Compounds that bind in the minor groove of
DNA have found use in the experimental treatment of
cancer and certain
infectious diseases. Furthermore, agents which target and can recognize discrete sequences of
DNA have the potential to offer selective
therapies by modulating the activity of specific
transcription factors or genes. For this reason, a number of sequence-selective
DNA binding agents have been evaluated with a range of affinities and recognition fidelities. In this respect, the pyrrolo[2,1-c][1,4]
benzodiazepines (PBDs) are of interest as they bind to
guanine residues in the minor groove with a preference for Pu-G-Pu sequences. A dramatic increase in cytotoxicity and sequence selectivity has been achieved by linking two PBD units to form PBD dimers as cross-linking agents on opposite
DNA strands (e.g., interstrand cross-links).
SJG-136 is currently undergoing Phase I evaluation in both the United States (through the NCI) and United Kingdom (through
Cancer Research United Kingdom). This review will focus on design, synthesis and structure activity relationship studies of pyrrolobenzodiazepines as anticancer
therapeutics reported since 2003.