Mitochondrial Complex I plays a crucial role in the proliferation, chemoresistance, and metastasis of breast cancer (BC) cells. This highlights it as an attractive target for anti-cancer drugs. Using submitochondrial particles, we identified FRV–1, an ortho-carbonyl quinone, which inhibits NADH:duroquinone activity in D-active conformation and reduces the 3ADP state respiration dependent on Complex I, causing mitochondrial depolarization, ATP drop, increased superoxide levels, and metabolic remodeling towards glycolysis in BC cells. Introducing methyl groups at FRV–1 structure produced analogs that acted as electron acceptors at the Complex I level or increased the inhibitory effect of FCCP-stimulated oxygen consumption rate, which correlated with their redox potential, but increased toxicity on RMF-621 human breast fibroblasts was observed. FRV–1 was inactive in the naphthoquinone oxidoreductase 1 (NOQ1)-positive BC cell line, MCF7, but the sensitivity was recovered by dicoumarol, a NOQ1 inhibitor, suggesting that FRV–1 is a NOQ1 substrate. Importantly, FRV–1 selectively inhibited the proliferation, migration, and invasion of NQO1 negative BC cell, MDA-MB-231, in an OXPHOS- and ROS-dependent manner and sensitized it to the BH3 mimetic drug venetoclax. Overall, FRV–1 is a novel Complex I inhibitor in D-active conformation, blocking possibly the re-activation to A-state, producing selective anti-cancer effects in NQO1-negative BC cell lines.

Intramolecular hydrogen bond (IMHB) interactions have attracted considerable attention due to their central role in molecular structure, chemical reactivity, and interactions of biologically active molecules. Precise correlations of the strength of IMHB’s with experimental parameters are a key goal in order to model compounds for drug discovery. In this work, we carry out an experimental (NMR) and theoretical (DFT) study of the IMHB in a series of structurally similar o-carbonyl hydroquinones. Geometrical parameters, as well as Natural Bond Orbital (NBO) and Quantum Theory of Atoms in Molecules (QTAIM) parameters for IMHB were compared with experimental NMR data. Three DFT functionals were employed to calculated theoretical parameters: B3LYP, M06-2X, and ωB97XD. O^…H distance is the most suitable geometrical parameter to distinguish among similar IMHBs. Second order stabilization energies ΔE_ij⁽²⁾ from NBO analysis and hydrogen bond energy (E_HB) obtained from QTAIM analysis also properly distinguishes the order in strength of the studied IMHB. ΔE_ij⁽²⁾ from NBO give values for the IMHB below 30 kcal/mol, while E_HB from QTAIM analysis give values above 30 kcal/mol. In all cases, the calculated parameters using ωB97XD give the best correlations with experimental ¹H-NMR chemical shifts for the IMHB, with R² values around 0.89. Although the results show that these parameters correctly reflect the strength of the IMHB, when the weakest one is removed from the analysis, arguing experimental considerations, correlations improve significantly to values around 0.95 for R².

A prospective study of the dye properties of non-toxic lawsone thiophenyl derivatives, obtained using a green synthetic methodology allowed for the description of their bathochromic shifts in comparison to those of lawsone, a well-known natural pigment used as a colorant that recently also has aroused interest in dye-sensitized solar cells (DSSCs). These compounds exhibited colors close to red, with absorption bands in visible and UV wavelength range. The colorimetric study showed that these compounds exhibited a darker color than that of lawsone within a range of colors depending on the substituent in the phenyl ring. Computational calculations employing Density Functional Theory (DFT) and Time-Dependent Density Functional Theory (TD-DFT), showed that the derivatives have lower excitation energies than lawsone, while the alignment of their frontier orbitals regarding the conduction bands of TiO₂ and ZnO and the redox potential of the electrolyte I⁻/I₃⁻ suggests that they could be employed as sensitizers. The study of the interactions of the lawsone and a derivative with a TiO₂ surface model by different anchoring modes, showed that the adsorption is thermodynamically favored. Natural bond orbital (NBO) analysis indicates a two-center bonding (BD) O-Ti as the main interaction of the dyes with TiO₂.

