Tetracyclines are a class of derivatives of polycyclic naphthacene carboxamide, which have attracted wide interest in the pharmaceutical field for their use as antibiotics. These molecules are characterized by a substantial conformational flexibility and by the presence of different binding sites which endow tetracycline with a noticeable capability in binding biological targets. A salient property of tetracyclines is the presence of multiple acidic groups: four equilibrium constants have been measured for the fully protonated tetracycline (TCH3+) but so far no clear information concerning the pK(a)s of the various sites has been reported. We present here a computational investigation on the correlation between the acid-base and the spectroscopic properties of this important class of compounds. Starting from the TCH3+ species, the pK(a) of all the possible deprotonation sites has been computed by DFT calculations. The computed pK(a)s nicely compare with the experimental data, within 1 pK(a) unit, allowing us to individuate the products of the first deprotonation. This procedure has been iteratively repeated using as starting species the products singled out from the previous deprotonation, thus individuating the stepwise products of each deprotonation step. Then, the optical absorption spectra have been computed for all the species involved in the protonation/deprotonation equilibria, comparing the results with the experimental data. The good agreement between theory and experiment has allowed us to rationalize the correlation between the solution pH and the absorption spectra.
DFT/TDDFT investigation of the stepwise deprotonation in tetracycline: pKa assignment and UV-vis spectroscopy
AMAT ALBERTI, ANNA;F. De Angelis;CARLOTTI, BENEDETTA;ELISEI, Fausto
2012
Abstract
Tetracyclines are a class of derivatives of polycyclic naphthacene carboxamide, which have attracted wide interest in the pharmaceutical field for their use as antibiotics. These molecules are characterized by a substantial conformational flexibility and by the presence of different binding sites which endow tetracycline with a noticeable capability in binding biological targets. A salient property of tetracyclines is the presence of multiple acidic groups: four equilibrium constants have been measured for the fully protonated tetracycline (TCH3+) but so far no clear information concerning the pK(a)s of the various sites has been reported. We present here a computational investigation on the correlation between the acid-base and the spectroscopic properties of this important class of compounds. Starting from the TCH3+ species, the pK(a) of all the possible deprotonation sites has been computed by DFT calculations. The computed pK(a)s nicely compare with the experimental data, within 1 pK(a) unit, allowing us to individuate the products of the first deprotonation. This procedure has been iteratively repeated using as starting species the products singled out from the previous deprotonation, thus individuating the stepwise products of each deprotonation step. Then, the optical absorption spectra have been computed for all the species involved in the protonation/deprotonation equilibria, comparing the results with the experimental data. The good agreement between theory and experiment has allowed us to rationalize the correlation between the solution pH and the absorption spectra.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
