Design, synthesis and evaluation of cyclothialidine analogues as DNA gyrase inhibitors

Cyclothialidine, a natural product isolated from Streptomyces .filipinensis NR0484, has been proven to be a potent and selective inhibitor of the bacterial enzyme DNA gyrase. Gyrase inhibition results in cell death, the enzyme being the target of several currently used antibiotics. Cyclothialidine showed poor activity against whole bacterial cells, highlighting scope for improvement regarding cell membrane pemeability in order for the full potential of this new class of antibiotics to be realised, Structurally, cyclothialidine contains a 12-membered lactone ring which is partly integrated into a pentapeptide chain, with a substituted aromatic moiety bordering the lactone, Retrosynthetically it can be traced back to cis-3-hydroxyproline, 3,5-dihydroxy-2,6-dimethylbenzoic acid and four commercially available amino acids; two serine, one cysteine and one alanine. In this work, a model of cyclothialidine was synthesised in order to establish the methodology for more complex compounds. Analogues with hydroxy, dihydroxy and dihydroxymethyl substituted aromatic moieties were then prepared to ensure successful protection methods could be performed and the pharmacophore synthesised. The key aromatic moiety, 2,6-dimethyl-3,5-dihydroxybenzoic acid was produced via two successive Mannich reaction/reduction steps. Acid protection using 4-nitrobenzyl bromide and TBDMS hydroxyl protection followed by bromination of one methyl afforded the desired intermediate. Reaction with a serine/cysteine dipeptide, followed by deprotection and cyclisation under Mitsunobu conditions lead to the 12-membered lactone. An amine substituted aromatic analogue and also replacement of the cysteine sulphur by oxygen were attempted but without success. In an effort to improve cell permeability, a conjugate was synthesised between the pharmacophore and a cholesterol moiety. It was hoped the steroid fragment would serve to increase potency by escorting the molecule through the lipid environment of the cell membrane. The pharmacophore and conjugate were tested against a variety of bacterial strains but the conjugate failed to improve activity.

Rationalisation and improvement of a company's engineering design procedures

There is a great deal of literature about the initial stages of innovative design. This is the process whereby a completely new product is conceived, invented and developed. In industry, however, the continuing success of a company is more often achieved by improving or developing existing designs to maintain their marketability. Unfortunately, this process of design by evolution is less well documented. This thesis reports the way in which this process was improved for the sponsoring company. The improvements were achieved by implementing a new form of computer aided design (C.A.D.) system. The advent of this system enabled the company to both shorten the design and development time and also to review the principles underlying the existing design procedures. C.A.D. was a new venture for the company and care had to be taken to ensure that the new procedures were compatible with the existing design office environment. In particular, they had to be acceptable to the design office staff. The C.A.D. system produced guides the designer from the draft specification to the first prototype layout. The computer presents the consequences of the designer's decisions clearly and fully, often by producing charts and sketches. The C.A.D. system and the necessary peripheral facilities were implemented, monitored and maintained. The system structure was left sufficiently flexible for maintenance to be undertaken quickly and effectively. The problems encountered during implementation are well documented in this thesis.

The role of industrial design in technological innovation

This is an exploratory study in a field which previously was virtually unexplored. The aim is to identify, for the benefit of innovators, the influence of industrial design on the commercial success of new science-based products used for professional and industrial purposes. The study is a contribution to the theory of success and failure in industrial innovation. The study begins by defining the terminology. To place the investigation in context, there is then a review of past attempts by official policy-making bodies to improve the competitiveness of British products of manufacture through good design. To elucidate the meaning of good design, attempts to establish a coherent philosophy of style in British products of manufacture during the same period are also reviewed. Following these reviews, empirical evidence is presented to identify what actually takes place in successful firms when industrial design is allocated a role in the process of technological innovation. The evidence comprises seven case studies of new science-based products used for professional or industrial purposes which have received Design Council Awards. To facilitate an objective appraisal, evidence was obtained by conducting separate semi-structured interviews, the detail of which is described, with senior personnel in innovating firms, with industrial design consultants, and with professional users. The study suggests that the likelihood of commercial success in technological innovation is greater when the form, configuration, and the overall appearance of a new product, together with the detail which delineates them, are consciously and expertly controlled. Moreover, uncertainty in innovation is likely to be reduced if the appearance of a new product is consciously designed to facilitate recognition and comprehension. Industrial design is an especially significant factor when a firm innovates against a background of international competition and comparable levels of technological competence in rival firms. The likelihood of success in innovation is enhanced if design is allocated a role closely identified with the total needs of the user and discrete from the engineering function in company organisation. Recent government measures, initiated since this study began, are corroborative of the findings.

