Synthesis, crystallography and biological activity of myo-inositol phosphates

The antioxidant property of myo-inositol hexakisphosphate is important in the prevention of hydroxyl radical formation which may allow it to act as a 'safe' carrier of iron within the cell. Here, the hypothesis that the recently discovered natural product, myo-inositol 1,2,3-trisphosphate represents the simplest structure to mimic phytate's antioxidant activity has been tested. The first synthesis of myo-inositol 1,2,3-trisphosphate has been completed, along with its X-ray structure determination and that of key synthetic intermediates. Iron binding studies of myo-inositol 1,2,3-trisphosphate demonstrated that phosphate groups with the equatorial-axial-equatorial conformation are required for complete inhibition of hydroxyl radical formation. myo-Inositol monophosphatase is a key enzyme in recycling myo-inositol from its monophosphates in the brain and its inhibition is implicated in lithium's antimanic properties. Current synthetic strategies require inositol compounds to be protected (often with more than one group), resolved, phosphorylated and deprotected to produce the desired optically active myo-inositol phosphates. Here, the synthesis of myo-inositol 3-phosphate has been achieved in only 4 steps from myo-inositol. The stereoselective addition of the chiral phosphorylating agent (2R,4S,5R)-2-chloro-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidin-2-one to a protected inositol intermediate allowed separation of diastereoisomers and easy deprotection to myo-inositol 3-phosphate. This strategy also allows the possible introduction of labels of oxygen and sulphur to give a thiophosphate of known stereochemistry at phosphorus which would be useful for the analysis of the stereochemical course of phosphate hydrolysis catalysed by inositol monophosphatase.

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.

The ecology of paper mill by-product and its evaluation as a casing medium in the culture of Agaricus bisporus (Lange) Pilat

Effluent from pulp and paper production at the Kemsley mill of Bowaters U.K. Paper Company Limited passes through two treatment stages before its discharge into the Swale estuary. Suspended material removed during treatment is deposited on wasteground as a thin sludge. The solids it contains are mainly wood components lost during pulp production, whilst it also has a high salt content, derived from chemicals used in pulping processes. After deposition the sludge undergoes an ageing process during which it dries out and its salt content is reduced. This ageing can be reproduced and accelerated by improved drainage under controlled conditions. The paper mill sludge was investigated as a casing medium in the culture of Agaricus bisporus (Lange) Pilat, the cultivated mushroom. It was unsuitable up to one year from deposition due largely to the inhibitory effect of its salt content on fruiting. Material eighteen months or more in age gave yields comparable to standard peat casing. Before use as a casing the material must be shredded to a satisfactory structure, neutralised with chalk, and pasteurised to eliminate organisms harmful to the crop. The prepared medium has a high water holding capacity and a structure resilient to management procedures, important requirements of a good casing. A passive movement of salts from the compost to the casing was shown to occur during culture, capable of enhancing the natural decline in cropping if sufficiently great. The ions chloride, potassium, sodium and sulphate were shown to be responsible, their damaging effects being due to high conductivity created in the casing. Studies of elements available during culture suggested phosphate availability in the compost could limit crop potential, whilst iron released by mycelium of A.bisporus in the casing may be utilised by associated micro-organisms.

Policy, economic federalism, and product market entry:the Indian experience

Productivity growth has long been associated with, among other things, contestability of markets which, in turn, is dependent on the ease with which potential competitors to the incumbent firms can enter the product market. There is a growing consensus that in emerging markets regulatory and institutional factors may have a greater influence on a firm's ability to enter a product market than strategic positions adopted by the incumbent firms. We examine this proposition in the context of India where the industrial policies of the 1980s and the 1990s are widely believed to be pro-incumbent and pro-competition, respectively, thereby providing the setting for a natural experiment with 1991 as the watershed year. In our analysis, we also take into consideration the possibility that the greater economic federalism associated with the reforms of the 1990s may have affected the distribution of industrial units across states after 1991. Our paper, which uses the experiences of the textiles and electrical machinery sectors during the two decades as the basis for the analysis, finds broad support for both these hypotheses.

Lessons from natural disasters, tsunami-affected Small and Medium-Sized Enterprises(SMEs) in Sri Lanka

The main objective of this paper is to identify some of the key issues encountered by tsunami-affected small and medium-sized enterprises (SMEs) in the process of rehabilitation and re-establishment in Sri Lanka. The second objective is to assess how far these affected industries have received various benefits and supports from bodies such as government agencies, private sector firms, donors and NGOs to help them get back into business. The final objective is to recommend policies and strategies to develop the tsunami-affected SMEs in a self-sustaining manner and within a certain time period. The main database of firms for this research has been obtained from the Industrial Development Board, which conducted a survey covering 4,389 tsunami-affected micro- and SMEs. In addition to this, information from various state organizations and NGOs-based sources has been used. This paper identifies the main issues related to tsunami-affected SMEs ranging from basic infrastructure provision up to finance, marketing, machinery, technology, training, product identification and development and so forth. In fact, it is shown that there are no significant differences between issues faced by SMEs in general and tsunami-affected SMEs, apart of course from the effects of a sudden disaster (the tidal wave). Consequently, these issues can be generalized as issues relevant to SMEs in Sri Lanka as a whole. However, under the flood and rain of local and foreign assistance, there have been more pledges and promises than actual deliveries and, so, tsunami-affected SMEs have received comparatively little support and assistance in recovering and no records can be found as to where the colossal amount of foreign assistance received has actually gone. Finally, this paper recommends various types of business incubator centres and entrepreneurial enhancing skill programmes for the revamping of tsunami-affected SMEs in addition to the normal disaster risk management plan.