Complexes of tetracyclines with divalent metal cations investigated by stationary and femtosecond-pulsed techniques

Abstract

Spectroscopic techniques both in steady-state (in absorption and emission) and pulsed (absorption of excited states with femtosecond resolution) conditions were used to study the complexation process between six molecules belonging to the tetracycline family and Mg(2+); in the case of TC the study was extended to the metal ions Ca(2+) and Cu(2+). The study was carried out in aqueous solution at various pH values, where one acid-base form of the substrate prevails over the others. The processing of experimental results, performed by means of Singular Value Decomposition and Global Analysis methods, allowed us to evaluate the extent of interaction through the association constants, to identify the number of equilibria present in solution and the stoichiometry (1:1 or 1:2) of the tetracycline:metal ion complex, and to define the spectral and photophysical properties of the latter (in terms of fluorescence quantum yields, lifetimes and rate constants). In fact, the (allowed) radiative decay process is a minor root for the lowest excited state of the complexes which mainly decay to the ground state by internal conversion. Details of the complexation sites are proposed for the various protonated forms of tetracyclines, and for the various cations in the case of TC. In particular, the molecular structure seems to affect significantly the dynamics of interaction when the upper peripheral region of tetracycline is rich in additional hydroxyl groups. Moreover, the state of protonation of the substrate produces changes in the order of the complexation sites, whose affinity for the cation increases significantly when they are negatively charged owing to the loss of protons. Magnesium and calcium (hard cations) give similar interactions, at least in acid solution, while copper(ii) (borderline cation) binds more efficiently on different sites, thus forming complexes with different properties.

DFT/TDDFT investigation of the stepwise deprotonation in tetracycline: pKa assignment and UV–vis spectroscopy

“…Since a pK a of 8.4 was computed for the TCH -(3,4) species, close to the 8.5 pH at which the spectrum was measured, we checked the possibility that the blue-shift with respect to the experimental spectrum was due to the presence of this species at the given pH. However, the simulated spectrum of the TCH -(3,4) species is very similar to that computed for TCH - (3,12), see Supporting Information, excluding this hypothesis as the origin of the deviation. The presence of a folded conformation at high pH was also investigated by optimizing the TCH -(3,12) folded species.…”

“…The two possible di-anionic species arising from these deprotonations are labeled TC 2- (3,12,4) and TC 2- (3,12,10), respectively. Similarly to what retrieved for the second deprotonation, the third deprotonation in site 10 leads to significant changes in the molecular structure.…”

“…The conformation flexibility and the presence of different complexation sites are among the reasons of tetracycline's success in binding biological targets [12]. Tetracyclines posses various carbonyl and hydroxyl groups which open the way to different complexation modes with metal ions [12]. Despite their clear role in pharmacology, tetracyclines have shown some side effects due to their phototoxicity and photosensitizing action [1,[26][27][28].…”

“…Due to tetracycline's various applications, the number of publications on this topic has quickly grown in the last years . The conformation flexibility and the presence of different complexation sites are among the reasons of tetracycline's success in binding biological targets [12]. Tetracyclines posses various carbonyl and hydroxyl groups which open the way to different complexation modes with metal ions [12].…”

Study of tetracycline adsorption by Zn-Al mixed oxides and layered double hydroxides

“…Based on the absorption spectra of TC, and according to [28], one can assume that the formation of complexes TC/Al 3+ = 2:1 and 1:1 is mediated by keto-enol group of the ВСD chromophore of TC molecule on C11, C11a and C12. The formations of the complex bind with the second ion Al 3+ occurs by involving a groups -С4-NH and С3О A chromophore [29].…”