title: Studies toward an optimized synthesis of a Novel Imidazopyridinone DNA-PK Inhibitor

authors: Mora, Daniel A.

abstract: Cancer is a disease of global significance, with cancer rates increasing year on year globally. A key challenge within the treatment of cancer is the cellular response to radiotherapy. When fractionated radiotherapy is targeted at cancerous cells DNA double strand breaks are promoted via free radical formation to induce cellular death. However, cellular responses activate the DNA double strand break repair mechanism to oppose these outcomes. Involved in this mechanism is the DNA-PK enzyme and the Auckland Cancer Society Research Centre (ACSRC) has developed an enzyme inhibitor SN39536 to inhibit the repair mechanism. Core aspects of the project surround the use and optimization of an alternative novel synthetic route to the drug as the original published route was developed allowing for structural diversity as opposed to efficiency.

There are three novel reactions at the beginning of the alternative route leading to a point of convergence with the ACSRC route at an imidazopyridinone intermediate; a nucleophilic aromatic substitution, a base-catalyzed hydrolysis and a Curtius rearrangement. Analogous reactions were originally reported by Astra Zeneca (AZ) with pyrimidine analogues however in this work they have been adapted and optimized for pyridine variants. Post optimization the highest yield achieved for the pyridine substrates were; 85.3% for the nucleophilic aromatic substitution, 89.9% for the base-catalyzed hydrolysis and 69.5% for the Curtius rearrangement. These are comparable to the AZ yields with their pyrimidine analogues however in each case the addition of heat and/or increased reaction times were consistently required to match the AZ yields – highlighting that the novel pyridine substrates are not as activated for these reactions.

The novel route generates the same imidazopyridinone intermediate as the ACSRC route in an overall yield of 53.3%. This is significantly lower than the 70.6% overall yield from the ACSRC route. Despite the novel route being viable for the synthesis of imidazopyridinones we propose it is currently an inferior alternative for the synthesis of SN39536.
A rearrangement of the novel route steps was then attempted to explore if the altered electronics of the substrates aid or diminish the synthetic yield of the novel reactions. We placed the final Buchwald-Hartwig amination of the original syntheses after the initial novel nucleophilic aromatic substitution however, we were unable to optimize this novel cross-coupling beyond a yield of 19.0%. Investigation into the reaction conditions were unable to discern why the cross-coupling was consistently unsuccessful. The limited information from our substrate studies suggests that the substrate for this reaction does not have the correct electronics to undergo the proposed cross-coupling. The 19.0% yield of this reaction currently renders the rearranged novel route an unviable alternative to both previous syntheses.

text: Studies toward an optimized synthesis of a Novel Imidazopyridinone DNA-PK Inhibitor Cancer is a disease of global significance, with cancer rates increasing year on year globally. A key challenge within the treatment of cancer is the cellular response to radiotherapy. When fractionated radiotherapy is targeted at cancerous cells DNA double strand breaks are promoted via free radical formation to induce cellular death. However, cellular responses activate the DNA double strand break repair mechanism to oppose these outcomes. Involved in this mechanism is the DNA-PK enzyme and the Auckland Cancer Society Research Centre (ACSRC) has developed an enzyme inhibitor SN39536 to inhibit the repair mechanism. Core aspects of the project surround the use and optimization of an alternative novel synthetic route to the drug as the original published route was developed allowing for structural diversity as opposed to efficiency.

There are three novel reactions at the beginning of the alternative route leading to a point of convergence with the ACSRC route at an imidazopyridinone intermediate; a nucleophilic aromatic substitution, a base-catalyzed hydrolysis and a Curtius rearrangement. Analogous reactions were originally reported by Astra Zeneca (AZ) with pyrimidine analogues however in this work they have been adapted and optimized for pyridine variants. Post optimization the highest yield achieved for the pyridine substrates were; 85.3% for the nucleophilic aromatic substitution, 89.9% for the base-catalyzed hydrolysis and 69.5% for the Curtius rearrangement. These are comparable to the AZ yields with their pyrimidine analogues however in each case the addition of heat and/or increased reaction times were consistently required to match the AZ yields – highlighting that the novel pyridine substrates are not as activated for these reactions.

The novel route generates the same imidazopyridinone intermediate as the ACSRC route in an overall yield of 53.3%. This is significantly lower than the 70.6% overall yield from the ACSRC route. Despite the novel route being viable for the synthesis of imidazopyridinones we propose it is currently an inferior alternative for the synthesis of SN39536.
A rearrangement of the novel route steps was then attempted to explore if the altered electronics of the substrates aid or diminish the synthetic yield of the novel reactions. We placed the final Buchwald-Hartwig amination of the original syntheses after the initial novel nucleophilic aromatic substitution however, we were unable to optimize this novel cross-coupling beyond a yield of 19.0%. Investigation into the reaction conditions were unable to discern why the cross-coupling was consistently unsuccessful. The limited information from our substrate studies suggests that the substrate for this reaction does not have the correct electronics to undergo the proposed cross-coupling. The 19.0% yield of this reaction currently renders the rearranged novel route an unviable alternative to both previous syntheses.

year: 2025

title: Interactive solar panel simulation tool - from GHI to PV output

authors: Suppers, Joris

subjects: computer science

abstract: The production and integration of solar panels is steadily growing in New Zealand and worldwide. The most common way to install solar panels in New Zealand is flat on top of the most north-facing roof. This method is used as it is space efficient, reduces mounting costs and will capture most of the sun’s movement throughout the day. New Zealand homes typically have a small roof pitch. This means an installed solar panel will have a low tilt, allowing for best input in summer. However, this may not be the best result for individuals, as they may want a different outcome such as: maximum energy output in winter, maximum yearly output or a balanced output throughout each month. This paper describes a solar panel tool, which has been developed to enable users to explore interactively the impact on electricity production based on the orientation of the panels.

