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Acute Myeloid Leukaemia (AML) continues to have a poor prognosis, especially in the elderly. One reason for this is that many treatment regimens are not well tolerated by elderly patients. Much current focus is on the development of therapies that can target specific vulnerabilities of AML while having fewer toxic side effects. However, despite much recent progress in developing better drugs, many patients with AML still die within a year of diagnosis, partly due to the fact that it is difficult to identify therapeutic targets that are effective across multiple AML subtypes. One common factor across AML subtypes is the presence of a block in differentiation. Thus screening for compounds that can overcome this block in genetically diverse AML models should allow for the identification of agents that are not dependent on a specific mutation for their efficacy. Here, we used a phenotypic screen to identify novel compounds that stimulate differentiation in several AML cell lines. Lead compounds were shown to decrease tumour burden and to increase survival in vivo. Using multiple complementary target deconvolution approaches, these compounds were revealed to be anti-mitotic tubulin disruptors that cause differentiation by inducing a G2-M mitotic arrest. Together, these results reveal a novel function for tubulin disruptors in causing differentiation of AML cells.

The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematological malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of molecular modeling and optimization studies, the intrinsic potencies and molecular properties of this series of compounds was significantly improved. An excellent pan-PIM isoform inhibition profile was observed across the series, while optimized examples show good selectivity over other kinases. Two PIM-expressing leukemic cancer cell lines, MV4-11 and K562, were employed to evaluate the in vitro anti-proliferative effects of selected inhibitors. Encouraging activities were observed for many examples, with the best example (44) giving an IC50 of 0.75μM against the K562 cell line. These data provide a promising starting point for further development of this series as a new cancer therapy through PIM kinase inhibition.

We have recently introduced the term “stemistry” to describe the search for low molecular weight compounds, which are able to selectively modulate the behavior of resident stem and stemlike or progenitor cells within the tissues in which they exist. Such behavior includes manipulating their proliferation and differentiation to particular, new, cell types. It is envisaged that such agents would represent a totally new approach to the treatment of long-term degenerative disorders including cardiovascular disease, neurological disorders, diabetes, and macular degeneration. Existing treatments for these conditions are inadequate at best and involve significant levels of patient suffering and considerable costs to health systems throughout the world. This article reviews the evidence that this approach is feasible and indicates that the skills of medicinal chemists could make very significant contributions to the discovery and development of these agents.

This article analyses a study that reveals employees using humour to resist an organization’s normative control attempts via a ‘workplace justice’ program. In an interesting ‘doubling’, the program used excerpts from the television comedy The Office which were intended to provide clear examples of inappropriate workplace behaviour and foster consensual understanding. However, The Office can be read as a parody of the performativity of management, gender and political correctness, a reading that problematizes the organizational purposes and one exploited by employees to construct alternate interpretations. Analysis focuses on a number of intersecting areas centring on identity work and humour. Firstly, resistance to normative control and its presumed intrusions, with resistance manifest in the form of humour. Related to this are employee perceptions that the organization required the mere performance of ‘appropriate behaviour’ in conformance with politically correct, managerially fashionable and legalistically expedient expectations. This raises questions about performance, identity and authenticity. Secondly, identity work takes place within power, but operates through a series of plateaux: actions may act resistively in relation to a managerial/hierarchical plateau whilst at the same time acting to reproduce forms of heteronormative masculinity in a different, gender power plateau. Thirdly, the article examines the role of humour in the complexities of identity work and in relation to different frameworks of power. It further theorizes and illustrates the ambiguities of humour and its double-edged capacity to contribute to the maintenance of the status quo and the performance of power as well as its resistive and subversive potential.

