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: Critically unpacking professionalism in hospitality: Knowledge, meaningful work and dignity

authors: Cockburn-Wootten, Cheryl

subjects: hospitality

abstract: Calls for change within the hospitality sector have argued for the industry to seriously consider the implementation of professionalism. Concerns have been raised about the workplace conditions of many employees, the readiness of graduates to meet or challenge these practices, and commitment to sustainability in promoting and respecting the rights of people in the workplace. In this conceptual article traditional perspectives of professionalism are critically examined. A key argument is that recent changes to professionalism have transformed the term into another discursive tool for discipline, performance and control. Rather than focusing on professionalism this article asserts that the sector should seriously consider implementing meaningful work and dignity. The article concludes that integrating these concepts through practices such as caring relationships, trust and education of managers starts to open up avenues for change in this hostile industry. Overall, the article argues that by adopting a broader understanding of professionalism, one that incorporates communication and collaboration, and challenges the lack of dignity in the workplace, we can start to open up possibilities for interdisciplinary work and more importantly, change.

text: Critically unpacking professionalism in hospitality: Knowledge, meaningful work and dignity Calls for change within the hospitality sector have argued for the industry to seriously consider the implementation of professionalism. Concerns have been raised about the workplace conditions of many employees, the readiness of graduates to meet or challenge these practices, and commitment to sustainability in promoting and respecting the rights of people in the workplace. In this conceptual article traditional perspectives of professionalism are critically examined. A key argument is that recent changes to professionalism have transformed the term into another discursive tool for discipline, performance and control. Rather than focusing on professionalism this article asserts that the sector should seriously consider implementing meaningful work and dignity. The article concludes that integrating these concepts through practices such as caring relationships, trust and education of managers starts to open up avenues for change in this hostile industry. Overall, the article argues that by adopting a broader understanding of professionalism, one that incorporates communication and collaboration, and challenges the lack of dignity in the workplace, we can start to open up possibilities for interdisciplinary work and more importantly, change.

year: 2012

title: Cultural identity and academic achievement among Māori undergraduate university students

authors: Bennett, Simon T.

subjects: Maori

abstract: Cultural identity and academic achievement were investigated among a nonrandom
sample of 72 undergraduate Māori university students studying at Massey
University. Student problems were examined to identify the types of difficulties
most prevalent among this population. The degree to which cultural identity
moderates the relationship between student problems and academic achievement
was then examined. Major findings were that (a) there is a consistent negative
relationship between student problems and academic achievement; and (b) cultural
identity moderates the effect of student problems on academic achievement, in that:
a high degree of problems were associated with decreases in grade point average
among respondents with low cultural identity; while among respondents with high
cultural identity, high levels of student problems had little negative effect on grade
point average. Despite the study having limitations, the findings have important
implications for Māori students, deliverers of tertiary education, tertiary education
providers, and those involved in the development and implementation of tertiary
education policy.

text: Cultural identity and academic achievement among Māori undergraduate university students Cultural identity and academic achievement were investigated among a nonrandom
sample of 72 undergraduate Māori university students studying at Massey
University. Student problems were examined to identify the types of difficulties
most prevalent among this population. The degree to which cultural identity
moderates the relationship between student problems and academic achievement
was then examined. Major findings were that (a) there is a consistent negative
relationship between student problems and academic achievement; and (b) cultural
identity moderates the effect of student problems on academic achievement, in that:
a high degree of problems were associated with decreases in grade point average
among respondents with low cultural identity; while among respondents with high
cultural identity, high levels of student problems had little negative effect on grade
point average. Despite the study having limitations, the findings have important
implications for Māori students, deliverers of tertiary education, tertiary education
providers, and those involved in the development and implementation of tertiary
education policy.

year: 2003