Thermodynamics of Chelation by Tetracyclines

Abstract

Thermodynamic data were determined for the complexation of five tetracycline analogs with cupric ion. Free energy values were calculated from data previously published by the authors. Enthalpy determinations were made in a Dewar calorimeter. Entropy values were determined from ΔG° and ΔH° at 25°. For the formation of 1:1 complexes, ΔH° was approximately — 12 Kcal./mole and ΔS° was approximately — 4 e.u. for the three chlor-analogs studied (4-epi-chlor-, demethylchlor-, and chlortetracycline), while a ΔH° of — 7.6 Kcal./mole and a ΔS° of+10.2 e.u. was obtained for tetracycline. It is suggested that all of the analogs studied form inner sphere 1:1 complexes with cupric ion but that the chlorine at C-7 compels the three chlorderivatives to undergo a more severe conformational change than tetracycline in order to reach a favorable configuration for chelation. All of the above analogs showed a small negative enthalpy change and a large positive entropy change for 2:1 complex formation. It is suggested that all four analogs form outer sphere or ion-pair complexes during 2:1 complexation.