Teachers are the motivating force and role models for many learners in our schools around the country. They take on the role of teacher, parent, diplomat, doctor, police officer, confidant, nanny, disciplinarian and moral compass, among other roles. They are vilified and slated in our media and are often the scapegoats for perceived ills, real or otherwise, found in our schools, to the detriment of the image of the profession. This is especially true where teachers and schools do not have a clear direction and clarity on what their duty of care is as regards truancy, safety and the pastoral role towards learners in our schools. Legislation provides a legal framework for this study, starting with the Constitution of the Republic of South Africa, and the legal dimensions include the Bill of Rights, various legislative Acts, common law and case law, with terms such as the in loco parentis principle also included, which govern the teacher’s duty of care for learners. The duty of care places an obligation on the teacher in a legal sense through the duty imposed by law, and in the professional sense through the expectation placed on the teacher through the employment contract that the teacher has with the Department of Basic Education. The literature suggests that truancy of learners has many causes and that teachers could be a contributing factor to the causes. Several contributions have been made regarding safety and discipline of learners in schools in South Africa. However, not much appears to have been done in this country to determine the causes of truancy and whether teachers have an influence on its occurrence in schools. The relevant literature further suggests that the social aspects that influence truancy are not clear. The question arises whether teachers should interrogate the social aspects to determine their influence on a case of truancy. The purpose of this study was therefore to determine the legal interpretation of the teachers’ duty of care with regard to truancy of learners. A qualitative approach was used for the study. Semi-structured interviews were conducted at schools and with a lawyer and a judge to determine how they view this duty of care in schools, whether pastoral care is practised, and if teachers realise the extent of the law as regards negligence, and their duty as regards truancy especially. The interpretive paradigm would, through the semi-structured interviews, reveal how schools view the duty of care and pastoral care, as well as truancy in schools. The main causes and the extent of truancy in schools, the guidance and support that teachers can expect from the Department of Education to fulfil the seven duties or roles that are expected from teachers in the National Education Policy Act (1996), as well as the common-law duty of in loco parentis, would become clearer. The interviews provided data that no person is above the law and that ignorance of the law is no excuse. The study could be helpful to schools, the Department of Education and universities that train teachers, to include more training on specific issues and case studies involving education law and the duties of teachers, from both a legal and a professional perspective. The Department of Basic Education could find it helpful in monitoring and control at schools about matters involving discipline, safety and care of learners, and the duties of teachers at schools. Although teachers may know something about the duty of care or have heard about it, they are in the dark regarding the interpretation of the legal requirements and the repercussions that could flow from that duty. The second conclusion is that pastoral care appears to be doing well in schools although teachers are under pressure with the implementation of the new syllabus. The third conclusion is that truancy is rife in high schools and that two of the causes, drugs and pregnancy, are chiefly to blame for it and must be addressed. Fourthly, the social structure and the environment in the family should be looked into to try to reduce truancy. The study provides a legal interpretation of the teacher’s duty of care owed to learners, specifically regarding truancy and its causes. It will mean making a contribution to the body of knowledge that will include, but not be limited to, the insight gained by a look into the life world of the teacher regarding learner truancy, as well as taking a factual journey through the courts, discussing cases brought before them. # Onderwysers dien as rolmodelle en bron van motivering vir baie leerders in ons skole landwyd. Hulle vervul