NQO1-directed antitumour quinones

Abstract

NAD(P)H:(quinone acceptor) oxidoreductase 1 (NQO1) is a cytosolic flavoenzyme that catalyses the obligatory two-electron reduction of several quinones to their corresponding hydroquinones by using both NADH and NADPH. NQO1 has relevance in chemotherapy because bioreductive drugs require enzymatic activation prior to conversion into cytotoxic compounds. Because levels of NQO1 are elevated in some tumours, the enzyme provides an opportunity to develop improved new chemotherapeutic drugs that are bioactivated by this enzyme. The classical NQO1-directed drugs are quinone-containing alkylating agents, such as the prototypical bioreductive agent mitomycin C, and different azirinidylbenzoquinones, such as 2,5 bis-[1-aziridyl]-1,4 benzoquinone, that target DNA crosslinks and strand breaks after reduction. New analogues of those quinones, such as EO9 and RH1, have been developed to overcome the poor substrate specificity and poor solubility in aqueous solution in order to improve its therapeutic utilisation. Also, NQO1 is implied in the activation of new drugs that act as inhibitors of different proteins. β-Lapachone is not a DNA damaging agent and preclinical studies have shown very promising results. The benzoquinone ansamycins, 17-allylamino,17-demethoxygeldanamycin and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin, which exhibit anticancer activity by binding to heat-shock protein 90 (Hsp90), are also in clinical trials. NQO1 activity needs a threshold value to induce cytotoxicity. As a polymorphism in NQO1, known as NQO1*2, results in dramatically decreased NQO1 enzyme activity, NQO1 polymorphism should be carefully monitored in the patients before the use of NQO1-directed drugs.

Preparation and biological evaluation of novel acylhydrazide derivatives of 2,3-dichloronaphthoquinone

“…[1][2][3][4][5] Thus, the naphthoquinone acylhydrazides 6a-j were evaluated for their cytotoxic activity against MCF-7 and HCT116 cell lines using MTT viability assay. As a positive control, the biological activity of Doxorubicin was evaluated in parallel at three different concentrations (0.75, 10, 50 µM) by the MTT viability assay (Figure 3).…”

“…4 Mitomycin C 2, a bioreductive alkylating agent, expresses antitumor activity by the reductive redox-cycling hydroquinone. 5 Another representative quinone derivative with antitumor activity, Doxorubicin 3, (Figure 1) acts as an intercalator. 6 The mechanism of cytotoxic action is related to the interference of naphthoquinones in the DNA synthesis.…”

An efficient method for the synthesis of 6,7-bis(alkylthio- or alkylamino-substituted)quinoline-5,8-diones via nucleophilic addition/oxidation of alkylthio and alkylamino derivatives to quinoline-5,8-dione

“…Quinolinequinones have shown promise in possible anti-tumor, [1][2][3][4] anti-cancer, 5 anti-bacterial, 6 trypanocidal, 7 anti-tuberculosis, 8 anti-inflammatory, 9 anti-malarial agents, 10 and anti-fungal. 11 Scheme 1.…”

Cytotoxicity of anticancer aziridinyl-substituted benzoquinones in primary mice splenocytes.

“…Aziridinyl-substituted benzoquinones (Fig. 1) comprise an important group of potential antitumour agents (Di-Francesco et al, 2004;Alcain & Villalba, 2007;Parkinson et al, 2013, and references therein). Their antitumour activity stems mainly from the net two-electron reduction by flavoenzyme NAD(P)H:quinone oxidoreductase (NQO1, EC 1.6.99.2) into corresponding hydroquinones, which alkylate DNA more rapidly than the parent quinones (Lee et al, 1992;DiFrancesco et al, 2004).…”