Binding to the DNA Minor Groove by Heterocyclic Dications: From AT‐Specific Monomers to GC Recognition with Dimers

Abstract

Compounds that bind in the DNA minor groove have provided critical information on DNA molecular recognition, they have found extensive uses in biotechnology and they are providing clinically useful drugs against diseases as diverse as cancer and sleeping sickness. This review focuses on the development of clinically useful heterocyclic diamidine minor groove binders. These compounds have shown us that the classical model for minor groove binding in AT DNA sequences must be expanded in several ways: compounds with nonstandard shapes can bind strongly to the groove, water can be directly incorporated into the minor groove complex in an interfacial interaction, and the compounds can form cooperative stacked dimers to recognize GC and mixed AT/GC base pair sequences.

Synthesis, crystal structure and docking studies of tetracyclic 10-iodo-1,2-dihydroisoquinolino[2,1-b][1,2,4]benzothiadiazine 12,12-dioxide and its precursors

“…The ability of small molecules to interact with DNA via minor-groove binding and intercalation is also known to inhibit DNA replication and nucleic acid synthesis in vivo, thereby promoting their use as antibiotics, antibacterials, antitumour agents and mutagens (Bunkenborg et al, 2000). This interaction also provides critical information on DNA molecular recognition and is being exploited in biotechnology (Nanjunda & Wilson, 2012).…”

“…Notably, many heterocyclic DNA minor-groove binders (MGBs) are providing clinically useful drugs against diverse diseases and are finding extensive uses in technology Isoquinolinobenzothiadiazine derivatives (Troschü tz & Heinemann, 1996;Kisel & Kovtunenko, 2000;Kisel et al, 2002). (Nanjunda & Wilson, 2012;Paul et al, 2019;Rahman et al, 2019). Moreover, MGBs with the tetrahydroisoquinoline ring system have been reported (D'Incalci & Galmarini, 2010;Feuerhahn et al, 2011).…”

Imino proton NMR guides the reprogramming of A•T specific minor groove binders for mixed base pair recognition

“…Non-covalent binding minor groove agents have been used in therapeutic targeting of DNA in various types of cells with successful application all the way to clinical trials ( 16 , 17 ). As described above, many minor groove binding compounds are highly A•T specific ( 18 ) but it is essential to be able to better target mixed, A•T and G•C base pair (bp) sequences ( 19 , 20 ). Such novel compounds would be useful for a new class of potential drug molecules that can target promoter DNA sequences to modulate TF binding ( 21–23 ).…”

Small Sequence‐Sensitive Compounds for Specific Recognition of the G⋅C Base Pair in DNA Minor Groove

“…For example, amidine cationic groups, which have been quite successful for targeting DNA, provide a hydrogen‐bond‐donating planar surface for optimizing interactions with A⋅T bps at flanking sites of G⋅C bps. Also, the twist dihedral between amidine and phenyl ring would help the compound structure to fit the helical curvature of the minor groove . Moreover, the groove binding ligand should include a H‐bond acceptor (N‐MeBI) to recognize G‐NH 2 .…”

“…Also, the twist dihedral betweena midine and phenyl ring would help the compound structure to fit the helical curvature of the minor groove. [30,31] Moreover, the groove binding ligand should include aH -bond acceptor (N-MeBI) to recognize G-NH 2 .I no rder to improveb inding specificity,i ti s important to attempt to take advantage differences in groove-width of targeted sequences. Based on Rohs [25] and our work, [22] the wider DNA minor groove at GC versusA Ts equences can be targeted.…”