Evaluating design implementation strategies using enterprise simulation

Concurrent engineering and design for manufacture and assembly strategies have become pervasive in use in a wide array of industrial settings. These strategies have generally focused on product and process design issues based on capability concerns. The strategies have been historically justified using cost savings calculations focusing on easily quantifiable costs such as raw material savings or manufacturing or assembly operations no longer required. It is argued herein that neither the focus of the strategies nor the means of justification are adequate. Product and process design strategies should include both capability and capacity concerns and justification procedures should include the financial effects that the product and process changes would have on the entire company. The authors of this paper take this more holistic view of the problem and examine an innovative new design strategy using a comprehensive enterprise simulation tool. The results indicate that both the design strategy and the simulator show promise for further industrial use. © 2001 Elsevier Science B.V. All rights reserved.

Improved production of industrially relevant recombinant proteins: application of multi-factorial design of experiments and scalable process modelling

The work described in this thesis focuses on the use of a design-of-experiments approach in a multi-well mini-bioreactor to enable the rapid establishments of high yielding production phase conditions in yeast, which is an increasingly popular host system in both academic and industrial laboratories. Using green fluorescent protein secreted from the yeast, Pichia pastoris, a scalable predictive model of protein yield per cell was derived from 13 sets of conditions each with three factors (temperature, pH and dissolved oxygen) at 3 levels and was directly transferable to a 7 L bioreactor. This was in clear contrast to the situation in shake flasks, where the process parameters cannot be tightly controlled. By further optimisating both the accumulation of cell density in batch and improving the fed-batch induction regime, additional yield improvement was found to be additive to the per cell yield of the model. A separate study also demonstrated that improving biomass improved product yield in a second yeast species, Saccharomyces cerevisiae. Investigations of cell wall hydrophobicity in high cell density P. pastoris cultures indicated that cell wall hydrophobin (protein) compositional changes with growth phase becoming more hydrophobic in log growth than in lag or stationary phases. This is possibly due to an increased occurrence of proteins associated with cell division. Finally, the modelling approach was validated in mammalian cells, showing its flexibility and robustness. In summary, the strategy presented in this thesis has the benefit of reducing process development time in recombinant protein production, directly from bench to bioreactor.

State-of-the-art in lean design engineering:a literature review on white collar lean

Lean is usually associated with the ‘operations’ of a manufacturing enterprise; however, there is a growing awareness that these principles may be transferred readily to other functions and sectors. The application to knowledge-based activities such as engineering design is of particular relevance to UK plc. Hence, the purpose of this study has been to establish the state-of-the-art, in terms of the adoption of Lean in new product development, by carrying out a systematic review of the literature. The authors' findings confirm the view that Lean can be applied beneficially away from the factory; that an understanding and definition of value is key to success; that a set-based (or Toyota methodology) approach to design is favoured together with the strong leadership of a chief engineer; and that the successful implementation requires organization-wide changes to systems, practices, and behaviour. On this basis it is felt that this review paper provides a useful platform for further research in this topic.

Design and evaluation of compound metformin/glipizide elementary osmotic pump tablets

A simple elementary osmotic pump (EOP) system that could deliver metformin hydrochloride (MT) and glipizide (GZ) simultaneously for extended periods of time was developed in order to reduce the problems associated with multidrug therapy of type 2 non-insulin-dependent diabetes mellitus. In general, both highly and poorly water-soluble drugs are not good candidates for elementary osmotic delivery. However, MT is a highly soluble drug with a high dose (500 mg) while GZ is a water-insoluble drug with a low dose (5 mg) so it is a great challenge to pharmacists to provide satisfactory extended release of MT and GZ. In this paper sodium carbonate was used to modulate the solubility of GZ within the core and MT was not only one of the active ingredients but also the osmotic agent. The optimal EOP was found to deliver both drugs at a rate of approximately zero order for up to 10 h in pH 6.8, independent of environment media. In-vivo evaluation was performed relative to the equivalent dose of conventional MT tablet and GZ tablet by a cross-study in six Beagle dogs. The EOP had a good sustained effect in comparison with the conventional product. The prototype design of the system could be applied to other combinations of drugs used for cardiovascular diseases, diabetes, etc.

Operando synchronous DRIFTS/MS/XAS as a powerful tool for guiding the design of Pd catalysts for the selective oxidation of alcohols

The selective aerobic oxidation of crotyl alcohol to crotonaldehyde was investigated by time-resolved synchronous DRIFTS/MS/XAS over silica and alumina supported Pd nanoparticles. Alcohol and oxygen reactant feeds were cycled through the catalyst bed while dynamic measurements of the palladium oxidation state, molecular adsorbates and evolved product distribution were made simultaneously on a sub-second timescale. Highly dispersed palladium nanoparticles remained in a partially oxidised state

Reactor design and its impact on performance and products

This chapter discusses engineering design and performance of various types of biomass transformation reactors. These reactors vary in their operating principle depending on the processing capacity and the nature of the desired end product, that is, gas, chemicals or liquid bio-oil. Mass balance around a thermal conversion reactor is usually carried out to identify the degree of conversion and obtain the amount of the various components in the product. The energy balance around the reactors is essential for determining the optimum reactor temperature and the amount of heat required to complete the overall reactions. Experimental and pilot-plant testing is essential for proper reactor design. However, it is common practice to use correlation and valid parameter values in determining the realistic reactor dimensions and configurations. Despite the recent progress in thermochemical conversion technology, reactor performance and scale up potential are the subjects of continuing research.

