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The manipulation of inflammation, immunity and infection by novel derivatives of halichlorine

Blackshaw, Sasha (2017) The manipulation of inflammation, immunity and infection by novel derivatives of halichlorine. Doctoral thesis (PhD), Manchester Metropolitan University.


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Halichlorine 1 is a marine spirocyclic alkaloid, which has shown to exhibit anti-inflammatory properties.1 Due to the complexity of this structure, and the low abundance in nature, the development of total and partial syntheses of this compound have become of interest to the organic chemist. This project aimed to evaluate the therapeutic potential of this class of compounds by producing a library of simplified halichlorine derivatives by addition of Grignard reagents onto a key spironitrone that maps onto the core structure of halichlorine and thence to monitor potential bioactivity by conducting a series of biological assays to determine what effects these compounds have on human U937 cells. Addition of a wide range of Grignard reagents to spironitrone 128 was successful and generally proceed with high diastereoselectivity. In addition, reductive cleavage of the resulting N-hydroxyspirocycles with Zn/AcOH provided a host of N-acetyl-C7-substiuted spirocyclic derivatives 167-172. Reduction with indium provided free amines 173-181. As additions to spironitrone 128 proceeded with undesired stereoselectivity attempts were made to access O-protected spironitrone 204 by oxidation of spiroamines such as 199. This strategy was unsuccessful. In order to explore alternative spirocyclic derivatives, synthetic studies were also directed in attempts to access un-substituted derivatives by ring closing metathesis (RCM) of diene precursors 222-224. While RCM substrates were accessed cyclisation of these did not proceed. It was discovered that heating 6,5-spiroisoxazolidine 102 under pressure in a microwave reactor provided access to the corresponding 6,6-isomer 164 which maps onto the core structure of the amphibian toxin histrionicotoxin (HTX). Oxidation to 6,6-spironitrone 192, as followed by conversion to cycloadducts 193-195, which represent new analogues of the HTX family of alkaloids. Grignard additions to this nitrone, did not proceed in general. Biological screenings using undifferentiated and LPS activated U937 cells helped to identify a number of biologically active derivatives, when tested in the NO and growth and viability assays. The NO assay using LPS activated cells, identified that the adducts containing larger alkyl or aryl chains, particularly the pentyl, hexyl and benzyl adducts, expressed significant differences in NO inhibition at both 10-4 M and 10-5 M concentrations tested, compared to the untreated cells.

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