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: A mobile reader for language learners

authors: König, Jemma Lynette

subjects: computer science

abstract: This paper describes a new approach to mobile language learning; a mobile reader that aids learners in extending the breadth of their existing vocabulary knowledge. The FLAX Reader supports L2 (second language) learners in English by building a personalized learner model of receptive vocabulary acquisition. It provides dictionary lookup for words that they struggle with, tracks a learner's reading speed, and models their vocabulary acquisition, generat-ing appropriate exercises to aid in a learner’s personal language growth.

text: A mobile reader for language learners This paper describes a new approach to mobile language learning; a mobile reader that aids learners in extending the breadth of their existing vocabulary knowledge. The FLAX Reader supports L2 (second language) learners in English by building a personalized learner model of receptive vocabulary acquisition. It provides dictionary lookup for words that they struggle with, tracks a learner's reading speed, and models their vocabulary acquisition, generat-ing appropriate exercises to aid in a learner’s personal language growth.

year: 2016

title: Ko te Pakiwaituhi Ko Au, Ko Au Ko te Pakiwaituhi: He Wewetenga o te Pakiwaituhi Tōra Mātātoa, He Whakapuakanga Pakiwaituhi Māori

authors: Ross, Kristin Cherie

subjects: Pakiwaituhi Māori

abstract: ARIĀ

Mai i ngā tau o te whitu tekau te pakanga a ētahi rōpū Māori kia rangona te Māori, kia kitea te Māori ki runga pouaka whakaata.  I kura takahi puni te whiua o rātou mā ki te Karauna kia whakamanahia tāna i oati ai i te Tiriti o Waitangi.  Otirā, ka tohua te Karauna ki te tiaki i ngā kura kāmehameha a te Māori, arā, ko te reo me ōna tikanga.  I kitea e rātou mā tētahi patanga oranga o tō tātou reo, o ā tātou tikanga mā te ao pāpāho.  E mara e, kua tuangahuru ngā tau e whakapāoho atu ana a Whakaata Māori mai i tōna whakarewanga i te tau 2004.  Nā aua kikopuku reo, nā aua mumu tikanga, nā aua matā mana motuhake i whai wāhi mai ai te Māori i te ao pāpāho, otirā, i te ao o te pouaka whakaata. 

Ka mutu, ko te ngako ia o tēnei tuhinga, he whakamahuki, he tirotiro, he ketuketu i te pakiwaituhi kōhungahunga, i a Dora the Explorer.  I whakamāorihia e Whakaata Māori ki a Tōra Mātātoa.  Mō te pakiwaituhi rongonui, kāhore he painga i a Tōra Mātātoa.  Kei te mātakitakihia e ngā iwi huhua ki ngā tōpito katoa o te ao.  Ko te pātai ia nā, he aha oti ngā ehunga Māori ka kitea, ka rangona rā roto mai i te pakiwaituhi kōhungahunga, i a Tōra Mātātoa?  Mā tēnei rangahau tonu e whakautu.  

Ko ngā pakiwaituhi katoa o Whakaata Māori mā te kōhungahunga he mea hanga e iwi kē atu i te Māori.  Ka mutu ka whakaarohia e tēnei rangahau ētahi huarahi e taea ai e tātou te whakaputa pakiwaituhi Māori mā te kōhungahunga.  Otirā, ka whakapua mai ai i tētahi pakiwaituhi Māori nāku tonu.  Ko tāku e whakapae nei, me kite ā tātou tamariki i a rātou anō rā roto mai i ngā pakiwaituhi.  Ko tāku e manako nei, kia kaha te iwi Māori ki te kimi huarahi e whakaputa ai i ā tātou ake pakiwaituhi nā te Māori, mā te Māori, mō te Māori. 

ABSTRACT

Since the 1970s select Māori groups have fought to be seen and heard in the broadcasting industry and particular television.  United and banded they challenged the Crown to honour what was promised to them in the Treaty of Waitangi.  They demanded that the Government maintain the Māori language and its customs.  They saw television as a means to retain and transmit our language and culture.  2014 marked the tenth year of broadcasting for Māori Television.  This prestigious achievement in Māori broadcasting was due to the efforts of our leaders who fought tirelessly to ensure our language and customs were and are maintained throughout broadcasting. 

The basis of this thesis is the analysis of the preschool animation, Dora the Explorer, which was broadcast and translated by Māori Television as Tōra Mātātoa.  Dora the Explorer is arguably the most famous preschool animation.  The show is watched by the masses all over the world. This thesis investigates the question; what representations of Māori are seen and heard in the preschool animation Tōra Mātātoa? 