A field study focused on a Western-led Corporate Social Responsibility (CSR) intervention into Pakistan’s soccer ball industry is used to explore the dynamics surrounding local Non-Governmental Organization (NGO) staff charged with implementation. Those dynamics include the post-colonial conditions pervasive in Third World contexts that frame the perception, interpretation, and reaction to Western interventions. NGO staff must navigate these conditions, which impel them into multiple subject positions and contradictory rationalities resulting in unsatisfactory experiences. Like many Western-led interventions resting on universalistic, paternalistic, de-contextualizing, and atomistic assumptions, this one brought negative unintended consequences. This leads to a suggested reconfiguration of CSR from a post-colonial perspective insistent on an inclusive ‘bottom-up’, ‘reversed engineered’ approach, wherein CSR problems are traced back to Western multinational corporations’ policies and practices.

A new paradigm for drug research has emerged, namely the deliberate search for molecules able to selectively affect the proliferation, differentiation, and migration of adult stem cells within the tissues in which they exist. Recently, there has been significant interest in medicinal chemistry toward the discovery and design of low molecular weight molecules that affect stem cells and thus have novel therapeutic activity. We believe that a successful agent from such a discover program would have profound effects on the treatment of many long-term degenerative disorders. Among these conditions are examples such as cardiovascular decay, neurological disorders including Alzheimer’s disease, and macular degeneration, all of which have significant unmet medical needs. This perspective will review evidence from the literature that indicates that discovery of such agents is achievable and represents a worthwhile pursuit for the skills of the medicinal chemist.

New pyrrolo derivatives of benzo[b]thiophene 1, 1-dioxide have been synthesised via 1, 3-dipolar cycloaddition reactions. Reaction of benzo[b]thiophene 1, 1-dioxide with stabilised azomethine ylides gave products in low yield but high stereoselectivity whereas reaction with non-stabilised azomethine ylides gave high overall yields but low stereoselectivity.

6-Oxiranyl- and 3-oxiranyl-2-phenylquinoline-4-carboxylic acid diisopropylamides react with secondary amines and lithium amides to give (aminohydroxyethyl)quinolines but with opposite regioselectivities. Upon epoxidation of 3-formylquinoline 2 a ∼5:1 mixture of atropisomers is formed. This ratio is maintained upon epoxide ring-opening with amines in ethanol at reflux, but with lithium amides at room temperature a 1.3:1 ratio of isomers is obtained.

The cyclin-dependent kinase inhibitor (R)-2-(6-benzylamino-9-isopropyl-9H-purin-2-ylamino)butan-1-ol (roscovitine, 1a), as well as its (S)-enantiomer 1b, were synthesised. The chemical structure and absolute configuration of both enantiomers was confirmed by X-ray crystallography. Furthermore, high enantiomeric excess (>98%) was demonstrated by chiral chromatography of 1a and 1b, as well as NMR analysis of the diastereomeric Mosher's ester derivatives 2a and 2b.

HR325 (2-cyano-3-cyclopropyl-3-hydroxy- N -[3′-methyl-4′(trifluoromethyl)-phenyl]-propenamide) is an immunomodulatory compound through pyrimidine biosynthesis inhibition with antiproliferative properties which was derived from the isoxazol compound A77 1726 [2-cyano-3-cyclopropyl-3-hydroxy-enoic acid (4-trifluoromethylphenyl)-amide]. During studies of the effects on early signal transduction events of this type of compound, it was found that HR325 dose-dependently inhibited adenosine 3′,5′-cyclic monophosphate (cAMP) synthesis by Jurkat cells stimulated with prostaglandin E 2 , (PGE 2 ), cholera toxin (CTX), or forskolin (FKN). The potency of inhibition by HR325 of FKN-stimulated cells ( ic 50 30.4 μM) was approximately 3-fold higher than that of the other agonists (11.6 and 11.7 μM) and was independent of time of preincubation for both PGE 2 and FKN. Interestingly, A77 1726, an analogue of HR325, displayed a markedly different profile of stimulus-dependent potencies. The inhibition of cAMP synthesis by HR325 when stimulated by both PGE 2 and FKN was unaffected by glucose supplementation, in contrast to HR325-inhibited ATP levels, which were restored under such conditions. Further studies revealed that HR325 reduced intracellular ATP levels by uncoupling oxidative phosphorylation, albeit with a 1000-fold lower potency than the antihelmintic drug niclosamide. In addition, glucose supplementation experiments showed that, in contrast to HR325, the niclosamide-mediated reduction of ATP levels was wholly responsible for its inhibition of PGE 2 - and FKN-stimulated cAMP synthesis.

