Hamaguchi, A.; (2006) Molecular and cellular pharmacology of novel pyrrolo [2,1-c] [1,4] diazepine-based anticancer agents. Doctoral thesis , University of London.

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Abstract

The pyrrolo 2,1-c 1,benzodiazepines (PBDs) are a family of naturally occurring antitumour antibiotics which includes anthramycin, DC-81, tomaymycin and sibiromycin. They exert their biological activity through covalent binding to the exocyclic N2 group of guanine in the minor groove of DNA and block transcription in a sequence-specific manner. These PBD monomers span three DNA base pairs and have a preference for binding to purine-G-purine triplets. The PBDs have been used as a scaffold to attach other moieties, leading to novel sequence-selective DNA minor groove alkylating agents. In addition, as part of a rational approach to producing more efficient and selective DNA interstrand crosslinking agents, two PBD monomers have been linked together to form PBD dimers. The research in this thesis is a study of the molecular and cellular pharmacology of several series of novel PBD-containing agents including novel PBD dimers with different linker lengths, PBD-nitrogen mustard conjugates, PBD-polyamide conjugates and C2-aryl PBD monomers. Cytotoxicity in human tumour cell lines, efficiency of DNA interstrand crosslinking in naked linear plasmid DNA, and DNA sequence specificity were assessed. DNA interstrand crosslink formation and repair in cells were also measured. Resulting from this work Q2lQT-exo-unsaturated PBD dimers have been characterised to be highly cytotoxic and efficient in producing interstrand crosslinks both in naked DNA and in cells that are not repaired up to 48 hours. Only two of the PBD-nitrogen mustard conjugates showed some interaction with DNA although several members of this group showed significant cytotoxicity. A PBD-tri-pyrrole conjugate was found to bind preferentially to the sequence 5'-AGATTATC. Novel C2-aryl PBD monomers were shown to bind selectively to 5'-purine-G-purine sequences and demonstrated significant cytotoxicity. In addition, a method utilizing fluorescently end-labelled oligonucleotides was developed and validated to screen libraries of PBD-containing molecules synthesised on beads by combinatorial chemistry. This method allowed the isolation and discrimination of beads containing compounds, which have a high affinity for specific DNA sequences.

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