Insight into the Mechanism of Action of Marine Cytotoxic Thiazinoquinones

Abstract

The electrochemical response of four natural cytotoxic thiazinoquinones isolated from the Aplidium species was studied using conventional solution-phase and solid-state techniques, based on the voltammetry of immobilized particles methodology. The interaction with O₂ and electrochemically generated reactive oxygen species (ROS) was electrochemically monitored. At the same time, a molecular modeling study including density functional theory (DFT) calculations was performed in order to analyze the conformational and electronic properties of the natural thiazinoquinones, as well as those of their reduced intermediates. The obtained electrochemical and computational results were analyzed and correlated to cytotoxic activity of these compounds, highlighting some features possibly related to their mechanism of action.

Keywords: DFT calculations; bioactive natural products; cytotoxic activity; electrochemistry; reactive radical species; thiazinoquinones.

Figure 1

Structures of thiaplidiaquinone B (1); conicaquinone A (2); conithiaquinones A and B (3, 4).

Figure 2

Cyclic voltammograms of 2 microparticulate films on a glassy carbon electrode immersed into 0.10 M PBS at pH 7.4. Potential scan initiated at 0.0 V (a) in the negative and (b) in the positive directions; potential scan rate 50 mV·s⁻¹.

Scheme 1

Reduction pathway for the electrochemical reduction of quinone to hydroquinone in aqueous environment.

Figure 3

Cyclic voltammograms, after semi-derivative convolution, of (a) 2; (b) 3; (c) 4; and (d) 1 microparticulate films on glassy carbon electrodes immersed into 0.10 M PBS at pH 7.4. Potential scan initiated at 0.0 V (a) in the negative and (b) in the positive directions; potential scan rate 50 mV·s⁻¹.

Figure 4

Cyclic voltammograms, after semi-derivative deconvolution, of an unmodified glassy carbon electrode in (a) air-saturated and (b) deoxygenated PBS solution at pH 7, and that electrode modified with (c) 3; (d) 2; and (e) 1 all in contact with air-saturated PBS. Potential scan rate 50 mV·s⁻¹.

Figure 5

Square-wave voltammograms at unmodified (red lines) and 3-modified (black lines) glassy carbon electrodes in contact with air-saturated PBS at pH 7.4. Potential scan initiated at −1.05 V in the positive direction; potential step increment 4 mV; square-wave amplitude 25 mV; frequencies of (a) 50 and (b) 5 Hz. Only the region of potentials around the peak A_ox is depicted.

Figure 6

Cyclic voltammograms at a glassy carbon electrode, after semi-derivative convolution, of different 0.10 M Bu₄NPF₆/DMSO solutions. (a) air-saturated and (b) deoxygenated electrolyte solution; 0.5 mM 3 in (c) deoxygenated and (d) air-saturated electrolyte; (c) 0.5 mM 1 in (e) deoxygenated and (f) air-saturated electrolyte. Potential scan rate 50 mV·s⁻¹.

Figure 7

Cyclic voltammograms at a glassy carbon electrode, after semi-derivative convolution, of different 0.10 M Bu₄NPF₆/DMSO solutions. (a) 0.5 mM of 2; (b) air-saturated 0.5 mM of 2 + 0.5 mM water; (c) air-saturated 0.10 M Bu₄NPF₆/DMSO +0.5 mM water. Potential scan rate 50 mV·s⁻¹.

Figure 8

Schematic representation of the formation of the two possible protonated semiquinone radicals in the reduction pathway of natural thiazinoquinones.

Figure 9

Q^•−, QH^•_i, QH^•_ii, QH_i⁻, QH_ii⁻, and QH₂ species of 3 obtained from DFT calculations.