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TITLE
DEDICATION
CERTIFICATE
DECLARATION
ACKNOWLEDGEMENT
ABBREVIATIONS
CONTENTS
1 SOLID PHASE PEPTIDE SYNTHESIS
1.1 Basic principle of Merrifields solid phase peptide synthesis
1.2 The support for SPPS
1.3 Advantages & Disadvantages of SPPS
1.3.1 Advantages
1.3.2 Disadvantages
1.4 Organisation of the thesis
1.5 Present work
2 PEPTIDOMIMETICS
2.1 Preparation of peptidomimetics
2.1.1 Modification of the amino acid units
2.1.2 Modification of the peptide bond
2.1.2.1 Replacement of amide bond by ketomethylene group carbapeptides
2.1.2.2 Replacement of a-CH group by a nitrogen atom- Azapeptides
2.1.2.3 Replacement of amide bond by 1, 5 disubstituted tetrazole ring
2.1.2.4 Replacement of amide bond by C=C
2.1.2.5 Replacement of amide bond by-CH2-NH
2.1.3 Retro-inverso modifications
2.1.4 Dipeptides with cis-configuration (cis-amide mimetics)
2.1.5 Vinylogous peptides
2.1.6 Introduction of conformation-stabilizing rings (Bridging)
2 1.6.1 Bridging within a single amino acid residue
2 1.6.2 Dipeptide analogues
2.1.6.2.1 Incorporation of lactams
2.l.6.2.2 Incorporation of piperazinone
2.1.6.2.3 Incorporation of y-lactams
2.1.7 Imitation of secondary structures
2.1.8 Scaffold peptidomimetics
2.1.9 Non-peptide mimetics
2.1.10 Peptoids
2.2 Peptidomimetics of somatostatin
2.2.1 Analogues of somatostatin
2.2.1.1 D-Phe-Octreotide
2.2.1.2 Tyr3-Octreotide
2.2.1.3 Vapreotide
2.2.1.4 Cyclo (Pro-Phe-D-Trp-Lys-Thr-Phe)
2.2.1.5 Cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe)
2.2.1.6 Cyclo (Aha-Cys-Phe-D-Trp-Lys-Thr-Cys)
3 EXPERIMENTAL
3.1 Preparation and functionalisation of polymer support
3.1.1 Materials and methods
3.1.2 Source of chemicals
3.1.3 Polymer synthesis
3.1.3.1 Preparation of polystyrene cross linked with 2% HDODA by suspension polymerization
3.1.3.2 Chloromethylation of PS-HDODA resin using chloromethyl methyl ether
a. Preparation of IM anhydrous ZnCl2 in THF
b. Determination of chlorine capacity by pyridine fusion method
3.2 Synthesis of peptides
3.2.1 Source of chemicals
3.2.2 Physical measurements
3.2.3 Purification of reagents and solvents
3.2.4 Identification of the peptides using tic
3.2.5 Protection of side chain functions of aminoacids
3.2.5.1 Blocking the sulfhydryl group of cysteine
3.2.5.2 Protection of s-amino group of lysine
3.2.5.3 Protection of hydroxyl group of threonine
3.2.5.4 Blocking the hydroxyl group of tyrosine
3.2.5.5 Protection of indol nitrogen in tryptophan
3.2.6 Preparation of Boc-amino acids
3.2.7 Procedure for solid phase peptide synthesis
3.2.7.1 Attachment of first aminoacid to the resin: Gisins cesium salt method
3.2.7.2 Estimation of amino groups by picric acid method
3.2.7.3 Deprotection procedure: Removal of Boc group
3.2.7.4 Activation and coupling
3.2.7.5 Cleavage of the peptide from the resin
3.2.8 Hydrogenation of the peptide
3.2.9 Cyclisation of the peptide via disulfide formation
3.2.10 Purification
3.3 Synthesis of somatostatin analogues on 2% PS-HDODA resin
3.3.1 Synthesis of octreotide
3.3.1.1 Attachment of Boc-Thr (O-Bzl) to the chloromethyl resin
3.3.1.2 Coupling of the subsequent amino acids
3.3.1.3 Cleavage of the peptide from the resin
3.3.1.4 Cyclisation of the peptide via disulfide formation
3.3.2 Synthesis of TOC
3.3.2.1 Attachment of Boc-Thr (O-Bzl) to the chloromethyl resin
3.3.2.2 Coupling of subsequent amino acid units
3.3.2.3 Cleavage of the peptide from the resin
3.3.2.4 Hydrogenation of the peptide
3.3.2.5 Cyclisation of the peptide via disulphide formation
3.3.3 Synthesis of RC 160
3.3.3.1 Coupling of Boc-Trp (N-CHO) to the chloromethylated resin
3.3.3.2 Coupling of remaining amino acids
3.3.3.3 Cleavage of the peptide from the resin
3.3.3.4 Hydrogenation of the peptide
3.3.3.5 Cyclisation of the peptide via disulphide formation
3.4 Synthesis of somatostatin analogues on 2%PS-DVB resin
3.4.1 Synthesis of octreotide
3.4.1.1 Attachment of Boc-Thr (O-Bzl) to the chloromethy resin
3.4.1.2 Coupling of the subsequent amino acids
3.4.1.3 Cleavage of the peptide from the resin
3.4.1.4 Cyclisation of the peptide via disulphide formation
3.4.2 Synthesis of Tyr3-Octreotide
3.4.2.1 Attachment of Boc-Thr (O-Bzl) to the chloromethylresin
3.4.2.2 Coupling of subsequent amino acids
3.4.2.3 Cleavage of the peptide from the resin
3.4.2.4 Hydrogenation of the peptide
3.4.2.5 Cyclisation of the peptide via disulphide formation
3.4.3 Synthesis of RC 160
3.4.3.1 Coupling of Boc-Trp (N-CHO) to the chloromethylated resin
3.4.3.2 Coupling of subsequent aminoacids
3.4.3.3 Cleavage of the peptide from the resin
3.4.3.4 Hydrogenation of the peptide
3.4.3.5 Cyclisation of the peptide via disulphide formation
4 RESULTS AND DISCUSSION
4.1 Preparation of the solid support
4.1.1 Preparation of 1, 6-hexanediol diacryiate cross linked polystyrene support
4.1.2 Chloromethylation of the resin
4.1.3 Determination of the chlorine capacity of the resin
4.2. Preparation of protected amino acids for peptide synthesis
4.2.1. Protection of side chain functions
4.2.1.1 Blocking the sulfhydryl group of cysteine as S-Acm-Cys
4.2.1.2 Protection of E-aminogroup of lysine
4.2.1.3 Blocking hydroxyl group of threonine
4.2.1.4 Blocking hydroxyl group of tyrosine
4.2.1.5 Protection of indole nitrogen of tryptophan
4.2.2 Preparation of Boc-amino acids
1R Values of the Boc-amino acids
Melting points of Boc-amino acids
4.3 Synthesis of somatostatin analogues on 2% PS-HDODA support
4.3.1 Synthesis of D-Phe1- octreotide
4.3.2 Synthesis of Tyr3- octreotide
4.3.3 Synthesis of RC 160
4.4 Synthesis of somatostatin analogues on 2% PS-DVB resin
4.4.1 Synthesis of D-Phe- octreotide
4.4.2 Synthesis of Tyr3- octreotide
4.4.3 Synthesis of RC 160
5 SUMMARY
6 REFERENCES