Leflunomide is currently in phase-III clinical trials for the treatment of rheumatoid arthritis. In this study, we have focused our efforts on the study of the mechanism of action of the active metabolite of leflunomide, A77 1726, in cells and tissue of human origin. The human high-affinity binding protein for radiolabelled A77 1726 was purified from solubilized U937 membranes by following the binding activity through the purification process and was characterized as the mitochondrial enzyme dihydro-orotate dehydrogenase (DHO-DH). The human and murine enzyme displayed identical pI and molecular mass values on SDS/PAGE (43 kDa), which contrasts notably with previous reports suggesting a molecular mass of 50 kDa for the human enzyme. DHO-DH activity was inhibited by A77 1726 and its analogue HR325 with similar potency in U937 and human spleen membrane preparations. HR325 was found to be anti-proliferative for phytohaemagglutinin-stimulated human peripheral blood mononuclear cells, at the same concentrations that caused accumulation of DHO and depletion of uridine. Supplementation of the cultures with exogenous uridine led to partial abrogation of the anti-proliferative effect. This is in line with our recent demonstration that the anti-proliferative effect in vitro of A77 1726 on lipopolysaccharide-stimulated mouse spleen cells was mediated by DHO-DH inhibition [Williamson, Yea, Robson, Curnock, Gadher, Hambleton, Woodward, Bruneau, Hambleton, Moss et al., (1995) J. Biol. Chem. 270, 22467–22472]. Thus, DHO-DH inhibition by A77 1726 and its analogues is responsible for the anti-proliferative effects in vitro of the compounds on human cells and is likely to be responsible for some of its effects in vivo.

A protein with high affinity (Kd 12 nM) for the immunomodulatory compound A77 1726 has been isolated from mouse spleen and identified as the mitochondrial enzyme dihydroorotate dehydrogenase (EC 1.3.3.1). The purified protein had a pI 9.6-9.8 and a subunit Mr of 43,000. Peptides derived from the mouse protein displayed high microsequence similarity to human and rat dihydroorotate dehydrogenase with, respectively, 35 and 39 out of 43 identified amino acids identical. Dihydroorotate dehydrogenase catalyzes the fourth step in de novo pyrimidine biosynthesis. The in vitro antiproliferative effects of A77 1726 are mediated by enzyme inhibition and can be overcome by addition of exogenous uridine. The rank order of potency of A77 1726 and its analogues in binding or enzyme inhibition was similar to that for inhibition of the mouse delayed type hypersensitivity response. It is proposed that inhibition of dihydroorotate dehydrogenase is an in vivo mechanism of action of the A77 1726 class of compounds. This was confirmed using uridine to counteract inhibition of the murine acute graft versus host response.

This article argues that Islamic management and organization knowledge (MOK) is relatively under- and mis-represented in the literature. This conclusion is reached following a detailed literature survey and analysis which also examines some of the core representational practices used to account for Islam in the literature: the persistence of essentialism and orientalism; the disposition to refract instances of Islamic MOK through Northern lenses; and the tendency for some Southern scholars and institutions to become intellectually captive to the North’s knowledge system. We discuss this in the context of a politics of knowledge that bears on knowledge production and dissemination processes in MOK. This reveals continued intellectual and cultural imperialism, sustained Western hegemony, and the exclusionary practices of the North’s associated discourses and institutional frameworks that valorise and elevate Northern epistemology, theory and method, but devalues and marginalize alternatives. We argue that any neglect of Islam is unwarranted given (a) its global significance on a range of dimensions, (b) the particularities of its relations to the North—characterized by orientalism and Islamophobia and (c) the presence of a distinctive Islamic worldview, epistemology and ethics that informs practical action, including management and organization. This entails that an Islamic MOK offers prospects of an alternative or complement to the North’s orthodox perspective and is deserving of a proper voice in the literature. We conclude by offering practical suggestions for change.

