Chemistry of DNA minor groove binding agents

Most of the clinically used anticancer drugs exert their antitumor effect by damaging the replication machinery of DNA either by covalent or non-covalent binding. Intercalation and groove fitting are the major modes of non-covalent interaction. Small crescent shaped molecules have been claimed to bind with DNA via minor grooves. A plethora of hybrid molecules based on distamycin or netropsin have been synthesised with the objectives of improved selectivity and specificity with no/reduced unwanted side effects. This review critically and objectively describes the previously known hybrid DNA minor groove binding agents based on five membered, distamycin or netropsin. Moreover, the future use of six-membered benzamides has also been highlighted. Special emphasis has been put on developing structure–activity relationships of DNA minor groove binding agents.

Small crescent shaped molecules interact with DNA via minor grooves. Minor grooves are usually untenanted and thus available for attack to small drug molecules. Distamycin and netropsin have been used as lead compounds in cancer research due to their binding ability to specific sequences within minor groove of double-helical DNA.Figure optionsDownload as PowerPoint slideHighlights
► Small crescent shaped molecules interact with DNA via minor grooves.
► Minor groove binders (MGBs) preferentially bind to adenine and thymine sequences.
► Distamycin and netropsin act as lead compounds in the design of anticancer drugs.
► ligands based on six-membered backbones are stronger MGBs than pyrrol based compounds.
► The synthetic strategies and sound structure–activity relationships of MGBs have been thoroughly discussed.