die rol van onderwyser, ouer, diplomaat, dokter, polisiebeampte, vertroueling, kinderoppasser, tugmeester en morele kompas, om maar ʼn paar te noem. Hulle word dikwels in die media swart gesmeer, gekritiseer en as sondebokke voorgehou vir gewaande of werklike ongerymdhede wat in ons skole plaasvind, baie keer tot nadeel van die beeld van die beroep. Dit kom veral voor wanneer onderwysers en skole nie duidelike leiding het oor wat hulle sorgsaamheidsplig is rakende stokkiesdraai, veiligheid en hul pastorale rol teenoor leerders in ons skole nie. Wetgewing voorsien ʼn regsraamwerk vir hierdie studie. Dit begin by die Grondwet van die Republiek van Suid Afrika wat die Handves van Menseregte omvat, en sluit in verskillende ander wette sowel as die gemene en regspraak. Die wetgewing inkorporeer konsepte soos die in loco parentisbeginsel, wat die sorgsaamheidsplig van onderwysers jeens leerders omskryf. Die sorgsaamheidsplig plaas ‘n regsverpligting op die onderwyser kragtens die wetgewing, tesame met die beroepsvereistes van die dienskontrak met die Departement van Basiese Onderwys. Die literatuur dui daarop dat daar talle redes is waarom leerders stokkies draai en dat onderwysers moontlik ‘n bydraende faktor kan wees. Verskeie bydraes is gelewer ten opsigte van die veiligheid en dissipline van leerders in skole in Suid-Afrika. Dit wil egter voorkom asof daar nog nie veel in die land nagevors is om die oorsake van stokkiesdraaiery te bepaal en of onderwysers ‘n invloed op die voorkoms daarvan in skole het nie. Die betrokke literatuur dui verder daarop dat die sosiale aspekte wat stokkiesdraaiery beїnvloed, nie duidelik is nie. Die vraag ontstaan nou of onderwysers sosiale aspekte moet ondersoek om hulle invloed op ‘n stokkiesdraai-geval te bepaal. Die doel van die studie was om die wetlike interpretasie van die sorgsaamheidsplig van onderwysers teenoor leerders wat stokkiesdraai, te ondersoek. ‘n Kwalitatiewe benadering is gebruik vir hierdie studie. Semi-gestruktureerde onderhoude is gevoer by skole en met ‘n regsgeleerde en ‘n regter om te bepaal wat hulle opvatting van die sorgsaamheidsplig in skole is, of pastorale sorg toegepas word en of onderwysers besef wat is die omvang van die wet ten opsigte van nalatigheid en spesifiek hulle plig ten opsigte van stokkiesdraaiery. Hierdie interpretatiewe paradigma bepaal, deur middel van die semi-gestruktureerde onderhoude, wat skole se opvattings van die sorgsaamheidsplig en pastorale sorg is, en ook jeens stokkiesdraaiery in skole. Dit kan ook lig werp op watter leiding en ondersteuning onderwysers van die Onderwysdepartement kan verwag om die sewe pligte of rolle van onderwysers wat in die Wet op Nasionale Onderwysbeleid (1996) omskryf word, te kan vervul, asook die gemeneregsplig van in loco parentis. Die onderhoude lewer ook data op wat aantoon dat geen mens bo die reg verhewe is nie en dat onkunde aangaande die reg nie ‘n verskoning is nie. Hierdie studie behoort nuttig te wees vir skole, die Onderwysdepartement en universiteite wat onderwysers oplei, om meer opleiding te verskaf oor spesifieke aspekte en gevallestudies aangaande onderwysreg en die pligte van opvoeders vanuit beide ʼn regsoogpunt en ʼn professionele oogpunt. Die Departement van Basiese Onderwys kan dit nuttig vind in monitering en beheer by skole met betrekking tot dissipline, veiligheid en sorg van leerders, en die pligte van onderwysers by skole. Dit blyk dat, alhoewel onderwysers moontlik iets weet of al gehoor het van die sorgsaamheidsplig, hulle min weet van die wetlike vereiste en die uitwerking daarvan op die plig. Die tweede gevolgtrekking is dat pastorale sorg in skole oënskynlik goed toegepas word alhoewel onderwysers onder druk verkeer met die uitvoering van die nuwe kurrikulum. Die derde gevolgtrekking is dat stokkiesdraaiery algemeen voorkom in die hoërskool en dat dwelms en swangerskap twee hoofoorsake is wat aandag moet kry. Vierdens, moet die sosiale struktuur en die gesinsomgewing ondersoek word om stokkiesdraaiery te probeer verminder. Hierdie studie verskaf ‘n wetlike vertolking van die sorgsaamheidsplig van onderwysers teenoor leerders, spesifiek rakende stokkiesdraai en die oorsake daarvan. Dit lewer ook ‘n bydrae tot die korpus van kennis, onder meer oor die insigte wat die ondersoek verleen in die lewenswêreld van die onderwyser teenoor leerders wat stokkies draai. Ten slotte onderneem dit ‘n feitlike reis deur sommige hofsake oor hierdie kwessie. / Thesis (PhD)--University of Pretoria, 2013. / lk2014 / Education Management and Policy Studies / PhD / Unrestricted