α-glucosidase, a pharmacological target for type 2 diabetes mellitus (T2DM), is present in the intestinal brush border membrane and catalyzes the hydrolysis of sugar linkages during carbohydrate digestion. Since α-glucosidase inhibitors (AGIs) modulate intestinal metabolism, they may influence oxidative stress and glycolysis inhibition, potentially addressing intestinal dysfunction associated with T2DM. Herein, we report on a study of an ortho-carbonyl substituted hydroquinone series, whose members differ only in the number and position of methyl groups on a common scaffold, on radical-scavenging activities (ORAC assay) and correlate them with some parameters obtained by density functional theory (DFT) analysis. These compounds’ effect on enzymatic activity, their molecular modeling on α-glucosidase, and their impact on the mitochondrial respiration and glycolysis of the intestinal Caco-2 cell line were evaluated. Three groups of compounds, according their effects on the Caco-2 cells metabolism, were characterized: group A (compounds 2, 3, 5, 8, 9, and 10) reduces the glycolysis, group B (compounds 1 and 6) reduces the basal mitochondrial oxygen consumption rate (OCR) and increases the extracellular acidification rate (ECAR), suggesting that it induces a metabolic remodeling toward glycolysis, and group C (compounds 4 and 7) increases the glycolysis lacking effect on OCR. Compounds 5 and 10 were more potent as α-glucosidase inhibitors (AGIs) than acarbose, a well-known AGI with clinical use. Moreover, compound 5 was an OCR/ECAR inhibitor, and compound 10 was a dual agent, increasing the proton leak-driven OCR and inhibiting the maximal electron transport flux. Additionally, menadione-induced ROS production was prevented by compound 5 in Caco-2 cells. These results reveal that slight structural variations in a hydroquinone scaffold led to diverse antioxidant capability, α-glucosidase inhibition, and the regulation of mitochondrial bioenergetics in Caco-2 cells, which may be useful in the design of new drugs for T2DM and metabolic syndrome.

The electrochemical behavior of N-methyl- and N-benzyl-4-piperidone curcumin analogs were studied experimentally and theoretically. The studied compounds present different substituents at the para position in the phenyl rings (-H, -Br, -Cl, -CF₃, and -OCH₃). We assessed their electrochemical behavior by differential pulse and cyclic voltammetry, while we employed density functional theory (DFT) M06 and M06-2x functionals along with 6-311+G(d,p) basis set calculations to study them theoretically. The results showed that compounds suffer a two-electron irreversible oxidation in the range of 0.72 to 0.86 V, with surface concentrations ranging from 1.72 × 10⁻⁷ to 5.01 × 10⁻⁷ mol/cm². The results also suggested that the process is diffusion-controlled for all compounds. M06 DFT calculations showed a better performance than M06-2x to obtain oxidation potentials. We found a good correlation between the experimental and theoretical oxidation potential for N-benzyl-4-piperidones (R² = 0.9846), while the correlation was poor for N-methyl-4-piperidones (R² = 0.3786), suggesting that the latter suffer a more complex oxidation process. Calculations of the BDEs for labile C-H bonds in the compounds suggested that neither of the two series of compounds has a different tendency for a proton-coupled electron transfer (PCET) oxidation process. It is proposed that irreversible behavior is due to possible dimerization of the compounds by Shono-type oxidation.

Synthesis, the complete ¹H- and ¹³C-NMR assignments, and the long-range C,H coupling constants (ⁿJ_C,H) of some hydrogen-deficient carbazolequinones, assessed by a J-HMBC experiment, are reported. In these molecules, the protons, used as entry points for assignments, are separated by several bonds with non-protonated atom carbons. Therefore, the use of long-range NMR experiments for the assignment of the spectra is mandatory; we used HSQC and HMBC. On the other hand, the measured heteronuclear (C,H) coupling constants ²J to ⁵J) allow us to choose the value of the long-range delay used in the HMBC experiment less arbitrarily in order to visualize a desired correlation in the spectrum. The chemical shifts and the coupling constant values can be used as input for assignments in related chemical structures.