Research into the synthesis and biological properties of the cyclopentenone prostaglandins has become the focus of many research groups over the past few years. The ability for cyclopentenone prostaglandins, for example prostaglandin AI. to reduce virus yields and inflammation, both in vitro and in vivo, and to act as anticancer agents in vitro has made them important biological targets. o .••",~COOH OH prostaglandin Al In view of this, a great deal of work is currently being undertaken towards the preparation of cyclopentenone prostaglandin analogues, in the hope of harnessing the innate biological activity of this system. Part of the ongoing research into the cyclopentenone prostaglandins is the work currently being undertaken at The University of Liverpool, and this Ph.D. thesis is part of the contribution made by the Roberts' group. This thesis begins with an introductory section, Chapter 1, outlining the background and biological properties of the natural prostaglandins, along with examples of their chemical syntheses and some of the work carried out on other, related cyclopentenone-based natural products. Chapter 2 goes on to elaborate upon the biological results obtained during the course of this Ph.D., the synthesis of various prostaglandin analogues and the discussion of these results. The latter part of Chapter 2 describes the synthesis and ultimately the revision of stereochemistry of a natural product isolated from ascomycete strain A23-98. It has been shown that a-iodo-cyclopentenone 160, generated in 7 steps from Dribose, can undergo a palladium-catalysed Stille reaction, followed by deprotection of the masked diol, to reveal the natural product syn-163. n-ribose steps i) (PhCNhPdCI2' CuI, AsPh] HO""' ..~ -~ HO,)JT~ syn-l63 (Z)-tributylpropenylstannane 160 ii) PPTS, MeOH Following the synthesis it was subsequently discovered that the geometry of the sidechain is cis, as shown in syn-163, and not trans as proposed by NMR studies and correlation to similar natural products. Finally, Chapter 3 describes the experimental details associated with the compounds prepared throughout this thesis, followed by a reference section giving relevant citations in the chemical literature.

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New methods were developed to produce thiolated analogues of Mycobacteria components. Thiolated tuberculostearic acid, (S)-18-mercapto-l O-methyloctadecanoic acid, was firstly produced in seven steps in an overall yield of 7.6 %. This was followed by the first synthesis of a thiolated simple mycolic acid, the disulfide, ((2R,2' R,3R,3' R)- 2,2' - (disulfanediylbis(tetradecane-14, I-diyl))bis(3-hydroxyhenicosanoic acid, in 11 steps in an overall yield of 2.6 %. The first synthesis of a thiolated u-rnethyl-zrcns-cyclopropane methoxy mycolic acid was also achieved using the newly developed methods with the thiol introduced at two different positions within the molecule. (S,S,S,R,S,R,2R,2R')-26-26'- Disulfanediylbis(2-((R)-I-hydroxy-19-((1 S,2R)-2-((2S, 19S,20S)-19-methoxy-20- methyloctatriacontan-2-yl)cyclopropyl)nonadecyl)hexacosanoic acid, which includes the thiolated disulfide at the end of the a-alkyl chain, was synthesised in 18 steps from synthetically prepared starting materials in an overall yield of2.6 %. (S)-2-((S)-I-Hydroxy- 19-((1R,2S)-2-((2R, 19R,20R)-19-methoxy-20-methyloctatriacontan-2- yl)cyclopropyl)nonadecyl)-N-(2-((2-((R)-2-((R)-I-hydroxy-19-((IS,2R)-2-((2S, 19S,20S)- 19-methoxy- 20-methyloctatria-contan- 2- yl)cyclopropyl)nonadecyl)hexacosanamido )ethyl)disulfanyl)ethyl)hexacosan-amide, which contais a thiolated linker on the carboxylic acid, was synthesised in two steps from the free synthetic mycolic acid in an overall yield of 8.7 %. The different methods attempted for the formation of the thiolated analogues are discussed. To attempt to maximise the inhibitory effect of sterculic acid against Plasmodium falciparum /19 desaturase, which is essential for parasite growth, analogues of sterculic acid were designed and synthesised. 7-(2-0ctyl-cycloprop-l-enyl)-heptanoic acid methyl ester and 9-(2-octyl-cycloprop-l-enyl)-nonanoic acid methyl ester which contain one more and one less carbon atoms than sterculic acid in their chain lengths respectively were both synthesised in five steps in overall yields of 8 % and 4.6 % respectively. (±)-8-Methoxy-8- (2-octyl-cycloprop-l-enyl)-octanoic acid methyl ester was subsequently synthesised in three steps in an overall yield of 36 % whilst (±)-8-hydroxy-8-(2-octyl-cycloprop-l-enyl)- octanoic acid methyl ester was also synthesised in three steps in an overall yield of 25 %. In four steps both (± )-8-(tert-butyldimethylsilyloxy)-8-(2-octyl-cycloprop-l-enyl)-octanoic iii acid methyl ester and (±)-8-acetoxy-8-(2-octyl-cycloprop-I-enyl)-octanoic acid methyl ester were synthesised in an overall yield of 22.7 % and 34.9 % respectively. The inhibitory effects of these analogues were investigated.

A new simplified particle-based computer model for hydrated phosphohpid bilayers is presented. In the model, each lipid molecule, in reality comprising more than one hundrec atoms, is reduced to a collection of ten "'coarse-grain'' macrounits. Compared with available arse-grain methods, three novel aspects are introduced. First, electrostatics are explicitly incorporated via charges and dipoles. Second, water is accurately (yet efficiently) described, on an individual level, by the soft sticky dipole model. Third, hydrocarbon tails are modelled using the anisotropic Gay-Berne potential. Simulations are conducted by rigid body molecular dynamics, using software specifically designed and implemented for this project.