Location: Forage and Livestock Production ResearchTitle: The thermodynamic effects of ligand structure on the molecular recognition of mononuclear ruthenium polypyridyl complexes with B-DNA
|MIKEK, CLINTON - Mississippi State University|
|WHITE, JAKE - Mississippi State University|
|MARTIN, LOGAN - Mississippi State University|
|ALATRASH, NAGHAM - University Of Texas|
|MACDONNELL, FREDRICK - University Of Texas|
|LEWIS, EDWIN - Mississippi State University|
Submitted to: European Journal of Organic Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/12/2017
Publication Date: 8/11/2017
Citation: Mikek, C.G., Dupont, J.I., White, J.C., Martin, L.R., Alatrash, N., Macdonnell, F.M., Lewis, E.A. 2017. The thermodynamic effects of ligand structure on the molecular recognition of mononuclear ruthenium polypyridyl complexes with B-DNA. European Journal of Organic Chemistry. doi:10.1002/ejic.201700462.
Interpretive Summary: Compounds containing transition metals are frequently used in cancer therapies. Leading chemotherapeutics such as cisplatin and oxaliplatin (containing the transition metal platinum) are believed to function by inhibiting the replication of DNA. While these therapies are effective, they are toxic to the host and have wide ranging and sometimes debilitating side effects. Additionally, cancers may reappear after apparent remission and not respond to the same chemotherapeutics due to the development of drug resistance. Complexes containing the transition metal ruthenium have been identified as less toxic than platinum drugs and do not exhibit the same propensity for resistance. Polypyridyl ruthenium complexes have been tested against cancer cell lines and have shown significant tumor regression in animal tumor studies. In this study, the method by which these polypyridyl ruthenium compounds are proposed to inhibit tumor growth, high affinity binding to DNA, was examined to determine how the structure of the compound influences its ability to bind to DNA. The results of this study provided important information to aid in the rational design of new compounds that may be able to more tightly bind to DNA, allowing for chemotherapeutics that may cause less side effects and decrease instances of resistance or desensitization to the drug.
Technical Abstract: The ruthenium(II) polypyridyl complexes (RPCs), [(phen)2Ru(tatpp)]Cl2 (3Cl2) and [(phen)2Ru (tatpp)Ru(phen)2]Cl4 (4Cl4), containing the large planar and redox-active tetraazatetrapyrido- pentacene (tatpp) ligand, cleave DNA in the presence of reducing agents in cell-free assays and show significant tumor regression in mouse tumor models with human non-small cell lung carcinoma xenografts. ITC, CD, and ESI-MS techniques were used to study the thermodynamics of RPC*DNA complex formation and the complex structure for binding three different RPCs to duplex DNA. The specific RPCs were [Ru(phen)3]2+ (12+), [Ru(phen)2(dppz)]2+ (22+), and [Ru(phen)2(tatpp)]2+ (32+). We report that the duplex DNA binding of the three RPCs is characterized by a combination of groove binding (including electrostatic effects) and intercalation. [Ru(phen)3]2+ (12+) is the weakest DNA binder, exhibiting a Ka = 1.3 x 104 M-1 while [Ru(phen)2(dppz)]2+ (22+) binds with significantly higher affinity, Ka,1 = 1.4 x 106 M-1, and [Ru(phen)2(tatpp)]2+ (32+) exhibits the tightest binding, Ka = 4.7 x 106 M-1, owing to increasingly long bridging ligands engaged in p-bonding with the DNA base pairs via a higher affinity intercalative binding mode. A second binding mode, two orders of magnitude weaker than the first, was also seen for binding 22+. We also report the complete set of thermodynamic parameters including values for the changes in Gibbs free energy, enthalpy, and entropy for the formation of the three RPC*DNA complexes. The ITC values for the change in Gibbs free energy range from -5.6 to -9.1 kcal mol-1 (12+*DNA and 32+*DNA respectively), while the ITC values for the change in enthalpy range from +4.9 to -5.0 kcal mol-1 (32+*DNA and mode 2 binding for 22+*DNA respectively). All of the primary complexes exhibit very negative values for the entropic term ranging from -7.3 to -14.0 kcal mol-1 (mode 1 binding for 22+*DNA and 32+*DNA respectively). To further understand the intercalation versus groove binding contributions to the overall binding energy we compared the thermodynamics for formation of the 12+*DNA, 22+*DNA, and 32+*DNA complexes to the thermodynamics for formation of the 44+*DNA complex. The RPC binding affinities to duplex DNA follow the trend: 12+ < 44+ < 22+ < 32+. Differences in the affinity for binding 12+ versus 22+ or 32+ are almost entirely due to the size of the intercalating moiety, e.g. phen which can only be partially intercalated to dppz and tatpp which can be completely intercalated. The lower affinity 44+ is due to the solvation penalty for the second Ru core complex that extends out from the major groove. By comparing all of these results, we have begun to develop the structure function relationships for the interaction of RPCs with duplex DNA.