Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486521
Title: Site specific cross-linking of thio-nucleosides
Author: Tummala, Srinivasa Rao
ISNI:       0000 0001 3537 6954
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2008
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Abstract:
Cancer is a devastating disease. Numerous drugs have been synthesised over the years aiming to cure cancer. Significant new advancements in anti-cancer therapy have been achieved over the past few years. This was made possible by the molecular level understanding of the cancer disease, which has led to the synthesis of various targeted drugs. The targets within the cancer cells are very limited for anti-cancer drug design because cancerous cells resemble normal cells in most of their molecular aspects. This makes it extremely difficult for cell specific incorporation of drugs or cell killing. So, alternative approaches have been followed for specific cell killing. However, such approaches are still at an early stage and a great deal of work needs to be done. Various DNA-targeted approaches, such as photo cross-linking and chemical cross-linking; have been developed for killing cancerous cells. These approaches have not completely solved the problem of specificity. Like traditional anti cancer drugs, these agents also indiscriminately cross-link DNA in both normal cells, cancerous cells leading to cell death. In this thesis, two modified nucleosides were chosen which can be incorporated into the DNA of the cells easily. These thio-modified nucleosides were proven to have more affinity towards the DNA of the cancerous cells. Such modified nucleosides have previously been exploited for anti-cancer activity, especially UVA cell killing. In this thesis the thio-modified nucleosides have been explored for their site specific cross-linking activity. The first modified nucleoside 4-thiothymidine was synthesised and reported in 1959. 4-Thiothymidine resembles thymidine, except for a modification at position 4 with sulphur instead of oxygen. Previous studies have shown that 4-thiothymidine behaves like thymidine when incorporated into the cells. Like thymidine, this is base-paired with adenine in DNA. In this thesis, at first the thiol group of 4-thiothymidine has been specifically activated by a stable and readily replaceable group. This group was then replaced by various thio-nucleophiles which lead to the cross-linking of the nucleoside. The standards of these cross-linked nucleosides were successfully synthesised and characterised. In the quest to improve specificity of incorporation into cancer cells a novel pro-drug, 4-thio-5-bromodeoxyuridine (S4-BrdU) was synthesised by members of our group in 2003. This nucleoside is another thymidine analogue which is modified by replacing oxygen at position 4 with sulphur and methyl at position 5 with bromine. The thiol group of S4-BrdU nucleoside was chosen for the purpose of cross-linking. Successful cross-linking of the nucleoside with various thiol nucleophiles has been explored. Firstly S4-BrdU was converted into a DNP derivative. The DNP was then replaced with mercaptoethanol, thioethanethiol and natural thiols such as cysteine (the only amino acid containing a thiol group in the molecule) and glutathione (a natural peptide which helps in detoxification pathways in the body). These cross-linked products have been characterised by various methods. After successfully cross-linking the nucleosides, oligomers containing 4-thiothymidine were synthesised. The oligomers were characterised and 4-thiothymidine was successfully incorporated into the oligomers.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.486521  DOI:
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