text: Interactive solar panel simulation tool - from GHI to PV output The production and integration of solar panels is steadily growing in New Zealand and worldwide. The most common way to install solar panels in New Zealand is flat on top of the most north-facing roof. This method is used as it is space efficient, reduces mounting costs and will capture most of the sun’s movement throughout the day. New Zealand homes typically have a small roof pitch. This means an installed solar panel will have a low tilt, allowing for best input in summer. However, this may not be the best result for individuals, as they may want a different outcome such as: maximum energy output in winter, maximum yearly output or a balanced output throughout each month. This paper describes a solar panel tool, which has been developed to enable users to explore interactively the impact on electricity production based on the orientation of the panels.

year: 2017

title: Māori men's positive and interconnected sense of self, being and place

authors: Rua, Mohi

subjects: Maori men, interconnected self, pluralistic identities, relational health

abstract: Māori  men are on the wrong side of the ledger when it comes to illness and crime rates. Correspondingly, there is a significant amount of research into issues such as abuse and premature death involving Māori men, who are also often characterised in public discourse as inarticulate, deviant and incapable of maintaining positive relationships. There is very little research on positive practices among Māori men who are caring and expressive, and who do not harm their partners, families, and communities. This thesis explores how Māori men negotiate a positive sense of self, relationships and a place in our society, which is awash with negative characterisations of Māori men. I document how Māori men's identities are pluralistic and on-going projects. These identities are negotiated within the settler society through interactions with other people and media characterisations. These identities are also negotiated within the Māori world through interactions with whānau (immediate and extended family) and participation in cultural rituals, including tangihanga (traditional Māori death ritual/funeral process). This research involves two separate, yet interrelated studies, and is guided by kaupapa Māori research, Māori cultural concepts, Māori relational understandings of being and health, and relevant social science theory and research. Study one explores Māori men’s relationships with other men, their families and media depictions of men in the settler society. The participants from study one are working class men who were also part-time members of a Territorial Army unit within which Māori and Pākehā  men come together through mutual interests and negotiate meaningful relationships, and various cultural similarities and differences. Study one drew upon an ethnographic orientation that included direct observations, narrative interviews, media diaries and photo elicitation projects to understand the everyday lived realities of participants’ in settler society. Study two explores the constructive engagement of working class ex-Army Māori men back in their communities of origin in order to investigate key aspects of their identities and relationships as men within the Māori world. An ethnographic approach was also used in study two and involved direct observations, participation in shared practices and narrative interviews. Overall, findings from these studies demonstrate how Māori men construct a positive sense of self that extends beyond the deficit-orientated characterisations offered by academic research and mainstream media depictions. In constructing understandings of themselves and their place in the world, my participants emphasise their meaningful relationships with partners, children, colleagues, friends and communities. These men invoke a positive sense of self through accounts of belonging, reciprocity, dialogue, intimacy, and care for themselves, their whānau, and traditions. Participants’ positive Māori self-constructions are fundamentally interconnected with other people, cultural traditions, physical and symbolic places, and shared practices. My research sheds light on Māori men’s ways of belonging and being that span, but manifest in unique ways within, the settler society and the Māori world. This research also contributes to scholarship on men that takes a strengths-based approach by considering the valuable everyday functions men serve within their families and communities.

text: Māori men's positive and interconnected sense of self, being and place Māori  men are on the wrong side of the ledger when it comes to illness and crime rates. Correspondingly, there is a significant amount of research into issues such as abuse and premature death involving Māori men, who are also often characterised in public discourse as inarticulate, deviant and incapable of maintaining positive relationships. There is very little research on positive practices among Māori men who are caring and expressive, and who do not harm their partners, families, and communities. This thesis explores how Māori men negotiate a positive sense of self, relationships and a place in our society, which is awash with negative characterisations of Māori men. I document how Māori men's identities are pluralistic and on-going projects. These identities are negotiated within the settler society through interactions with other people and media characterisations. These identities are also negotiated within the Māori world through interactions with whānau (immediate and extended family) and participation in cultural rituals, including tangihanga (traditional Māori death ritual/funeral process). This research involves two separate, yet interrelated studies, and is guided by kaupapa Māori research, Māori cultural concepts, Māori relational understandings of being and health, and relevant social science theory and research. Study one explores Māori men’s relationships with other men, their families and media depictions of men in the settler society. The participants from study one are working class men who were also part-time members of a Territorial Army unit within which Māori and Pākehā  men come together through mutual interests and negotiate meaningful relationships, and various cultural similarities and differences. Study one drew upon an ethnographic orientation that included direct observations, narrative interviews, media diaries and photo elicitation projects to understand the everyday lived realities of participants’ in settler society. Study two explores the constructive engagement of working class ex-Army Māori men back in their communities of origin in order to investigate key aspects of their identities and relationships as men within the Māori world. An ethnographic approach was also used in study two and involved direct observations, participation in shared practices and narrative interviews. Overall, findings from these studies demonstrate how Māori men construct a positive sense of self that extends beyond the deficit-orientated characterisations offered by academic research and mainstream media depictions. In constructing understandings of themselves and their place in the world, my participants emphasise their meaningful relationships with partners, children, colleagues, friends and communities. These men invoke a positive sense of self through accounts of belonging, reciprocity, dialogue, intimacy, and care for themselves, their whānau, and traditions. Participants’ positive Māori self-constructions are fundamentally interconnected with other people, cultural traditions, physical and symbolic places, and shared practices. My research sheds light on Māori men’s ways of belonging and being that span, but manifest in unique ways within, the settler society and the Māori world. This research also contributes to scholarship on men that takes a strengths-based approach by considering the valuable everyday functions men serve within their families and communities.

year: 2015