Use this URL to cite or link to this record in EThOS:
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: 2007
Availability of Full Text:
Access from EThOS:
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. 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: Open University, 2007 Qualification Level: Doctoral
EThOS ID:  DOI: Not available