The cycloaddition reactions of three cyclic imidate esters, 2-ethoxypyrrolin-5-one (6), 2-ethoxyisoindol-3-one (7) and 2-ethoxy-1H-indol-3-one (8) with various 1,3-dipoles were investigated. Dipolarophile 6 added only to nitrile oxides; 8 added to nitrile oxides and to nitrilimines; 7 failed to undergo cycloaddition reactions with either nitrile oxides or nitrilimines.

The cyclin-dependent kinase (CDK) inhibitor seliciclib (1, CYC202) is in phase II clinical development for the treatment of cancer. Here we describe the synthesis of novel purines with greater solubility, lower metabolic clearance, and enhanced potency versus CDKs. These compounds exhibit novel selectivity profiles versus CDK isoforms. Compound αSβR-21 inhibits CDK2/cyclin E with IC(50)=30 nM, CDK7-cyclin H with IC(50)=1.3 μM, and CDK9-cyclinT with IC(50)=0.11 μM; it (CCT68127) inhibits growth of HCT116 colon cancer cells in vitro with GI(50)=0.7 μM; and shows antitumour activity when dosed p.o. at 50mg/kg to mice bearing HCT116 solid human tumour xenografts.

2-Ethoxy- and 2-(ethylthio)-1-azetines readily undergo 1,3-dipolar cycloadditions with nitrile oxides and nitrile ylides to give stable 4,5-bicyclic cycloadducts. With nitrilimines, however, the expected 1,3-dipolar cycloadducts and/or unexpected ring-opened products, namely 1,2,4-triazoles, are formed depending on the nature of the nitrilimine N-substituent. In contrast, the azetines fail to react with nitrile sulphides, azomethine ylides, nitrones, aryl azides, and various dienes. X-ray crystallographic data on the nitrile oxide, nitrile ylide, and nitrilimine cycloadducts, and on the 1,2,4-triazoles, are presented. Also a mechanistic rationale for triazole formation is offered.

4,5-Dihydro-2-metyloxazole 1a and 4,5-dihydro-2,4,4-trimethyloxazole 1b, which are examples of cyclic imidate esters, undergo 1,3-dipolar cycloaddition reactions with benzonitrile N-oxide, to give the appropriate 5,6-dihydro-7a-methyl-3-phenyl-7aH-oxazolo[3,2-d]-1,2,4-oxadiazole (2a and 2b respectively). 4,5-Dihydro-2-methylthiazole 1c gives the thia analogue 2c. With alkanoyl and aroyl cyanide N-oxides (RCOCNO), 4,5-dihydro-2-methyloxazole 1a and 4,5-dihydro-2-methylthiazole 1c give the open-chain compounds, RCOXCH2CH2N(CN)COMe (X = O and S respectively).

The cycloaddition reactions of three cyclic imidate esters, 2-ethoxypyrrolin-5-one (6), 2-ethoxyisoindol-3-one (7) and 2-ethoxy-1H-indol-3-one (8) with various 1,3-dipoles were investigated. Dipolarophile 6 added only to nitrile oxides; 8 added to nitrile oxides and to nitrilimines; 7 failed to undergo cycloaddition reactions with either nitrile oxides or nitrilimines.

4,5-Dihydro-2-metyloxazole 1a and 4,5-dihydro-2,4,4-trimethyloxazole 1b, which are examples of cyclic imidate esters, undergo 1,3-dipolar cycloaddition reactions with benzonitrile N-oxide, to give the appropriate 5,6-dihydro-7a-methyl-3-phenyl-7aH-oxazolo[3,2-d]-1,2,4-oxadiazole (2a and 2b respectively). 4,5-Dihydro-2-methylthiazole 1c gives the thia analogue 2c. With alkanoyl and aroyl cyanide N-oxides (RCOCNO), 4,5-dihydro-2-methyloxazole 1a and 4,5-dihydro-2-methylthiazole 1c give the open-chain compounds, RCOXCH2CH2N(CN)COMe (X = O and S respectively).

