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The synthesis of peptides can be considered as the rate-limiting step in the development of peptide-based medicines. Synthetic methods currently available are limited by several aspects, including the high cost of production or excessive waste when applied to large-scale synthesis. The development of a new solution-phase synthesis of peptides is described herein. Initial studies focus on the synthesis of α-peptides in the C-terminal direction, though the occurrence of epimerisation during chain elongation shows the limitation of this approach. Attempts to reduce this problem and to gain a better insight into the epimerisation processes involved are described. The unsuccessful application of this initial strategy to the synthesis of β-peptides is also discussed. A new procedure involving the coupling of amino acids or peptide acids with slight excesses of pentafluorophenyl esters in a THF/water solvent mixture in the N-terminal direction is developed and discussed. Contrary to modern repetitive solution-phase peptide synthesis procedures, this approach does not require time-consuming neutralisation reactions and reduces significantly the number of operation units that are necessary to obtain peptide intermediates. The efficiency of the new method is demonstrated by the rapid synthesis of short hydrophobic and hydrophilic peptides, the antimalarial cyclopeptide mahafacyclin B and a protected form of the hydrophilic pentapeptide Gly-Arg-Gly-Asp-Ser. Binding studies of the complex between 1-(3-Dimethylaminopropyl)-3-ethylurea hydrochloride (EDU.HCl) and triethylammonium trifluoroacetate are described and the potential application of EDU.HCl as an artificial carboxylate receptor to increase the acidity of trifluoroacetic acid is discussed.

The preparation and physical properties of the estertin halides X 4-nSn[ (CH2)mCO2R]n, where n = 1 or 2, m = 1, 2 or 3 and R is a alkyl or aryl substituent are reported. During the course of this work the molecular structures of Cℓ3SnCH 2CH2CO2Pri and Cℓ3SnCH 2CH2CO2CO2Et were determined. The preparations of Ph3Sn(CH2)3R compounds, where R is a functional group, are reported. The reactions of these compounds with electrophiles were investigated as a route to organotin halides. Explanations on their reactivity are postulated. The preparation of Ph3Sn[CHRR'] compounds where R and R' are the same or different functional groups, from the reaction of (Ph3Sn) 2S with Hg[CHRR']2 is also reported along with the physical properties and evidence for their particular structures. Investigations into the Lewis acidity of estertin halides were undertaken. Chloride ion acceptor strengths, adduct formation with nitrogen bases and catalysis of allylic rearrangement were used as a basis for the evaluation of the Lewis acidity. Explanations are offered for the various observations made during these studies. Finally the preparations of estertin mercaptides, [Et02C(CH 2)]n Sn(SCH2CO2C8H 17)4-n, where n = 1 or 2 are reported. Comparisons of the P.V.C. stabilising ability of these estertin mercaptides were made with the commercially available octyltin tris-mercaptide. Explanations are offered for the apparent difference in stabilising ability of each of these compounds in thermally processed P.V.C. during oven testing.

The possible role of the prostaglandins (PGs) in the regulation of protein turnover was investigated, firstly in hypertrophying rat skeletal muscle at 20 hours, 3 days and 7 days after synergist tenotomy, and secondly, in various tissues of the rainbow trout (Salmo gairdneri, Richardson) following re-feeding. An inhibitor of PG synthesis was used in both cases (fenbufen and indomethacin, respectively). 1) Fenbufen (at a dose of 1200mg/kg of diet) did not inhibit the hypertrophy of the soleus and plantaris muscles although there appeared to be an initial reduction in muscle RNA content. 2) Muscle growth was generally increased in fenbufen fed rats by 7 days after synergist tenotomy (10 days on fenbufen diet). 3) The fractional rate of protein synthesis in both control and overloaded muscles was reduced by fenbufen at this time (in 86g rats). The calculated rates of protein breakdown were also reduced in these muscles but to a greater extent than synthesis. This inhibition of protein degradation was most marked in the overloaded soleus and plantaris muscles. 4) The tenotomised gastrocnemius muscle experienced a true atrophy in the fenbufen-treated rats by 7 days. This atrophy involved greatly elevated rates of protein degradation when compared to the tenotomised muscle from rats fed a normal diet. In 6 day fasted rainbow trout, tissue protein synthesis was measured at 3 hours, 6 hours and 12 hours after re-feeding. The rapidity of the stimulation of protein synthesis by re-feeding and the nature of the response was tissue-specific. The administration of indomethacin (at a dose of 2mg/100g body weight) one hour prior to the meal, partially blocked the re-feeding response of protein synthesis in the gill at 6 hours after the meal, but stimulated protein synthesis in the liver and white muscle at this time.

No description available.

No description available.