Exploiting anthracycline scaffold for designing DNA-targeting agents

One possible approach to controlling the effects of pathogenic genes is to control their expression at the transcription level. However, only a small number of high-affinity DNA-binding agents are currently available, and their sequence selectivity is limited. Clearly, there is an urgent need to develop new molecules that are small enough to permeate cells, can bind tightly and selectively to extended sequences of DNA, and can consequently regulate transcription of specific genes. The approach we present in this chapter is new and complementary to the current research efforts of other laboratories. This new approach to the design of high affinity sequence-selective DNA binders can incorporate different classes of ligands. It has been named “modular design approach”. The whole process involves (1) identifying existing and creating new basic structural fragments (blocks) that display an ability to interact with DNA (for the clarity of the concept these fragments can be treated as the molecular equivalents of Lego blocks), (2) assessing them for their binding affinity and sequence specificity, and (3) assembling the resulting blocks into high-affinity DNA-binding agents.