Thermolysis, in boiling o-dichlorobenzene, of the cycloadducts 5 and 10a,b of diphenylcyclopropenone and 2-(alkylthio)azetines 4 and 9a,b yield the title compound 8.

Purpose Sapacitabine is an oral deoxycytidine nucleoside analog with a unique mechanism of action that is different from cytarabine. Patients and Methods To define the dose-limiting toxicities (DLT) and maximum-tolerated dose (MTD) of sapacitabine given orally twice daily for 7 days every 3 to 4 weeks, or twice daily for 3 days for 2 weeks (days 1 through 3 and days 8 through 10) every 3 to 4 weeks, in refractory-relapse acute leukemia and myelodysplastic syndrome (MDS). A total of 47 patients were treated in the phase I study that used a classical 3 + 3 design. Sapacitabine was escalated from 75 to 375 mg twice daily for 7 days (n = 35) and from 375 to 475 mg twice daily for 3 days on days 1 through 3 and days 8 through 10. Results The DLTs with both schedules were gastrointestinal. The MTDs were 375 mg twice daily for 7 days and 425 mg twice daily for 3 days on days 1 through 3 and days 8 through 10. The recommended phase II single-agent dose schedules were 325 mg twice daily for 7 days and 425 mg twice daily for 3 days on days 1 through 3 and days 8 through 10. Responses were observed in 13 patients (28%); four were complete responses, and nine were marrow complete responses. Conclusion Sapacitabine is a new, safely administered, oral deoxycytidine analog that has encouraging activity in leukemia and MDS. Phase II studies are ongoing.

In Chapter 2 we attempted to delineate the target for our critical interrogation and map the current intellectual terrain of ICCM. We identified a dominant discourse in ICCM in which particular modes of knowledge and the epistemologies and ontologies upon which they depend are valorized: a functionalist paradigm, positivist methods and Western interests. As with all discourses, there is an inclusionary/exclusionary power effect mirrored in the commitments and omissions we have explicated. The maintenance and sustenance of such a dominant discourse and intellectual orthodoxy is dependent, naturally, on a particular institutional frame. ICCM, as a discourse and as a domain of disciplinary and professional practice, has an elaborate institutional frame associated with it. This frame serves to manage and control the processes of knowledge production, dissemination and consumption for the field. It also constitutes mechanisms and practices that regulate the points and modes of entry, the nature and extent of participation, and the processes of evaluation, assessment, development and progression of persons, groups, other institutions and knowledges in the field. It is the nature and dynamics of that institutional frame, as it is presently constituted and enacted, that we examine in this chapter.

By the time we enter the 1980s, ICCM has become a significant subdiscipline within MOS, significant enough to suggest that something approaching a canon had emerged. By canon, we refer to: a) a set of core texts that are considered valid and referential within the field, and taken as (virtually) axiomatically central to it; b) a body of knowledge, methods and principles that are held to be valid and taken as a guiding frame for activity within the field; c) as a result of the preceding two, a set of boundaries that can be used to delimit or demarcate the field. The canon is built on the foundations established by Kerr and colleagues as well as other foundational figures such as Richman, Farmer, Haire, Abegglen, McClelland and others. However, it begins to coalesce more visibly and institutionally around the work of Hofstede following the publication of Culture’s Consequences in 1980. This represented a watershed (Boyacigiller et al., 1996); indeed for some, it is taken as the birth of cross-cultural management as a bone fide empirical field of study. We elect, however, not to focus directly on the Hofstede text here, principally because it is already so well known and has received more than adequate critical treatment in the literature (for example Ailon, 2008; Dorfman & Howell, 1988; Fougere & Moulettes, 2006; Kirkman, Lowe & Gibson, 2006; McSweeney, 2002; Sondergaard, 1994; Triandis, 1982).

