| Title
| - Ground-State Stability and Rotational Activation Parameters forIndividual Rotamers of (R,S,S,R)-(N,N‘-Dimethyl-2,3-diaminobutane)PtG2Complexes (G = 9-EtG, 3‘-GMP, and 5‘-GMP)
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| Abstract
| - Rate constants for guanine rotation about the Pt−N7 bond in (R,S,S,R)-Me2DABPtG2 complexes (Me2DAB = N,N‘-dimethyl-2,3-diaminobutane; G = 9-EtG, 3‘-GMP, and 5‘-GMP) were evaluated from line-shape analysis of H8resonances. Three diastereomers, two in head-to-tail (ΔHT and ΛHT) and one in head-to-head (HH) conformations,exist in equilibrium in solution. The two guanines are equivalent in ΔHT and ΛHT conformers and nonequivalentin the HH form; therefore, four rate constants (kΔHT, kΛHT, kHHs, and kHHd; sub-subscripts s and d stand for H8-shielded and -deshielded guanine, respectively) were evaluated. Activation parameters (ΔH⧧ and ΔS⧧) were evaluatedfrom the rate constant dependence on temperature. High values of ΔH⧧ (78−93 kJ mol-1) and ΔS⧧ (51−71 J K-1mol-1) were found for G rotation in the preferred ΔHT rotamer having the six-membered ring of each guaninemore canted toward the cis-G and a favorable dipole−dipole internucleotide interaction. Lower values of ΔH⧧(64−76 kJ mol-1) and very small values of ΔS⧧ (−7−11 J K-1 mol-1) were found for G rotation in the less favorableΛHT rotamer, indicating that the ground-state entropy of this rotamer is close to that of the activated complex andthe ground-state enthalpy closer to that of the activated complex than for the ΔHT rotamer. For the two guaninesin the HH rotamer there is no large difference in activation parameters. In general ΔH⧧ falls in the range 66−84kJ mol-1 (rather close to the values for the ΛHT rotamer) and ΔS⧧ in the range 14−41 J K-1 mol-1. The equilibriumconstant between HT and HH rotamers was also evaluated together with the corresponding thermodynamicparameters (ΔH and ΔS). It is found that the low enthalpy is the major stabilizing factor for ΔHT as compared toHH, while the entropy factor would favor the latter rotamer. In contrast the greater entropy is the stabilizing factorfor the ΛHT rotamer (the second most abundant conformer for 9-EtG and 3‘-GMP) over the HH rotamer. In thelatter case the enthalpy would favor the HH rotamer. In the case of the 5‘-GMP derivative the greater entropy ofthe ΛHT rotamer is not such to compensate for the lower enthalpy of the HH rotamer, and the latter remains thesecond most abundant rotamer. This investigation has allowed for the first time the enthalpic and entropic contributionsfavoring different rotamers to be distinguished.
- For the first time the ground-state stability of different rotamers in cis-PtA2G2 complexes (model compounds of the major DNA adducts of antitumoral cisplatin) has been quantified in terms of enthalpy and entropy. The variations in thermodynamic parameters have been correlated with specific chemical interactions. It has also been found that the ground-state stability of the conformers modulates the activation parameters for G rotation about the Pt−N7 bond.
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