DNA-binding metallo-intercalators are positively charged,

planar Planar is an adjective meaning "relating to a plane (geometry)". Planar may also refer to: Science and technology * Planar (computer graphics), computer graphics pixel information from several bitplanes * Planar (transmission line technologies), ...

, polycyclic,

aromatic compounds Aromatic compounds, also known as "mono- and polycyclic aromatic hydrocarbons", are organic compounds containing one or more aromatic rings. The parent member of aromatic compounds is benzene. The word "aromatic" originates from the past groupin ...

that unwind the DNA double helix and insert themselves between DNA

base pairs A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...

. Metallo- intercalators insert themselves between two intact base pairs without expelling or replacing the original

nitrogenous bases Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the basic b ...

; the

hydrogen bonds In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...

between the nitrogenous bases at the site of intercalation remain unbroken.Gill, Martin R., and Jim A. Thomas. "Ruthenium(ii) Polypyridyl Complexes and DNA-from Structural Probes to Cellular Imaging and Therapeutics - (RSC Publishing)." Chem Soc Rev, n.d. Web. 26 Jan. 2015. .Pages, Benjamin J., Dale L. Ang, Elise P. Wright, and Janice R. Aldrich-Wright. "Metal Complex Interactions with DNA." Royal Society of Chemistry, n.d. Web. 26 Jan. 2015. . In addition to π-stacking between the aromatic regions of the intercalator and the nitrogenous bases of DNA, intercalation is stabilized by van der Waals,

hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, th ...

electrostatic Electrostatics is a branch of physics that studies electric charges at rest (static electricity). Since classical times, it has been known that some materials, such as amber, attract lightweight particles after rubbing. The Greek word for amber ...

, and

entropic Entropy is a scientific concept, as well as a measurable physical property, that is most commonly associated with a state of disorder, randomness, or uncertainty. The term and the concept are used in diverse fields, from classical thermodynam ...

interactions. This ability to bind to specific DNA base pairs allows for potential therapeutic applications of metallo-intercalators.

Synthesis of metallo-intercalators

In the case of

ruthenium Ruthenium is a chemical element with the Symbol (chemistry), symbol Ru and atomic number 44. It is a rare transition metal belonging to the platinum group of the periodic table. Like the other metals of the platinum group, ruthenium is inert to ...

intercalators, the general synthesis consists of preparing intercalative ligands followed by their coupling to a ruthenium metal complex coordinated by specific ancillary ligands. Examples of prior ruthenium complexes used as precursors for metallo-intercalators include cis- u(bpy)₂Cl₂and cis- u(phen)₂Cl₂��2H₂O, which can be synthesized into u(bpy)₂(maip)sup>2+, u(bpy)₂(paip)sup>2+, u(bpy)₂(bfipH)ClO₄)₂, and Ru(phen)₂(bfipH)](ClO₄)₂.Vargiu, Attilio V., and Alessandra Magistrato. "Detecting DNA Mismatches with Metallo-Insertors: A Molecular Simulation Study." Inorganic Chemistry. Inorganic Chemistry, n.d. Web. 26 Jan. 2015. .

Mechanism of DNA-intercalation

Metallo-intercalators π-stack with unbroken DNA base pairs after entering via a groove, typically the major, (in contrast to metallo-insertors, which replace expelled base pairs after entering double stranded DNA via the minor groove).Lauria, Antonino, Riccardo Bonsignore, and Alessio Terenzi. "Nickel(ii), Copper(ii) and Zinc(ii) Metallo-intercalators: Structural Details of the DNA-binding by a Combined Experimental and Computational Investigation - (RSC Publishing)." Royal Society of Chemistry, n.d. Web. 26 Jan. 2015. .Alessandro Biancardi, Azzurra Burgalassi, Alessio Terenzi, Angelo Spinello, Giampaolo Barone, Tarita Biver, and Benedetta Mennucci. , title="A Theoretical and Experimental Investigation of the Spectroscopic Properties of a DNA‐Intercalator Salphen‐Type ZnII Complex" , journal=Chemistry–A European Journal, , date=2015 , volume=20 , issue=24 , pages=7439-7447. , doi=10.1002/chem.201304876 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. Intercalation of metal compounds between DNA base pairs effectively stabilizes the double helix, increasing the melting temperature of the DNA duplex. 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”. For example, square planar complexes penetrate deeper into the DNA base pairs than octahedral or tetrahedral complexes do. Also, positive charges on the metallo-intercalator strengthen DNA-binding because of electrostatic attraction to the negatively charged sugar-phosphate backbone.

Therapeutic applications

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. 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. After intercalation, the sample can be photoactivated by absorbing energy during irradiation with short wavelength light. 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. 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.

References

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