Influence of substituent modifications on the binding of 2-amino-1,8-naphthyridines to cytosine opposite an AP site in DNA duplexes: thermodynamic characterization.
Here, we report on a significant effect of substitutions on the binding affinity of a series of 2-amino-1,8-naphthyridines, i.e., 2-amino-1,8-naphthyridine (AND), 2-amino-7-methyl-1,8-naphthyridine (AMND), 2-amino-5,7-dimethyl-1,8-naphthyridine (ADMND) and 2-amino-5,6,7-trimethyl-1,8-naphthyridine (ATMND), all of which can bind to cytosine opposite an AP site in DNA duplexes. Fluorescence titration experiments show that the binding affinity for cytosine is effectively enhanced by the introduction of methyl groups to the naphthyridine ring, and the 1:1 binding constant (10(6) M(-1)) follows in the order of AND (0.30) < AMND (2.7) < ADMND (6.1) < ATMND (19) in solutions containing 110 mM Na(+) (pH 7.0, at 20 degrees C). The thermodynamic parameters obtained by isothermal titration calorimetry experiments indicate that the introduction of methyl groups effectively reduces the loss of binding entropy, which is indeed responsible for the increase in the binding affinity. The heat capacity change (DeltaC(p)), as determined from temperature dependence of the binding enthalpy, is found to be significantly different between AND (-161 cal/mol K) and ATMND (-217 cal/mol K). The hydrophobic contribution appears to be a key force to explain the observed effect of substitutions on the binding affinity when the observed binding free energy (DeltaG(obs)) is dissected into its component terms.
Sato
Yusuke
Y
Department of Chemistry, Graduate School of Science, Tohoku University, CREST, Japan Science and Technology Agency, Aoba-ku, Sendai 980-8578, Japan.
Nishizawa
Seiichi
S
Yoshimoto
Keitaro
K
Seino
Takehiro
T
Ichihashi
Toshiki
T
Morita
Kotaro
K
Teramae
Norio
N
D002151:Calorimetry; D003596:Cytosine / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D009287:Naphthyridines / Q000737:chemistry*; D009691:Nucleic Acid Denaturation; D013050:Spectrometry, Fluorescence; D013816:Thermodynamics
C427025:2-amino-1,8-naphthyridine; D009287:Naphthyridines; D003596:Cytosine; D004247:DNA