This thesis entitled “Design and Access to Disallowed and Unusual Conformers of Peptides in Crystals and in Solution: Structural Consequences of the Imidate and Thioimidate Isosteres for the Peptide bond” is divided into eight chapters. Imidate Modification The range of disallowed dihedral angles for residues in peptides is governed by their local steric and electrostatic clashes. Rare tolerances of violations in these angles are attributed to distortions in both local and global bond characteristics of the peptides. Discerning the origins of such disallowed angles and the consequent distortions in body of the peptides is essential, for a complete understanding of the protein fold, to improve the crystal database for validation of rare but acceptable residue conformations and for validation and improvement of theoretical models that evaluate the interactions that define the Ramachandran space. Unlike for the ordered secondary structures such as β-sheets α-helices and β-turns currently there are no models for residues constrained in disallowed folds. We reasoned that residues may be stabilized in disallowed folds in peptides if a neighbouring group and The range of disallowed dihedral angles ( , ψ) for residues in peptides is governed by their hence its local unfavorable clashes can be selectively modified to a motif that favors such space Steric clashes of the type H•••Xi±n involving the backbone amide hydrogen (H) contribute to ~60% of disallowed ,ψspace. Conversion of an amide to an imidate (A→I) will remove the corresponding H and hence the steric clashes related to it in peptides. Importantly, this will introduce an H-bond acceptor N (of imidate) in place of an H-bond donor NH (of amide), which will allow formation of unusual H-bonding interactions between the imidate N and the neighbouring Hs and hence constrain residues in otherwise inaccessible dihedral angles. The conversion of A→I is challenging owing to difficulties in selective synthesis, stability and purification of the imidate motif. We address all these concerns by the selective conversion of a backbone amide in peptides to the relatively stable cyclic 5,6-dihydro-4H-1,3-oxazine imidate isostere, by an intra¬molecular nucleophilic cyclo-O-alkylation reaction. Chapter 1:SectionB: Autocyclo-O-Alkylation of N-(3-Bromopropyl)amides into 2-Alkyl-5,6-Dihydro-4H-1,3-Oxazinehydrobromides We are describing the reactivity of N-(3-bromopropyl)amides that are precursors for 2-peptide-5,6-dihydro-4H-1,3-oxazine. The starting materials, 3-bromopropylamides, were synthesized in good yields by coupling the corresponding carboxylic acids and anhydrides with 3-bromopropylaminehydrobromide using standard mixed anhydride peptide coupling protocol. N-(3-bromopropyl)-acylamides are unstable during the isolation. Time-dependent 1H NMR of all the acetamides revealed that they underwent clean auto-cyclization to form the corresponding 2-alkyl-5,6-dihydro-4H-1,3-oxazine hydrobromides following first order rate. The salts were easily isolated in high purity by trituration of the mixtures with ether. The t1/2 of autocycliation of decreased upon increase in electron density on the R-carbon. Notably, the tert-butyl substituent cyclized significantly faster than acetamide which have enolizable hydrogens at the R-carbon. Thus, the cyclization rate is affected predominantly by the inductive effect of the R-carbon substituents. The formamide remained stable and unchanged due to the poor electron-donating ability of hydrogen. Chapter 1: Section C: Intramolecular Hydrogen Bond Assistance Improves Autocyclization in N-(3-Bromopropyl)amides The autocyclisation do not go to 100% completion. This is because the released hydrobromic acid quenches the nucleophilicity of amide carbonyl oxygen. In order to scavenge hydro bromic acid, we used 1 equivalent of DIEA base is acting only acid scavenger which conformed by unaffecting the reaction rate upon increasing equivalents of DIEA. We found that autocyclisation of N-(3-bromopropyl)amides rates in peptides involved in intramolecular backbone H-bonding interactions improve the autocyclization rates significantly than unstructured (random coil) peptides. Even with in the ordered structures the rate depends on the proximity of H-bonding distances as well as the H-bond acceptor strength. Half-life of autocyclisation in various peptide secondary structures are determined from time variant 1H NMR studies performed at 60 mM peptide concentration in CDCl3 at 32 oC. Chapter 2: Section A: Synthesis and Isolation of 5,6 Dihydro-4H-1,3-Oxazine Containing Peptidomimetics We