Synthesis, Half-Wave Potentials and Antiproliferative Activity of 1-Aryl-substituted Aminoisoquinolinequinones

Abstract

Abstract: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 727(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).

Antiproliferative Activity of New 6-Bromine Derivatives of 7-Anilino-1-Arylisoquinolinequinones

“…The required 7-anilino-isoquinoline-5,8-quinone precursors 1a-g were prepare from the respectives isoquinolinequinones according to previously reported procedures [17].…”

“…The E I 1/2 values for the first electron, which are related with the formation of the semiquinone radical anion [19,20], are in the potential range −407 to −485 mV (Figure 2; Table 1). 1/2 values of compounds 2a-g and precursors 1a-g [17] are showed in Figure 3 and Table 1. Analysis of the data indicate that the insertion of bromine into the scaffold of compounds 1a-g, as in 2a-g, induces the displacement of the half-wave potentials of the precursors 1a-g (E I : -407 to -485 mV).…”

“…In a previous work we reported that a number of anilinoisoquinolinequinone exhibit interesting antiproliferative activity against human gastric adenocarcinoma, human lung and human bladder carcinoma cancer cells [17]. On the basis of this background information we decided to design a new series of isoquinoline-5,8-quinone containing aniline and bromine substituents in the quinone ring to evaluate the combined electronic effects (push pull) of these groups on the redox and antiproliferative properties of the scaffold.…”

“…a The IC50 and E I 1/2 values were taken from ref [17]. b Data represent mean average values for six independent determinations; c Normal human lung fibroblasts cell line; d Human gastric adenocarcinoma cell line; e Promyelocytic leukemia cell line; f Determined by the ChemBioDraw Ultra 11.0 software.…”

“…Silica gel Merck 60 (70-230 mesh) was used for preparative column chromatography and TLC aluminium foil 60F 254 for analytical TLC. Compounds 1a-g were prepared according to a previously reported procedure [17].…”