Tiberghien, Arnaud;
(2007)
Design, Synthesis, and Evaluation of Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) Pyrrole/Imidazole polyamide conjugates.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The aim of the project presented in this thesis, was to design and synthesise DNA binding agents with superior sequence selectivity. Ultimately, the challenge was to be able to make compounds with the potential to bind specifically to predetermined DNA sequences. Molecules with such properties could be used to knock-out oncogenes with minimal damage to healthy DNA. Pyrrole/imidazole polyamides are extensively studied small oligomers which bind non-covalently to DNA with high selectivity. Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are naturally occurring antitumour antibiotics which bind preferentially to AGA DNA sequences through an aminal bond. There is currently great interest in studying the beneficial interactions that can be gained from tethering the two types of molecules together. To this end, new PBD capping units were designed and synthesised. Crucially, base driven racemisation problems at C11a were resolved by protecting the C11-hydroxy position. The pyrrole and imidazole building block syntheses were successfully optimised. Seven PBD dimers, featuring pyrrole/imidazole polyamides in their core were synthesised, as well as eleven PBD pyrrole/imidazole "hairpin" conjugates. The majority of conjugates were more active than either of their constituent moieties in the National Cancer Institute 60 cell lines in vitro cytotoxicity assay. The dimers were found to crosslink DNA efficiently in the whole cell "comet" assay. The selectivity of the compounds was evaluated by DNase I footprinting assay. Clear footprints were observed at discrete locations in Bcl-2 and AR fragments, although not always in a predictable fashion.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Design, Synthesis, and Evaluation of Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) Pyrrole/Imidazole polyamide conjugates |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. |
| Keywords: | Health and environmental sciences; DNA binding agents |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10105291 |
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