DNA-binding metallo-intercalators

Figure 1: Chemical structure of the DNA-binding metallo-intercalator complex [Ru(bpy)2(paip)]2+ with intercalative and ancillary ligands labeled.[4][5]

In the case of ruthenium intercalators, the general synthesis consists of preparing intercalative ligands followed by their coupling to a ruthenium metal complex coordinated by specific ancillary ligands.[6][7] Examples of prior ruthenium complexes used as precursors for metallo-intercalators include cis-[Ru(bpy)₂Cl₂] and cis-[Ru(phen)₂Cl₂]∙2H₂O, which can be synthesized into [Ru(bpy)₂(maip)]²⁺, [Ru(bpy)₂(paip)]²⁺, [Ru(bpy)₂(bfipH)](ClO₄)₂, and Ru(phen)₂(bfipH)](ClO₄)₂.[4][5]

Figure 2: Metallo-intercalators enter double stranded DNA via the major groove and π-stack between adjacent unbroken base pairs. Here, the phi ligand of a rhodium complex intercalates a DNA segment with the sequence 5'-G(5IU)TGCAAC-3' (PDB ID 454D).[8]

Metallo-intercalators π-stack with unbroken DNA base pairs after entering via a groove, typically the minor, (in contrast to metallo-insertors, which replace expelled base pairs after entering double stranded DNA via the minor groove).[9][10] Intercalation of a metallo-intercalator creates less strain in the DNA duplex than insertion; metallo-insertors induce an untwist of the double helix and an opening of the phosphate backbone while metallo-intercalators marginally increase the rise and width of the major groove.[1][9] Intercalation of metal compounds between DNA base pairs effectively stabilizes the double helix, increasing the melting temperature of the DNA duplex.[8] Binding of metallo-intercalators to DNA is reversible and depends on the properties of the intercalating molecule. Metallo-intercalators with different metal centers, oxidation states, coordination geometries, and overall sizes will exhibit varying “depths of insertion”.[3] For example, square planar complexes penetrate deeper into the DNA base pairs than octahedral or tetrahedral complexes do.[3] Also, positive charges on the metallo-intercalator strengthen DNA-binding because of electrostatic attraction to the negatively charged sugar-phosphate backbone.[6]

Figure 3: The wide structure of metallo-intercalators containing the ligand 5,6-chrysenequinone diimine (chrysi) can be used in anticancer therapeutics to identify mismatched DNA base pairs.[11][12]

Metallo-intercalators have a variety of potential therapeutic applications as a result of their structural diversity and universal photooxidative properties. One possible therapeutic application of metallo-intercalators is to combat cancerous tumor cells within the body by targeting specific mismatched DNA base pairs; the ability to modify the ligands bound to the metal center allows for a high degree of specificity in the binding interactions between the metallo-intercalator and the DNA sequence.[11][12][13] For example, the ligand 5,6-chrysenequinone diimine (chrysi) and its analogues are designed to be too wide to fit inside the normal span of the base pairs of B-DNA, causing it to bind instead to the wider portions of the helix at destabilized sites of mismatched bases.[11][12] After intercalation, the sample can be photoactivated by absorbing energy during irradiation with short wavelength light.[1] This activation causes the metallo-intercalator's photooxidative properties to induce a cleavage of the sugar phosphate backbone at the site of mismatch through a radical mechanism.[1][11][12] Even in the absence of irradiation, the interactions between the metallo-intercalator and DNA can substantially decrease the proliferation of cells containing DNA with mismatched base pairs.[13]