The critical analyses presented in the previous two parts of the book suggest that ICCM can be viewed as Western and Eurocentric discourses that exhibit historical as well as contemporary resonance with what might broadly be labelled ‘the colonial project’. Part II located ICCM within the historical development of a political-commercial-military complex whose evolution links Europe’s erstwhile empires with present-day geopolitics. Part III identified and discussed the continuing presence of Orientalism and appropriating representational practices, as well as alternatives and resistances to these colonizing forms, in a selection of texts that formed part of an emerging ICCM canon. In sum, these two sections reveal a latent structure of domination in ICCM as a system of knowledge. In this final part of the book, we move on to ask where we can go from here.

To reiterate where we are, in Chapter 4 we argued that there is a historical debt to the colonial encounter within ICCM. Our field relies unwittingly on discourses of science, anthropology and earlier colonial commercial practices that were directly involved in the pursuit of formal European Empire. In Chapter 5, we looked at the changes to this complex of economic, political and military interests in the first half of the 20th century. We placed particular focus on the immediate post-World War Two period, when the US emerged as a world power enabled by a commercial-industrial complex. We demonstrated how selected foundational studies of ICCM were infused with the key contextual factors of the day, notably the Cold War and decolonization processes. This final chapter of Part II moves our temporal frame forward to the latter quarter of the 20th century. Whilst the two decades after World War Two were dominated by the institutional practices of modernization, industrialization and development, it might be said that a new paradigm for economic and cultural life emerged over the last three decades of last century: that of globalization. What is the nature of economic and cultural life under globalization? What, if anything, has changed or remained the same? And what implications might it have for our historicizing account of ICCM?

This chapter, and the one that follows, set out to demonstrate why a postcolonial interrogation of international and cross-cultural management is essential for its theoretical and political development. We will identify in ICCM the multiple parochialisms (contextual, quantitative, qualitative) that Boyacigiller and Adler found in organizational science. Consequently, we will argue that the field is marked by a lack of demographic and epistemic diversity, ineluctably embedded in the values and interests of the West (and more especially North America) and reproductive of a highly limited and limiting functionalist and positivist theory culture that eschews the possible development of a critical trajectory for theory development. The multiple resources of postcolonial theory can thereupon be used appropriately to guide us to different locations from which different questions might be asked by a greater diversity of voices from a greater number of positions about our domain of inquiry.

In Part I of the book, we set out our domain of interrogation and specified the contours of its topography. We sought to explicate the current location of that domain in terms of its contextual, quantitative and qualitative parochialisms. In these respects, we identified and critiqued the limited and limiting paradigmatic location of most ICCM research, the hegemonic practices and institutional structure by which its orthodoxy is sustained, and the resultant commitments and omissions. In the second part of the book, we examined the historical conditions in which science, anthropology and colonial commerce, key knowledge systems and material practices for the later development of ICCM, emerged. Our examination revealed the foundational significance of the colonial encounter, and thus the colonial legacies of ICCM as a modernist project, as well as the future configurations of these knowledge systems and material practices in the post-World War Two discourses of modernization, industrialization, development and globalization.

In the previous chapter we outlined and discussed the historical conditions of possibility, and thus the material and discursive precursors, of the fields of international and cross-cultural management: Western science, anthropology and imperial commercial and organizational practices. This chapter looks at how these knowledge systems became entwined and inter-related through the discourses of modernization, industrialization and development that emerged in the US post-World War Two period. We shall argue that these discourses reflected the manifold economic, military, political and cultural concerns of the United States, the new dominant power at this juncture in history. These contextual factors and associated discourses would find direct expression in the early classics of ICCM: Harbison and Myers’ (1959) Management in the Industrial World: An International Analysis, and Kerr et al.’s (1960) Industrialism and Industrial Man: The Problems of Labor and Management in Economic Growth. We offer a critical analysis of central aspects of these texts.

