The synthesis of five novel homodimers is reported based on the anilinoisoquinolinequinone scaffold. In these twin-drug derivatives, two units of the anilinoquinone pharmacophores are linked through a methylene spacer. The formation of dimers was achieved by reaction of isoquinolinequinones with 4, 4’-diaminodiphenylmethane via a sequence of two oxidative amination reactions. A preliminary in vitro screening of the homodimers reveals moderate to high cytotoxic activities against MDA-MB-21 breast adenocarcinoma and B16-F10 murine metastatic melanoma cell lines. The asymmetrical homodimer 15 stands out due to its cytotoxic potencies at submicromolar concentrations and high selectivity index (mean IC₅₀ = 0.37 μM; SI = 6.97) compared to those of etoposide (mean IC₅₀ = 3.67; SI = 0.32) and taxol (mean IC₅₀ = 0.35; SI = 0.91) employed as reference anticancer drugs.

The synthesis of a variety of 1-aryl-7-phenylaminoisoquinolinequinones from 1,4-benzoquinone and arylaldehydes via the respective 1-arylisoquinolinequinones is reported. The cyclic voltammograms of the new compounds exhibit two one-electron reduction waves to the corresponding radical-anion and dianion and two quasi-reversible oxidation peaks. The half-wave potential values (E^I_½) of the members of the series have proven sensitive to the electron-donor effect of the aryl group (phenyl, 2-thienyl, 2-furyl) at the 1-position as well as to the phenylamino groups (anilino, p-anisidino) at the 7-position. The antiproliferative activity of the new compounds was evaluated in vitro using the MTT colorimetric method against one normal cell line (MRC-5 lung fibroblasts) and two human cancer cell lines: AGS human gastric adenocarcinoma and HL-60 human promyelocytic leukemia cells in 72-h drug exposure assays. Among the series, compounds 5a, 5b, 5g, 5h, 6a and 6d exhibited interesting antiproliferative activities against human gastric adenocarcinoma. The 1-arylisoquinolinequinone 6a was found to be the most promising active compound against the tested cancer cell lines in terms of IC50 values (1.19; 1.24 µM) and selectivity index (IS: 3.08; 2.96), respect to the anti-cancer agent etoposide used as reference (IS: 0.57; 0.14).

In the search for new quinoid compounds endowed with potential anticancer activity, the synthesis of novel heterodimers containing the cytotoxic 7-phenylaminoisoquinolinequinone and 2-phenylaminonaphthoquinone pharmacophores, connected through methylene and ethylene spacers, is reported. The heterodimers were prepared from their respective isoquinoline and naphthoquinones and 4,4′-diaminodiphenyl alkenes. The access to the target heterodimers and their corresponding monomers was performed both through oxidative amination reactions assisted by ultrasound and CeCl₃·7H₂O catalysis “in water”. This eco-friendly procedure was successfully extended to the one-pot synthesis of homodimers derived from the 7-phenylaminoisoquinolinequinone pharmacophore. The electrochemical properties of the monomers and dimers were determined by cyclic and square wave voltammetry. The number of electrons transferred during the oxidation process, associated to the redox potential E^I_1/2, was determined by controlled potential coulometry.

In this study, new homodimers and monoamination products based on the pharmacophore amino-1,4-naphthoquinone were synthesized. To perform a structure–activity study, three precursor quinones (2,3-dichloro-1,4-naphthoquinone, 1,4-naphthoquinone, and 2-hydroxy-1,4-naphthoquinone) and four diamines (4,4′-diaminodiphenylmethane, 4,4′-ethylenedianiline, ethylenediamine and 1,3-diaminopropane) were used. The reactions of the compounds were accomplished in the presence or the absence of Lewis acid as a catalyst. The new derivatives were evaluated as potential inhibitors of the enzyme glutathione-S-transferase (GST) by conjugating reduced glutathione (GSH) with the substrate 1-chloro-2,4-dinitrobenzene (CDNB). The study of the GST activity showed a clear structure–activity relationship in which the chlorinated compound 8 was the best inhibitor, with inhibition percentage values of 57%, being in the inhibition range as other GST inhibitors such as hexachlorophene and ethacrynic acid. These experimental results are consistent with molecular docking studies which show that compound 8 binds to the enzyme close to the catalytic site (G-site) and the chlorine group shows up to be essential for the stability of the ligand. Additionally, from the in silico exploration, a directly proportional trend between lipophilicity and enzyme affinity was noted, correlating with the experimental results of GST activity where the chlorine atom contributes positively to it. Finally, the electrochemical characterization provided another significant insight: the compounds with higher formal potential values (E⁰) had the electron-withdrawing group chlorine being the most active against GST.