Sequence-specific recognition and modification of double-helical DNA by minor-groove binding conjugates structurally related to netropsin and distamycin

Abstract

Publisher Summary Netropsin and distamycin have largely contributed to the understanding of the molecular basis of drug-DNA recognition. The understanding of how these two antibiotics recognize and bind to AT sequences in DNA gave perceptions of how to design sequence-specific DNA binding molecules. The knowledge arising from these two antibiotics has inspired the rational design of DNA reading molecules. This chapter shows that the chemical structure of netropsin-like DNA reading elements may be varied in many synthetically convenient fashions, to produce different repertoires of sequence-selective DNA binding molecules with a range of functionalities. Sterically demanding groups can be attached to netropsin and distamycin without abolishing their sequence recognition properties. The fact that certain netropsin analogues can readily recognize a specific sequence in DNA shows DNA targeting with minor-groove binding drugs is no longer a possibility but a practical reality. There is good reason to believe that netropsin and distamycin will continue to inspire the development of new anticancer agents. In the many examples presented in the chapter, netropsin and distamycin are almost always used to deliver cytotoxic drugs to specific sequences in DNA, but they can also be used to deliver DNA to cells.