Deoxynyboquinones as NQO1-Activated Cancer Therapeutics

Abstract

One of the major goals of cancer therapy is the selective targeting of cancer cells over normal cells. Unfortunately, even with recent advances, the majority of chemotherapeutics still indiscriminately kill all rapidly dividing cells. Although these drugs are effective in certain settings, their inability to specifically target cancer results in significant dose-limiting toxicities. One way to avoid such toxicities is to target an aspect of the cancer cell that is not shared by normal cells. A potential cancer-specific target is the enzyme NAD(P)H quinone oxidoreductase 1 (NQO1). NQO1 is a 2-electron reductase responsible for the detoxification of quinones. Its expression is typically quite low in normal tissue, but it has been found to be greatly overexpressed in many types of solid tumors, including lung, breast, pancreatic, and colon cancers. This overexpression is thought to be in response to the higher oxidative stress of the cancer cell, and it is possible that NQO1 contributes to tumor progression. The overexpression of NQO1 and its correlation with poor patient outcome make it an intriguing target. Although some have explored inhibiting NQO1 as an anticancer strategy, this has generally been unsuccessful. A more promising strategy is to utilize NQO1 substrates that are activated upon reduction by NQO1. For example, in principle, reduction of a quinone can result in a hydroquinone that is a DNA alkylator, protein inhibitor, or reduction-oxidation cycler. Although there are many proposed NQO1 substrates, head-to-head assays reveal only two classes of compounds that convincingly induce cancer cell death through NQO1-mediated activation. In this Account, we describe the discovery and development of one of these compounds, the natural product deoxynyboquinone (DNQ), an excellent NQO1 substrate and anticancer agent. A modular synthesis of DNQ was developed that enabled access to the large compound quantities needed to conduct extensive mechanistic evaluations and animal experiments. During these evaluations, we found that DNQ is an outstanding NQO1 substrate that is processed much more efficiently than other putative NQO1 substrates. Importantly, its anticancer activity is strictly dependent on the overexpression of active NQO1. Using previous crystal structures of NQO1, novel DNQ derivatives were designed that are also excellent NQO1 substrates and possess properties that make them more attractive than the parent natural product for translational development. Given their selectivity, potency, outstanding pharmacokinetic properties, and the ready availability of diagnostics to assess NQO1 in patients, DNQ and its derivatives have considerable potential as personalized medicines for the treatment of cancer.

Formation and Biological Targets of Quinones: Cytotoxic versus Cytoprotective Effects

“…190 Since NQO1 activity is much higher in cancer cells compared to that in normal cells, quinone-mediated inhibition of NQO1 could be an effective anticancer strategy. 191 For example, the natural product deoxynyboquinone is a potent NQO1 substrate and inhibitor through an NQO1-catalyzed redox cycling mechanism and deoxynyboquinone could have considerable potential as a chemotherapeutic agent (Table 2). 191 …”

“…191 For example, the natural product deoxynyboquinone is a potent NQO1 substrate and inhibitor through an NQO1-catalyzed redox cycling mechanism and deoxynyboquinone could have considerable potential as a chemotherapeutic agent (Table 2). 191 …”

Reactive Oxygen Species Synergize To Potently and Selectively Induce Cancer Cell Death

“…29 Reduction of DNQ by NQO1 generates an unstable hydroquinone, which is rapidly and spontaneously oxidized back to the parent, forming superoxide in the process (Figure 1A). 24 Greater than 60 mols of superoxide are generated by each mole of DNQ; 22, 24 this burst of superoxide overwhelms the cellular capacity to convert it to hydrogen peroxide, thus DNQ is an outstanding compound for generation of rapid and persistent cellular superoxide. LDH-A catalyzes the conversion of pyruvate to lactate, and high LDH-A levels are frequently found in tumors and correlate with poor prognosis and low response to chemotherapy.…”

Combined molecular modelling and 3D‐QSAR study for understanding the inhibition of NQO1 by heterocyclic quinone derivatives

“…DNA alkylation and cross‐linking after chemical or enzymatic reduction are more frequently described . Among the enzymes that reduce quinones, NAD(P)H:quinone oxidoreductase 1 (NQO1, DT‐diaphorase, EC 1.6.99.2) has received considerable attention recently as a potential cancer‐specific target, because it is overexpressed in many tumour tissues . NQO1 is a homodimeric flavoprotein that catalyses the obligatory two‐electron reduction of quinone to hydroquinone using NADH or NADPH as cofactor .…”

“…[9] Among the enzymes that reduce quinones, NAD(P)H:quinone oxidoreductase 1 (NQO1, DT-diaphorase, EC 1.6.99.2) has received considerable attention recently as a potential cancer-specific target, because it is overexpressed in many tumour tissues. [10][11][12][13][14][15] NQO1 is a homodimeric flavoprotein that catalyses the obligatory two-electron reduction of quinone to hydroquinone using NADH or NADPH as cofactor. [16,17] In general, this process is considered a detoxification mechanism because a relatively stable hydroquinone is formed, preventing production of a highly reactive semiquinone that undergoes redox cycling and generation of reactive oxygen species (ROS).…”