Decision-making in product quality based on failure knowledge

Decision-making in product quality is an indispensable stage in product development, in order to reduce product development risk. Based on the identification of the deficiencies of quality function deployment (QFD) and failure modes and effects analysis (FMEA), a novel decision-making method is presented that draws upon a knowledge network of failure scenarios. An ontological expression of failure scenarios is presented together with a framework of failure knowledge network (FKN). According to the roles of quality characteristics (QCs) in failure processing, QCs are set into three categories namely perceptible QCs, restrictive QCs, and controllable QCs, which present the monitor targets, control targets and improvement targets respectively for quality management. A mathematical model and algorithms based on the analytic network process (ANP) is introduced for calculating the priority of QCs with respect to different development scenarios. A case study is provided according to the proposed decision-making procedure based on FKN. This methodology is applied in the propeller design process to solve the problem of prioritising QCs. This paper provides a practical approach for decision-making in product quality. Copyright © 2011 Inderscience Enterprises Ltd.

Linking design and manufacturing domains via web-based and enterprise integration technologies

The manufacturing industry faces many challenges such as reducing time-to-market and cutting costs. In order to meet these increasing demands, effective methods are need to support the early product development stages by bridging the gap of communicating early design ideas and the evaluation of manufacturing performance. This paper introduces methods of linking design and manufacturing domains using disparate technologies. The combined technologies include knowledge management supporting for product lifecycle management systems, Enterprise Resource Planning (ERP) systems, aggregate process planning systems, workflow management and data exchange formats. A case study has been used to demonstrate the use of these technologies, illustrated by adding manufacturing knowledge to generate alternative early process plan which are in turn used by an ERP system to obtain and optimise a rough-cut capacity plan. Copyright © 2010 Inderscience Enterprises Ltd.

Motivations for servitization:the impact of product complexity

Purpose – The purpose of this paper is to identify the commonalities and differences in manufacturers’ motivations to servitise. Design/methodology/approach – UK study based on interviews with 40 managers in 25 companies in 12 sectors. Using the concept of product complexity, sectors were grouped using the Complex Products and Systems (CoPS) typology: non-complex products, complex products and systems. Findings – Motivations to servitise were categorised as competitive, demand based (i.e. derived from the customer) or economic. Motivations to servitise vary according to product complexity, although cost savings and improved service quality appear important demand-based motivations for all manufacturers. Non-complex product manufacturers also focus on services to help product differentiation. For CoPS manufacturers, both risk reduction and developing a new revenue stream were important motivations. For uniquely complex product manufacturers, stabilising revenue and increased profitability were strong motivations. For uniquely systems manufacturers, customers sought business transformation, whilst new service business models were also identified. Research limitations/implications – Using the CoPS typology, this study delineates motivations to servitise by sector. The findings show varying motivations to servitise as product complexity increases, although some motivational commonality existed across all groups. Manufacturers may have products of differing complexity within their portfolio. To overcome this limitation the unit of analysis was the strategic business unit. Practical implications – Managers can reflect on and benchmark their motivation for, and opportunities from, servitisation, by considering product complexity. Originality/value – The first study to categorise servitisation motivations by product complexity. Identifying that some customers of systems manufacturers seek business transformation through outsourcing.

New product development proficiency and multi-country product rollout timeliness

Purpose: The purpose of this paper is to address a gap in the understanding of the indirect effects of marketing and technical factors on time efficiency in developing a new product and international new product launch. Design/methodology/approach: This paper adopts a contingency perspective in examining the relationships between antecedents and on-time completion (or timeliness) of new product development (NPD) and international new product rollout (INPR). A conceptual framework is tested based on data obtained on 232 NPD projects undertaken by Korean firms. Findings: The results show that NPD proficiencies mediate to a greater or lesser extent the effects of key antecedents (e.g. cross-functional linkages, project fit with available marketing resources, and effective coordination of headquarters-subsidiary/agents' activities) on timeliness in NPD and INPR. Research limitations/implications: Empirical research on the role of marketing and technical proficiencies in improving NPD timeliness and rollout timeliness in the context of international NPD affirms the importance of adopting a contingency perspective in examining the antecedents of NPD and multi-market entry timeliness. Practical implications: This paper lends insight into the role of overseas subsidiaries or agents in helping to build the technical proficiencies of emerging country companies. Originality/value: This is the first review focusing on the mediating influences on time dimensions (e.g. timeliness) in multi-country product launches. © Emerald Group Publishing Limited.