This book presents a critique of the related academic fields of international and cross-cultural management (ICCM) based on certain commitments, concepts and practices from postcolonial theory (PCT). Our core argument is that these academic management disciplines are Western and Eurocentric discourses (knowledge systems and associated institutional practices) that exhibit historical as well as contemporary resonances with what we might call ‘the colonial project’ — that is, the formal expansion, conquest and colonial occupation by Western European imperial powers of multiple nations in Africa, the Caribbean, Latin America, South and South-East Asia, and Oceania up to the late-19th and early- to mid-20th centuries. As a contemporary form of cultural imperialism, we will argue that the discursive workings of ICCM render the field limited demographically, skewed theoretically and generative of politically contentious effects on the manner in which researchers, students and practitioners of management across national and/or cultural borders are called to understand the values and behaviours of their various ‘Others’ (research subjects, managers, employees, customers, organizations and so on).

The preceding two chapters presented an analysis of a set of texts that form(-ed) part of an emergent canon of knowledge in ICCM. Our analysis illuminated a persistent series of ethnocentric, universalizing, essentializing and appropriating representational practices that very often rest upon and reproduce Orientalist tropes. The focus on Western and predominantly American texts may have conveyed the impression that the engagements with the Other in this corpus of work are unidirectional, homogeneous and monolithic and that the non-West has simply been a passive recipient of these practices and their effects. This is assuredly not the case. In what follows we give recognition to the fact that we are dealing with an engagement, an interaction, and not a unilateral relationship between centre and periphery. We therefore examine the nature and consequences of that engagement and the various modes of action/reaction that the non-Western Other, conceived as active agent, has adopted, or might adopt. Such actions/reactions might include inter alia: assertions of indigeneity; modes of hybridization; forms of mimicry; reappropriation and return; avoidance and isolationism; silence. In this chapter, we illuminate and provide a theoretical discussion of instances of these different responses to the representational practices of the Western centre, and thus consider their role in resisting, challenging, altering and/or subverting the cultural hegemony and the dominant power relations that support it. We turn first to theoretical matters.

We have argued that a radical transformation of ICCM is not merely a matter of methodological refinement, but also one of trenchant reconfiguration of the ontological, epistemological, ethical and political commitments of research practice in the field. Such a reframing is a necessary precursor to any reconsideration of methodology and methods. Given our assessment of the institutional present of ICCM in Chapter 3, it is apparent that any reconsideration of theoretical and methods commitments in ICCM needs to be supported at the institutional level. The field’s current institutional framework maintains and perpetuates the damaging modes of representation discussed in Chapters 6 and 7, and contributes simultaneously to the reproduction of the hegemony of Western knowledge systems. In this chapter, we address the possibilities of an alternative, more inclusive institutional frame that is compatible with the reconfigured commitments and alternate methods we have articulated. The central goal of this reconfiguration is to allow for the proper and effective inclusion of non-Western voices.

The observation that the imidazoquinoxaline ethyl ester RU32180 possessed an affinity of 175 nM for benzodiazepine (BDZ) receptors led to the discovery of several series of potent receptor ligands such as esters ofimidazoquinolines and imidazobenzothiazoles. The lack of oral activity shown by these esters was rectified in the benzoyl imidazoquinolne RU31719, which possessed nearly all the properties of a classical BDZ agonist but with reduced muscle relaxant activity. Structure-activity studies led to the benzoyl imidazoquinazoline RU32514 and from there to the imidazopyrimidine RU32698, which has robust anxiolytic activity, but induces little sedation and no muscle relaxation in a range of animal models. Further studies yielded the oxadiazolyl imidazopyrimidines such as RU33203, a potent partial agonist, and the thiazolyl imidazopyrimidine RU33356, the first member of the series to possess antagonist/inverse agonist properties.

General methods for the preparation of 3-substituted 5-aryl-1λ4,2,4-thiadiazine 1-oxides are described. The chemical properties of these new heterocyclic systems have been explored, for example their susceptibility to electrophilic and nucleophilic attack. The 3-bromomethyl derivative can undergo a base-catalysed ring expansion to a seven-membered thiadiazepine; some initial studies at generating fused bicyclic systems from these heterocyclic precursors are also reported.

Iminophosphoranes have been used in intramolecular aza-Wittig reactions to prepare pyrrolo[1,2-a]benzimidazoles, fused quinazolinones, quinolines, and an isoindolo[1,3,4]benzotriazepinone.