Synthetic approaches to c-ring unsaturated DNA cross-linking pyrrolo[2,1-c][1,4]benzodiazepine dimers.
The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a diverse group of antitumour
antibiotics in which there has been growing interest over the past 30 years. These
compounds bind covalently within the minor groove of DNA via the formation of an aminal
bond between the N10-C11 imine functionality of the PBD and the exocyclic C2-NH2 of a
guanine base, resulting in the inhibition of processes including DNA replication and
transcription, thus leading to cell death.
PBD `dimers' have the ability to form irreversible interstrand cross-links with DNA. One
example, DSB-120, has been shown to recognise six base pairs compared to the monomer
DC-81 that recognises only three. A second example, SJG-136, has unsaturation at the C2
position and is cytotoxic at the picomolar level in glutathione-rich cell lines resistant to a
number of agents including DSB-120. The major part of this project concerns the synthesis
of novel PBD dimers specifically designed to investigate the effect of sp1 hybridisation at
the C2 position of the molecule. One problem has been that only small amounts of PBD
dimers were previously available through the original synthetic routes. Through this
project, three new synthetic methodologies have been devised to produce two novel PBD
dimers KEC-570 and KEC-5130, as well as the known PBD dimers SJG-136 and DSB-120.
These syntheses utilise novel cyclisation procedures that involve fewer steps than existing
synthetic methods and afford cleaner products in higher yields and on a larger scale. This
has allowed, for the first time, a full pharmacological evaluation of these molecules.
KEC-570 has been shown to form interstrand DNA cross-links and to be cytotoxic in three
human carcinoma cell lines. Presently, both KEC-570 and DSB-120 are being evaluated
across the standard panel of tumour cell lines at the National Cancer Institute. SJG-136 has
proved successful in the NCI's Hollow Fibre assay and has progressed to in vivo xenograft
assays at the NCI.