title: pH-sensitive Anticancer Model Prodrug: Amide of Kemp's Acid

authors: Brooks, Robert Turongo

subjects: Anticancer Model prodrug

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 μ = 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
ONHCOOHCOO-OMe(58)
iv
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, μ = 1.00 mol L-1 with KCl).

text: pH-sensitive Anticancer Model 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 μ = 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
ONHCOOHCOO-OMe(58)
iv
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, μ = 1.00 mol L-1 with KCl).

year: 2009

title: The social work regulation project in Aotearoa New Zealand

authors: Hunt, Sonya

subjects: social work regulation

abstract: INTRODUCTION: In this second of two articles on the history of professionalisation of social work in Aotearoa New Zealand, consideration is given to the more recent coalescing of forces from the 1990s to the initial implementation of the Social Workers Registration Act (2003), which led to our country’s example of a social work regulation project. 
APPROACH: This critical consideration of social work regulation in Aotearoa New Zealand situates it within the international social work professionalisation context alongside the national context. Consideration is given to the place of leadership and buy-in from the profession, political sponsorship, cultural considerations, and another ministerial review. Overlaying this, an examination of concepts of public trust, respect, and confidence in professions such as social work, are linked to crises of trust in professions in general, and placed within the current neoliberal, market-driven environment in which this project is anchored. 
CONCLUSION: The literature serves to document the history of social work regulation in Aotearoa New Zealand and as background for an ongoing research project which aims to uncover interests at work and interrogate the legitimacy of those interests, while enabling the voices of key actors from the time to surface, be explored, and be recorded.

text: The social work regulation project in Aotearoa New Zealand INTRODUCTION: In this second of two articles on the history of professionalisation of social work in Aotearoa New Zealand, consideration is given to the more recent coalescing of forces from the 1990s to the initial implementation of the Social Workers Registration Act (2003), which led to our country’s example of a social work regulation project. 
APPROACH: This critical consideration of social work regulation in Aotearoa New Zealand situates it within the international social work professionalisation context alongside the national context. Consideration is given to the place of leadership and buy-in from the profession, political sponsorship, cultural considerations, and another ministerial review. Overlaying this, an examination of concepts of public trust, respect, and confidence in professions such as social work, are linked to crises of trust in professions in general, and placed within the current neoliberal, market-driven environment in which this project is anchored. 
CONCLUSION: The literature serves to document the history of social work regulation in Aotearoa New Zealand and as background for an ongoing research project which aims to uncover interests at work and interrogate the legitimacy of those interests, while enabling the voices of key actors from the time to surface, be explored, and be recorded.

year: 2017

title: Imagining our own approaches

authors: Smith, Linda Tuhiwai

abstract: I spent some formative years of my life either in the back of museums or their basements helping my father, a scholar of Māori Studies, and keeping myself out of trouble. In the late 1960s I had one small job in the library basement of the Peabody Museum in Salem, Massachusetts, typing new labels for the captains’ log books of ships that were sailing during the American Revolution. I read most of those journals that consisted of pages and pages of wind directions with the rare glimpse of an encounter with another ship or a list of supplies. Why were we there in Salem when we came from Aotearoa, New Zealand? We were there because Salem was the home base for ships that sailed into the Pacific and returned home with collections of materials from the various Pacific Islands countries they visited. My father was studying elaborately carved items from the Marquesa Islands that looked very much like Māori designs.

text: Imagining our own approaches I spent some formative years of my life either in the back of museums or their basements helping my father, a scholar of Māori Studies, and keeping myself out of trouble. In the late 1960s I had one small job in the library basement of the Peabody Museum in Salem, Massachusetts, typing new labels for the captains’ log books of ships that were sailing during the American Revolution. I read most of those journals that consisted of pages and pages of wind directions with the rare glimpse of an encounter with another ship or a list of supplies. Why were we there in Salem when we came from Aotearoa, New Zealand? We were there because Salem was the home base for ships that sailed into the Pacific and returned home with collections of materials from the various Pacific Islands countries they visited. My father was studying elaborately carved items from the Marquesa Islands that looked very much like Māori designs.

year: 2015