepresented.5 Even when Māori have turned their back on the writing of New Zealand history it has been, and will still be, a history of being or becoming ‘native’. Yes, New Zealand history is Māori history – so why does it feel like the story of Pākehā settlers?

text: New Zealand history is Maori history: Tikanga as the ethical foundation of historical scholarship In Aotearoa New Zealand IT SHOULD COME AS NO SURPRISE TO FIND that New Zealand history is Māori history. In 1987 when Tipene O’Regan stated that the ‘the past belongs to all New Zealanders, but first it is ours’, he was drawing attention to New Zealand history’s foundation in Māori history.1 Thinking about New Zealand history as Māori history does not mean denying the histories of European, Asian and Pasifika immigrants, but draws attention to the notion that ‘settler’ aspirations to claim ‘Aotearoa’ as home occur within a much broader narrative of indigenous occupation and struggle.2 Indeed, how can New Zealand history be the story of ‘here’ when it has ‘othered’ indigenous narratives that speak to the heart of what it is to belong in the land of the long white cloud? Yes, New Zealand history is Māori history – and that presents a problem for tangata whenua self-determination. Likewise, for Pākehā, it is an issue because until New Zealand history recognizes and enables the centrality of Māori history it will always fail to articulate the collective ‘us’ that is so often assumed in the discourse of ‘full and final settlement’.3 In its current form it will never be able to ethically or adequately account for the shaping of a New Zealand identity that finds ‘composure’ in the story of how Pākehā became ‘native’ New Zealanders.4 For Māori, these issues are keenly felt, because while New Zealand history has always been about us, it has predominantly been articulated on the colonizers’ terms. In the ‘discursive constructions’ that are New Zealand histories, the indigenous have regularly been culturally appropriated, dislocated and misrepresented.5 Even when Māori have turned their back on the writing of New Zealand history it has been, and will still be, a history of being or becoming ‘native’. Yes, New Zealand history is Māori history – so why does it feel like the story of Pākehā settlers?

year: 2015