have introduced 5,6-Dihydro-4H-1,3-oxazine as the imidate isostere at C-terminus of a number of peptides through NaH (base) mediated intramolecular cyclo-O-alkylation of N-(3-bromopropyl)amides. The amide to imidate (A→I) modification reaction is faster (1-5.5 h), Exhibiting no electronic and structural effects under these conditions. The side product NaBr can be easily separated by filtration through celite. No side products were observed and there is no need of further purification to get pure 1,3-oxazines in quantitative yields in all the peptidomimetics. Using this synthetic protocol we have synthesised a variety of 1,3-oxazine containing peptide analogues including aliphatic, branched aliphatic, polar side chains and larger peptides. We show that the retention of configuration at Cαof peptides during the base mediated cyclo-O-alkylation reaction. that the C5i.structures are more populated at Aib due to operation of The Thorpe-Ingold effect. The strength of hydrogen bonding interaction in C5i structure is similar to those of the highly buried backbone hydrogen bonding interaction found in the middle of a model 310-helical peptide as indicated by DMSO titration experiments. Chapter 3: Section A: Consequences of "Disallowed" Conformations on Constrained β-Turn Peptides Here we are describe the consequence of disallowed conformations the on a C-terminus of a type-II β-turn. We choose stereochemically constrained Type-II β-turn Pro-Aib dipeptide analogue which is the ideal model to mirror the structural effects of introducing the A→I modification at the C-terminus. The imidate containing peptidomimetic crystallised in dichloromethane and hexane mixture. Analysis of crystal structure revealed that Aib NH is involved in 3-centered H-bonding interactions with the N of oxazine and N of proline. This constrains Aib in a conformation that is natively disallowed to it. The (, ) angles of Aib residue fall in the (180,0) region which is strictly disallowed for natural peptides due to steric clashes involving the back bone amide N-H. More importantly there are two C•••O interactions which are accomidated in the crystal structures. Both oxygen‟s were place in staggered orientation of the Pro oxygen (OPro) between the two β-CH3 groups of Aib, which is again strictly disallowed in natural peptides due to strong C•••Oi-1 hard sphere clashes. However no vdW space violations are observed between these atoms. Chapter 3: Section B: Conformational Effects of “Disallowed Aib on a 310-Helical peptide In order to investigate the origins and consequences of “disallowed” conformations on a folded helical peptide body, the conformationally stable peptide sequence Boc-Leu1-Aib2-Ala3-Leu4-Aib5-Ala6-Phe7-Aib8-OMe (310-helix-OMe)was chosen which is known to adopt 310-helix in crystal structure. Analyses of the ROESY spectra, DMSO titration experiments, and CD spectra of 310-helix-OMe and its Oxa analogue reveal that their solution conformations are identical to those of the crystal structure of 310-helix-OMeSix sequential i+3→i intramolecular backbone H-bonds stabilize the 310-helical peptide fold in both peptides in solvents of varying polarity. The N-terminal and central segments of the helical molecules are quite structurally rigid and are not deformed. The presence of the disallowed Aib*8 residue in Oxa analogue has a clear conformational effect mainly on the residue Phe7. It looks like the Phe7 amide H is involved in shielding, the Aib*8 amide H through a bifurcated hydrogen bonding interactions with the nitrogen of oxazine and carbonyl oxygen of Ala6 residue. Maximum structural distortion effect on the registers closest to the putative imidate bond. Our results show that “disallowed folds need not denature order in the peptide fold”. Chapter 4: Synthetic Methods for Introducing the A → I Modification anywhere along the Peptide Chain Here we describe the incorporation of imidate isostere in the middle of any peptide sequence. In Oxa selectivity is towards 5-exo-cyclo-O-alkylation in 1 : 4. In Thi it is towards 6-exo-cyclo-S-alkylation in 3 : 1 ratio. This is because of better nucleophile of sulphur (S). We saw that Thi is stable to peptide coupling, N-and C-terminus protection, deprotection conditions and can be easily incorporated in middle of peptide. Chapter 5: Section A: Cis-trans Isomerism in the X-Pro Peptide Bond In tertiary amides like X-Pro peptides having high propensity to access cis conformations due to similar environment in both cis and trans around the Cof X. X-Pro peptide bonds, constrained in s-cis conformations are prevalently