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Synthesis of biologically active heterocyclic compounds

Wilson, Jennifer M. (2007) Synthesis of biologically active heterocyclic compounds. PhD thesis, University of Glasgow.

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Abstract

More than 11 million people worldwide are diagnosed with cancer every year. New cancer drugs are required that are more effective and selective. Nitrogen mustard alkylating agents crosslink DNA inhibiting transcription and replication. Use of the mustard pharmacophore as part of a macrocycle allows metal complexation and produces a prodrug. Hypoxic tumour cells have increased concentrations of reductase enzymes which could lead to reduction of the complex in situ and release of a cytotoxic drug. Human African Trypanosomiasis is commonly known as Sleeping Sickness and affects over 36 countries of sub-Saharan Africa. It is transmitted to humans by the tsetse fly which carries the parasitic subspecies Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Any compounds synthesised would also be tested to assess their potential as anti-parasitic agents. Parker synthesised a range of polyazamacrocycles. Testing of compound A in vitro gave highly efficient DNA crosslinking activity. Copper complexes were formed of the macrocycles and B was found to be 24 times more toxic against hypoxic cells than oxic cells thus exploiting tumour hypoxia and creating a selective drug. Jones synthesised a range of oxaazamacrocycles such as C which when tested in vitro exhibited comparable cross-linking activity to the azamacrocycles although it proved impossible to synthesise the corresponding copper complexes. It was decided to vary the leaving group on the alkylating arms to see if the DNA crosslinking results could be improved. Eight carbamates and the corresponding copper complexes were synthesised. The R-groups were alkyl and aromatic. Anti-cancer DNA crosslinking and hypoxia selectivity results were disappointing however, a number of compounds displayed significant activity when tested against T. brucei. A range of thiaazamacrocycles would complete the set of heteroatom-containing macrocycles (N, O, S) and might produce good DNA crosslinking results. It might also be possible to synthesise the corresponding copper complexes producing prodrugs. Six thiaazamacrocycles were synthesised and 2-hydroxyethyl arms were attached. However it proved impossible to isolate the desired alkylating agents with the 2-chloroethyl arms. In the body, the p53 protein activates the transcription of specific genes. In healthy cells, the levels of p53 have to be kept to a minimum to allow the normal running of the cell, e.g. growth and replication. This function is carried out by the HDM2 protein, which forms an auto-regulatory feedback loop with p53. In some tumours, the p53 function is disrupted due to genetic mutations of p53. However other tumours possess ‘wild type’ p53 – this type of p53 has lost the ability to respond to oncogenic stress due to over-expression of HDM2. Drugs that inhibit HDM2 should cause stabilisation of p53 and induce apoptosis in cancer cells. A small library of 5-deazaflavins were synthesised and biologically tested producing some interesting biological results.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Alkylating agents, bioreducible prodrugs, human african trypanosomiasis, macrocycles, p53, deazaflavins, HDM2.
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Supervisor's Name: Sutherland, Dr Andrew and Robins, Prof David
Date of Award: 2007
Depositing User: Dr Jennifer M Wilson
Unique ID: glathesis:2007-45
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 01 Apr 2008
Last Modified: 10 Dec 2012 13:15
URI: http://theses.gla.ac.uk/id/eprint/45

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