title: Studies Towards a pH-Sensitive Anticancer Prodrug Model

authors: Teng, Xiao Shi

subjects: tumour-activated prodrug (TAP)

abstract: Tumour-activated prodrug (TAP) is designed to aim at increasing the prodrug selectivity to kill cancer cells. One strategy to is to design a TAP containing an amine cytotoxin, present as an amide function, which could be released more rapidly in the low pH environment of tumour tissues when amide undergoes hydrolysis.
The prodrug model (1) was the subject of the current study. At lower pH its un-ionised carboxylic acid group provides neighbouring catalysis of hydrolysis of the adjacent amide. It was synthesised via ring-opening of the imide (2) which itself was directly synthesised from endo-bicyclo[2.2.2]octa-5-ene-2,3-dicarboxylic anhydride and p-methoxyaniline.
The pH-rate profile of (1) was established over the pH range of 3-10, covering rapid hydrolysis of un-ionised acid-amide at lower pH but slower imide formation above pH 8 from the ionised acid-amide. From the kinetic data were calculated the dissociation constant for (1) (pKa: 5.1 at 30 C) and limiting lower pH rate constant for hydrolysis of (1) in its fully neutral form (klim: 0.44 min-1 at 30 C). The data in the pH range of 8-10 provided klow (0.067 min-1) representing formation of (2) from fully ionised (1).
The following equilibrium reaction was also investigated at high pH, at which (1) was in its fully ionised amide carboxylate form, by kinetic studies on (2) in hydroxide solutions.
Imide + OH- Amide carboxylate
The second order rate constant for the forward reaction, kf, was 74 L mol-1 min-1 which with klow for the reverse reaction gave K as 1100 L mol-1.

text: Studies Towards a pH-Sensitive Anticancer Prodrug Model Tumour-activated prodrug (TAP) is designed to aim at increasing the prodrug selectivity to kill cancer cells. One strategy to is to design a TAP containing an amine cytotoxin, present as an amide function, which could be released more rapidly in the low pH environment of tumour tissues when amide undergoes hydrolysis.
The prodrug model (1) was the subject of the current study. At lower pH its un-ionised carboxylic acid group provides neighbouring catalysis of hydrolysis of the adjacent amide. It was synthesised via ring-opening of the imide (2) which itself was directly synthesised from endo-bicyclo[2.2.2]octa-5-ene-2,3-dicarboxylic anhydride and p-methoxyaniline.
The pH-rate profile of (1) was established over the pH range of 3-10, covering rapid hydrolysis of un-ionised acid-amide at lower pH but slower imide formation above pH 8 from the ionised acid-amide. From the kinetic data were calculated the dissociation constant for (1) (pKa: 5.1 at 30 C) and limiting lower pH rate constant for hydrolysis of (1) in its fully neutral form (klim: 0.44 min-1 at 30 C). The data in the pH range of 8-10 provided klow (0.067 min-1) representing formation of (2) from fully ionised (1).
The following equilibrium reaction was also investigated at high pH, at which (1) was in its fully ionised amide carboxylate form, by kinetic studies on (2) in hydroxide solutions.
Imide + OH- Amide carboxylate
The second order rate constant for the forward reaction, kf, was 74 L mol-1 min-1 which with klow for the reverse reaction gave K as 1100 L mol-1.

year: 2010

title: Nanosecond protein dynamics:  First detection of a neutron incoherent spin−echo signal

authors: Bellissent-Funel, Marie-Claire

subjects: biology

abstract: Motions in proteins occur over a wide range of time scales, from femtoseconds to seconds or longer.¹⁻³ Therefore, their characterization requires the application of a correspondingly wide range of experimental probes. Among these incoherent neutron scattering (INS) is a particularly direct source of information on time scales and forms of hydrogen motions.⁴⁻⁸ However, due to limited accuracy in the measurement of energy changes of scattered neutrons, INS work has been limited to the 10⁻¹⁵-10⁻¹⁰s time scales. The neutron spin-echo technique was developed to overcome this limitation.⁹ Neutron spin-echo allows precise measurement of velocity changes of neutrons via Larmor precession of the neutron’s spin. This has led to the possibility of extracting information on atomic motions on nanosecond and longer time scales.

