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Synthetic, structural and biological studies on C2-substituted pyrrolo[2,1-c][1,4]benzodiazepines.

Antonow, Dyeison; (2008) Synthetic, structural and biological studies on C2-substituted pyrrolo[2,1-c][1,4]benzodiazepines. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Over 110 C2-substituted PBD analogues have been synthesized via palladium catalyzed cross-coupling. The synthetic effort focussed on modifications in the C-ring of the pyrrolo[2,1-c][1,4]benzodiazepine (PBD) ring system but preserving the C2/C3-endo unsaturation observed in naturally occurring compounds. A combination of N10-C11 imine containing PBDs and PBD-dilactams (that possess an amide functionality instead of imine but still bind to DNA through non-covalently interactions) has been synthesised. The development of combinatorial synthetic methodologies has allowed the timely synthesis of a diverse set of PBDs for cytotoxicity and DNA binding assays. The feedback from the biological results has been used to guide the design of new molecules and, ultimately, "hits" have been selected for further chemical/biological investigation. The results showed that the introduction of an additional aryl group at the 2-position of PBDs significantly enhanced the in vitro performance of PBDs as antitumour agents. Although a pronounced selectivity towards melanoma cell-lines has been observed amongst the library members, further biological selectivity was pursued through the synthesis of a novel C2-aryl PBD prodrug for use in immunoconjugate therapy, which is designed to selectively deliver cytotoxic substances to neoplastic cells. These novel C2-aryl PBDs have not been observed in nature and the role played by the additional aryl fragment in the biological activity is not fully understood. As a consequence, NMR spectroscopy was employed for structural analysis of a leading library member with the intention of explaining the outstanding in vitro results at a molecular level. The C2-2-naphthyl compound DA046 was incubated with a short DNA fragment to give the DA046-DNA adduct which was then subjected to several NMR experiments. Two-dimensional NOESY experiments, revealed the areas of the molecule that maximize the interaction with DNA. NMR also revealed that the enhanced DNA binding affinity of DA046 arises from van der Waals interactions between the naphthalene ring and the walls of the minor groove. These strong lipophilic interactions pull the two DNA strands together narrowing the minor groove and further stabilizing the DNA duplex.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Synthetic, structural and biological studies on C2-substituted pyrrolo[2,1-c][1,4]benzodiazepines.
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; Biological; C2-substituted; C][1,4]benzodiazepines; Pyrrolo[2,1-c][1,4]benzodiazepines
URI: https://discovery.ucl.ac.uk/id/eprint/10105922
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