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The Thermodynamic Effects of Ligand Structure on the Molecular Recognition of Mononuclear Ruthenium Polypyridyl Complexes with B‐DNA
Author(s) -
Mikek Clinton G.,
DuPont Jesse I.,
Machha Venkata R.,
White Jake C.,
Martin Logan R.,
Alatrash Nagham,
MacDonnell Frederick M.,
Lewis Edwin A.
Publication year - 2017
Publication title -
european journal of inorganic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.667
H-Index - 136
eISSN - 1099-0682
pISSN - 1434-1948
DOI - 10.1002/ejic.201700462
Subject(s) - chemistry , intercalation (chemistry) , ruthenium , dna , ligand (biochemistry) , stereochemistry , crystallography , base pair , receptor , biochemistry , inorganic chemistry , catalysis
The ruthenium(II) polypyridyl complexes (RPCs), [(phen) 2 Ru(tatpp)]Cl 2 ( 3 Cl 2 ) and [(phen) 2 Ru (tatpp)Ru(phen) 2 ]Cl 4 ( 4 Cl 4 ), 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+ ( 1 2+ ), [Ru(phen) 2 (dppz)] 2+ ( 2 2+ ), and [Ru(phen) 2 (tatpp)] 2+ ( 3 2+ ). We examined the enatiomerically pure Δ‐RPC and Λ‐RPC isomers as well as the racemic mixture in terms of their binding to B‐DNA. B‐DNA binding of the three RPCs is characterized by a combination of groove binding (including electrostatic effects) and intercalation, with the thermodynamics being very similar for binding both the enantiomerically pure compounds and the racemic mixture. 1 2+ is the weakest DNA binder, exhibiting a K a = 1.3 × 10 4 m –1 while 2 2+ binds with significantly higher affinity, K a,1 = 1.4 × 10 6 m –1 , and 3 2+ exhibits the tightest binding, K a = 4.7 × 10 6 m –1 . The trend is to increase the affinity as longer bridging ligands engage in additional π‐bonding with the DNA base pairs via an intercalative binding mode. A second binding mode, two orders of magnitude weaker was also seen for 2 2+ . The ITC values for binding the racemic mixtures exhibit Δ G s ranging from –5.6 to –9.1 kcal mol –1 ( 1 2+ · DNA and 3 2+ · DNA respectively), while the ITC values for Δ H range from +4.9 to –5.0 kcal mol –1 ( 3 2+ · DNA and mode 2 binding for 2 2+ · DNA respectively). All of the primary complexes exhibit very negative values for – T Δ S ranging from –7.3 to –14.0 kcal mol –1 (mode 1 binding for 2 2+ · DNA and 3 2+ · DNA respectively). To further understand the intercalation vs. groove binding contributions to the overall binding energy we compared the thermodynamics for formation of the 1 2+ · DNA, 2 2+ · DNA, and 3 2+ · DNA complexes to the thermodynamics for formation of the 4 4+ · DNA complex. The RPC binding affinities to duplex DNA follow the trend: 1 2+ < 4 4+ < 2 2+ < 3 2+ . Differences in the affinity for binding 1 2+ vs. 2 2+ or 3 2+ are almost entirely due to the size of the intercalating moiety, e.g. phen which can only be partially intercalated in comparison to dppz and tatpp which can be completely intercalated. The lower affinity for the dinuclear ruthenium 4 4+ is due to the solvation penalty for the second Ru core complex that extends out from the major groove. Comparing these results, we have begun to develop the structure function relationships for the interaction of RPCs with B‐DNA.