text: Nanosecond protein dynamics:  First detection of a neutron incoherent spin−echo signal Motions in proteins occur over a wide range of time scales, from femtoseconds to seconds or longer.¹⁻³ Therefore, their characterization requires the application of a correspondingly wide range of experimental probes. Among these incoherent neutron scattering (INS) is a particularly direct source of information on time scales and forms of hydrogen motions.⁴⁻⁸ However, due to limited accuracy in the measurement of energy changes of scattered neutrons, INS work has been limited to the 10⁻¹⁵-10⁻¹⁰s time scales. The neutron spin-echo technique was developed to overcome this limitation.⁹ Neutron spin-echo allows precise measurement of velocity changes of neutrons via Larmor precession of the neutron’s spin. This has led to the possibility of extracting information on atomic motions on nanosecond and longer time scales.

year: 1998

title: Te mana o ngā toa: Māori experiences of Ngāti Tūmatauenga, the New Zealand Army

authors: Kohere, Cheyenne Atairehia Mere

subjects: Kaupapa Māori

abstract: Diverse realities impact Māori people and their capacity to flourish. It is well- established that Māori are significant contributors to the New Zealand Defence Force (NZDF), and especially the New Zealand Army. Noteworthy participation in major conflicts, especially WWI and WWII create a whakapapa of military tradition which contributed to institutional change within the Army in the 1990s. The inclusion of Māori cultural training in the New Zealand Army can contribute to morale and the effectiveness of the organisation (Hohaia, 2016). This master’s thesis aims to deepen understandings of the experiences of Māori personnel in the Army by exploring the role of the New Zealand Army in the health and wellbeing of Māori soldiers, as well as how the Army can be a career pathway for Māori and their whānau to flourish.
This research employs the use qualitative methods such as Kaupapa Māori theory, phenomenology, and pūrākau as a form of narrative analysis. Semi-structured interviews with five participants (three retired personnel and two currently serving) explores these factors that contribute to the flourishing of Māori soldiers in the New Zealand Army. Each pūrākau developed from interview data is an acknowledgment of the personal journeys of the five participants and contains philosophical thought, epistemological constructs, cultural codes, and worldviews (Lee, 2009).
The findings of the research highlight the complexities that arise when considering the health and wellbeing of Māori soldiers. A range of interconnected factors conceptualised within five themes contributes to participants’ ability to flourish. These five themes include hauora (health), whanaungatanga (relationships), manaakitanga (support), whanonga pono (values) and whakapāwera (hardships). These results suggest that flourishing for Māori personnel is complex, and there is not a simple route to enable Māori to flourish. There are many ‘trade-offs’ for Māori and their experiences. However, Māori service provides opportunities and obstacles for an individual, as well as their whānau, hapū and iwi.

text: Te mana o ngā toa: Māori experiences of Ngāti Tūmatauenga, the New Zealand Army Diverse realities impact Māori people and their capacity to flourish. It is well- established that Māori are significant contributors to the New Zealand Defence Force (NZDF), and especially the New Zealand Army. Noteworthy participation in major conflicts, especially WWI and WWII create a whakapapa of military tradition which contributed to institutional change within the Army in the 1990s. The inclusion of Māori cultural training in the New Zealand Army can contribute to morale and the effectiveness of the organisation (Hohaia, 2016). This master’s thesis aims to deepen understandings of the experiences of Māori personnel in the Army by exploring the role of the New Zealand Army in the health and wellbeing of Māori soldiers, as well as how the Army can be a career pathway for Māori and their whānau to flourish.
This research employs the use qualitative methods such as Kaupapa Māori theory, phenomenology, and pūrākau as a form of narrative analysis. Semi-structured interviews with five participants (three retired personnel and two currently serving) explores these factors that contribute to the flourishing of Māori soldiers in the New Zealand Army. Each pūrākau developed from interview data is an acknowledgment of the personal journeys of the five participants and contains philosophical thought, epistemological constructs, cultural codes, and worldviews (Lee, 2009).
The findings of the research highlight the complexities that arise when considering the health and wellbeing of Māori soldiers. A range of interconnected factors conceptualised within five themes contributes to participants’ ability to flourish. These five themes include hauora (health), whanaungatanga (relationships), manaakitanga (support), whanonga pono (values) and whakapāwera (hardships). These results suggest that flourishing for Māori personnel is complex, and there is not a simple route to enable Māori to flourish. There are many ‘trade-offs’ for Māori and their experiences. However, Māori service provides opportunities and obstacles for an individual, as well as their whānau, hapū and iwi.

year: 2022