found in the turn regions of peptides with the residue „X‟ in the i+1position and Pro at the i+2position of the β¬turn. These types of turns are termed as the type VI β-turns. For better understanding of the molecular recognition at specific cis X-Pro peptide bonds in biological events, the structure and dynamics of various constrained cis X-Pro peptide bond analogues with varying steric and electronic perturbations have been studied. Many models have been developed for stabilizing cis conformer by perturbation of molecular recognition surface of proline by employing steric and electronic interaction. In biological functions proline molecular recognition surface and cis X-Pro peptide bond more important. There is need of novel method for stabilizing X-Pro peptide bond in cis conformer without modifying the pyrolidine ring in proline. Chapter 5: Section B: Biasing the cis/trans Equilibrium in X Pro Peptides using Reverse ni → ni-1 * Interactions Here we present our findings that peptidomimetics containing the 5,6-dihydro-4H-1,3¬oxazine (Oxa) and 5,6-dihydro-4H-1,3-thiazine (Thi) functional groups at the C-terminus of Pro selectively and remotely stabilize the s-cis rotamers of the preceding pyrrolyl (Xaa-Pro) 3° amide bonds, while conserving these recognition elements. The cis/trans equilibrium of Xaa-Pro peptide bonds is shifted significantly in favor of the satirically disfavored cis isomers in these peptidomimetics (upto ~90%). We also provide evidence for the influence of an unusual n→ πi-1 * interaction in the cis, and the n)(n repulsion in the trans, conformers of these molecules to beat the origin of such the origin of such cis stabilization. Chapter 6: Steric Interactions in the cis Piv-Pro Peptide Bond The inaccessibility of cis Piv-Pro rotamer in any peptide is believed to be because the steric clashes between substituents on CX and CPro are unavoidable in this conformer. Here we access the cisPiv-Pro conformer in crystal structure of Piv-Pro-Aib-OMe and that it is sufficiently flexible to undergo bond distortions and avoid all steric clashes between substituents on CPiv and CPro . It is however the unavoidable distortions in the dihedral angle of the Prothe cisPiv-Proconformer. The cisPiv -Pro conformer is indeed accessible, if such distortions are accommodated in the peptide. Chapter 7: Steric and Electronic Interactions in the cis Isomer of Piv-Pro Peptide Bond in Solution We have studied the electronic and steric interactions and the conformational equilibrium in two sets of homologous peptides, X-Pro-Aib-OMe (which contain Aib) and X-Pro-NH-Me, where X is acetyl, propionyl, isobutyryl and pivaloyl, in solvents of varying polarities consisting of carbontetrachloride, chloroform or dimethylsulfoxide, by means of their 1H and 13C-NMR, and FT-IR spectra. Formation of n * interactions between the carbonyls that flank the Aib residue, influences the alleviation of steric interactions that are believed to preclude access to the cis conformer of the Piv-Pro peptide bond. The cis Piv-Pro conformer is observable in the Aib containing peptides, at ambient conditions by FT-IR and at temperatures as low as 273 K by NMR. We estimate that the steric interactions contribute < 0.5 kcal/mol to the conformational free energy of X-Pro peptide bond isomerism, irrespective of the steric bulk on the acyl (X) group. The relative strengths of intramolecular hydrogen bonding interactions involving the X-Pro peptide motif in different conformers of these peptides influence their relative conformational stabilities. Chapter 8: Remote Effect of Oxa and Thi Functional Groups on cis-trans Isomerism at X-Pro Peptide Bonds The C5a interaction at Pro residue occurs in the transition states for the intramolecular acid catalysis of cis → trans isomerization in peptidyl prolyl isomerases (PPIs) and enables the decrease in transition energy barrier for the isomerization process. We show that the NPro….HAib interactions in C5a structures can be remotely effected in order to control in equilibrium constant values of the cis/trans isomerism (Kc/t) in X-Pro¬Aib-Oxa and Thi containing peptides. By this method we observed improvement in Kc/t values from 0.18 in esters to 0.56 in Thi and 0.66 in Oxa containing peptides. Analyses of the ROESY spectra, DMSO titration experiments, variable temperature experiments and FT-IR spectra of R-CO-Pro-Aib-Oxa (R = Me, Et, iPr) and its Thi analogues reveals that both interactions (C5a and C5i) are persistent in cis and trans conformers of this peptidomimetics. (for structural formula pl. see the abstract.)