DNA minor groove binding agents

Minor groove binding agents are molecules able to interact with the minor groove of DNA and to covalently bind residues lying in this groove. A common characteristic of this class of anticancer agents is their peculiar mechanism of action. In fact, the majority of them have a mechanism of action very distinct from that of the classic major groove DNA interacting agents and more in common with that of classic anticancer agents used in the clinic. Minor groove binding agents are characterized by potent antitumor activity in vitro and in vivo. One of the major limitations in their clinical use has been the potent and often unexpected myelotoxicity which prevents using potentially active doses. Many efforts have been made in the past to synthesize new minor groove binding agents retaining high antitumor activity and an acceptable toxicity profile. Molecules such as brostallicin and trabectedin represent clear examples of minor groove binding agents with relatively moderate undesired effects which are now in clinical evaluation. The peculiar mechanism of interaction of brostallicin with glutathione and glutathione-S-transferase, and the peculiar interaction of trabectedin with the nucleotide excision repair system, make these molecules particularly attractive for combination studies with classic anticancer agents with which synergism has been described at preclinical levels. Based on the interesting features of these new molecules, studies on minor groove DNA binding agents are still warranted and either natural or synthetic compounds are continuously being evaluated for their antitumor properties.