Half-Wave Potentials and In Vitro Cytotoxic Evaluation of 3-Acylated 2,5-Bis(phenylamino)-1,4-benzoquinones on Cancer Cells.

Julio Benites,Giulio G Muccioli,Angélica Guerrero-Castilla,Jaime A Valderrama,Pedro Buc Calderon,Maudy Valenzuela,Maryan Ramos

doi:10.3390/molecules24091780

Julio Benites, Giulio G Muccioli + Show 5 more

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https://doi.org/10.3390/molecules24091780

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Abstract

A broad range of 3-acyl-2,5-bis(phenylamino)-1,4-benzoquinones were synthesized and their voltammetric values, as well as in vitro cancer cell cytotoxicities, were assessed. The members of this series were prepared from acylbenzoquinones and phenylamines, in moderate to good yields (47–74%), through a procedure involving a sequence of two in situ regioselective oxidative amination reactions. The cyclic voltammograms of the aminoquinones exhibit two one-electron reduction waves to the corresponding radical-anion and dianion, and two quasi-reversible oxidation peaks. The first and second half-wave potential values (E1/2) of the members of the series were sensitive to the push-pull electronic effects of the substituents around the benzoquinone nucleus. The in vitro cytotoxic activities of the 3-acyl-2,5-bis(phenylamino)-1,4-benzoquinones against human cancer cells (bladder and prostate) and non-tumor human embryonic kidney cells were measured using the MTT colorimetric method. The substitution of both aniline groups, by either methoxy (electron donating effect) or fluorine (electron withdrawal effect), decreased the cytotoxicity in the aminoquinones. Among the members of the unsubstituted phenylamino series, two of the 18 compounds showed interesting anti-cancer activities. A preliminary assay, looking for changes in the expression of selected genes, was performed. In this context, the two compounds increased TNF gene expression, suggesting an association with an inflammatory-like response.

Highlights

The molecular frameworks of diverse naturally-occurring cytotoxic compounds, such as smenospongine [1], streptonigrin [2], and mansouramicyn C [3], contain the aminoquinoid moiety as their key structural component (Figure 1)
2a–q was accomplished through a sequence involving: Oxidation precursors 1a–q were synthesized by the solar Friedel Crafts photoacylation of (a)
2-acylquinones resulting in (b) with-1,4-benzoquinones 2a–q was accomplished through a sequence involving: (a) phenylamines (2 equiv.) in ethanol under aerobic conditions

Summary

Introduction

The molecular frameworks of diverse naturally-occurring cytotoxic compounds, such as smenospongine [1], streptonigrin [2], and mansouramicyn C [3], contain the aminoquinoid moiety as their key structural component (Figure 1). In the field of synthetic cytotoxic aminoquinones, those derived from 1,4-naphthoquinone [4,5,6,7,8] and their heterocyclic analogues [9,10,11,12,13,14,15,16,17] have received considerable attention. The synthesis and cytotoxic evaluation of aminobenzoquinones has hitherto received little attention and was mainly focused on the 2,5-bis(arylamino)-1,4-benzoquinone. Molecules 2019, 24, 1780 derivatives as compounds A and B. The earlier findings of Verter and Rogers [18] reported that derivatives as compounds A and B. 2,5-bis(alkylamino)-3,6-dimethoxy-1,4-benzoquinones, prepared from polyporic acid, increased increased the survival of L1210-bearing mice by 50%.

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