All of the preschool animations shown on Māori Television have been created by non-Māori.  Therefore, the purpose of this research is to create new ways of thinking that will initiate the production of locally made preschool animation.  This thesis looks at a Māori animation example that I have created based on the findings of this research.  It is imperative that our children see themselves on the television screen.  I hope Māori actively seek avenues to ensure the production of preschool animation by Māori, for Māori and about Māori.

text: Ko te Pakiwaituhi Ko Au, Ko Au Ko te Pakiwaituhi: He Wewetenga o te Pakiwaituhi Tōra Mātātoa, He Whakapuakanga Pakiwaituhi Māori ARIĀ

Mai i ngā tau o te whitu tekau te pakanga a ētahi rōpū Māori kia rangona te Māori, kia kitea te Māori ki runga pouaka whakaata.  I kura takahi puni te whiua o rātou mā ki te Karauna kia whakamanahia tāna i oati ai i te Tiriti o Waitangi.  Otirā, ka tohua te Karauna ki te tiaki i ngā kura kāmehameha a te Māori, arā, ko te reo me ōna tikanga.  I kitea e rātou mā tētahi patanga oranga o tō tātou reo, o ā tātou tikanga mā te ao pāpāho.  E mara e, kua tuangahuru ngā tau e whakapāoho atu ana a Whakaata Māori mai i tōna whakarewanga i te tau 2004.  Nā aua kikopuku reo, nā aua mumu tikanga, nā aua matā mana motuhake i whai wāhi mai ai te Māori i te ao pāpāho, otirā, i te ao o te pouaka whakaata. 

Ka mutu, ko te ngako ia o tēnei tuhinga, he whakamahuki, he tirotiro, he ketuketu i te pakiwaituhi kōhungahunga, i a Dora the Explorer.  I whakamāorihia e Whakaata Māori ki a Tōra Mātātoa.  Mō te pakiwaituhi rongonui, kāhore he painga i a Tōra Mātātoa.  Kei te mātakitakihia e ngā iwi huhua ki ngā tōpito katoa o te ao.  Ko te pātai ia nā, he aha oti ngā ehunga Māori ka kitea, ka rangona rā roto mai i te pakiwaituhi kōhungahunga, i a Tōra Mātātoa?  Mā tēnei rangahau tonu e whakautu.  

Ko ngā pakiwaituhi katoa o Whakaata Māori mā te kōhungahunga he mea hanga e iwi kē atu i te Māori.  Ka mutu ka whakaarohia e tēnei rangahau ētahi huarahi e taea ai e tātou te whakaputa pakiwaituhi Māori mā te kōhungahunga.  Otirā, ka whakapua mai ai i tētahi pakiwaituhi Māori nāku tonu.  Ko tāku e whakapae nei, me kite ā tātou tamariki i a rātou anō rā roto mai i ngā pakiwaituhi.  Ko tāku e manako nei, kia kaha te iwi Māori ki te kimi huarahi e whakaputa ai i ā tātou ake pakiwaituhi nā te Māori, mā te Māori, mō te Māori. 

ABSTRACT

Since the 1970s select Māori groups have fought to be seen and heard in the broadcasting industry and particular television.  United and banded they challenged the Crown to honour what was promised to them in the Treaty of Waitangi.  They demanded that the Government maintain the Māori language and its customs.  They saw television as a means to retain and transmit our language and culture.  2014 marked the tenth year of broadcasting for Māori Television.  This prestigious achievement in Māori broadcasting was due to the efforts of our leaders who fought tirelessly to ensure our language and customs were and are maintained throughout broadcasting. 

The basis of this thesis is the analysis of the preschool animation, Dora the Explorer, which was broadcast and translated by Māori Television as Tōra Mātātoa.  Dora the Explorer is arguably the most famous preschool animation.  The show is watched by the masses all over the world. This thesis investigates the question; what representations of Māori are seen and heard in the preschool animation Tōra Mātātoa? 

All of the preschool animations shown on Māori Television have been created by non-Māori.  Therefore, the purpose of this research is to create new ways of thinking that will initiate the production of locally made preschool animation.  This thesis looks at a Māori animation example that I have created based on the findings of this research.  It is imperative that our children see themselves on the television screen.  I hope Māori actively seek avenues to ensure the production of preschool animation by Māori, for Māori and about Māori.

year: 2015