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com Current Opinion in

ScienceDirect Electrochemistry

Review Article

Quinone-based molecular electrochemistry and their

contributions to medicinal chemistry: A look at the
present and future
Thaissa L. Silva1,2, Maria de Lourdes S. G. de Azevedo1,
Fabricia R. Ferreira1, Danyelle Candido Santos1,
Christian Amatore3,4 and Marília O. F. Goulart1

Abstract Introduction
Molecular electrochemistry is closely linked to life sciences. Redox processes are central to life through sustaining
Electron transfers play important roles in the bioactivation of most fundamental bioprocesses, from bioenergetics to
redox-active drugs, in their metabolism/catabolism, and in their metabolism, and life functions such as cellular respira-
targeted release at precise destinations and frequently pro- tion, photosynthesis, and neurotransmission [1]. The
mote their ligand–target interactions. Altogether, this rich quest for understanding molecular mechanisms under-
chemistry and the complexity of cellular environments and lying biological redox processes has revealed the need
biocompartmentation often impede full investigation in situ of for multidisciplinary approaches in which electrochem-
the whole chain of processes that sustain their therapeutic istry plays a central unifying role. There is a growing
applications. Conversely, electrochemical ex situ investigations interest about electrobioactive compounds to increase
of drug properties and interactions performed in aqueous/ or modulate their activities while avoiding undesirable
aprotic/micellar/membrane/cell-mimetic media, combined with results, by designing more effective drugs prone to
in vitro and in vivo data, are expected to provide extremely successfully find their way toward their targets or more
useful information on these processes. Therein, considering prosaically simply for a better understanding of biolog-
the ubiquitous case of quinones, we exemplified how such ically relevant redox mechanisms, and so on. In this
strategies allow controlling their beneficial or negative impact context, we wish to present molecular electrochemistry
on cellular environments. in relation to the life sciences by emphasizing the
importance of quinones, with multiple redox function-
Addresses alities in medicinal chemistry, by providing recent in-
1
Instituto de Química e Biotecnologia, Universidade Federal de
formation in the field of redox medicine and relevant
Alagoas, Maceió, AL, CEP: 57072-970, Brazil
2
Núcleo de Ciências Exatas - NCEx, Universidade Federal de interfaces.
Alagoas, Campus de Arapiraca, Arapiraca, AL, CEP: 57309-005, Brazil
3
PASTEUR, Département de Chimie, École Normale Supérieure, PSL As sketched in Figure 1, medicinal electrochemistry and
University, Sorbonne University, CNRS, 75005 Paris, France its interfaces created a new domain through integration
4
State Key Laboratory of Physical Chemistry of Solid Surfaces, Col-
of new techniques with longstanding ones for moni-
lege of Chemistry and Chemical Engineering, Xiamen University,
Xiamen, 361005, China toring, detecting, and possibly orienting biological ac-
tions of new molecular drugs in vivo toward desired
Corresponding author: Goulart, Marília O.F (mofg@qui.ufal.br) scopes and targets based on their electrochemical
mechanisms which often involves bond activation by
sequential or concerted electron transfers [2].
Current Opinion in Electrochemistry 2020, 24:79–87
This reviews comes from a themed issue on Organic and Molecular
Redox processes also enable direct transfer of informa-
electrochemistry
tion (in the form of electrons or light) between biolog-
Edited by Olivier Buriez
ical and electronic systems [3], such as, for instance, a
For a complete overview see the Issue and the Editorial redox-based electrogenetic clustered regularly inter-
Available online 13 July 2020 spaced short palindromic repeats (CRISPR) system [4]
https://doi.org/10.1016/j.coelec.2020.06.011 or in electrochemical luminescence for detection of
2451-9103/© 2020 Elsevier B.V. All rights reserved.
important biomolecules by entangling a priori inde-
pendent processes [5] possibly in new materials [6].
Keywords
In fact, the strong interaction of molecular electro-
Medicinal electrochemistry, Redox mechanisms, Interaction ligand-
target, Drug delivery, Metabolism, Clinical trials.
chemistry toward biomedical purposes operates not
necessarily in this direction, but investigations primarily

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80 Organic and Molecular electrochemistry

aimed to biomedical purposes [7,8] may find unsus- Biological activities of quinones have been investigated
pected applications in modern technologies. Multiredox and reported for decades, and the most relevant,
systems and multiple electron transfer reactions are included in Figure 3, are presented by the World Health
broadly relevant to areas such as high energy density Organization (WHO) among essential medicines
batteries, solar fuel production, catalysis, sensors, and (Figure 3A), with examples obtained from DrugBank,
photosynthesis, which require stable reduced and/or clinical trials (https://clinicaltrials.gov/, accessed on 24/
oxidized intermediate states of organic molecules 05/2020), and Clinical Trials Registry Platform (https://
[9,10]. In this context, it is worth recalling that qui- www.who.int/ictrp/en/, accessed on 24/05/2020). At
nones, which are the main subject of this article, have least 7 quinones (coenzyme Q10, idebenone, EPI-
proven useful through providing a large range of cell A0001, mitoquinone, SkQ1, troloxamide quinone, vati-
voltages because their chemical and redox properties quinone) (Figure 3A) are under clinical evaluation
can be easily modified via functionalization [11]. toward mitochondrial diseases, several being in phase II,
others in phase III and IV [7,21]. The majority had been
Why quinones? the subject of electrochemical investigations, especially
Quinones, quinonoids (quinoneimines, quinoneme- those included in Figure 3B, which were shown to have
thides, hydrazones), and their metallic complexes or anticancer [12,22e25], antibacterial [26], antifungal
their phenolic precursors represent a class of important [27], leishmanicidal [28,29], trypanocidal [30e33],
compounds per se, especially as biological intermediates antimalarial [34], and molluscicidal [35] properties,
leading to a variety of beneficial/hazardous effects in vivo among others.
[12e15] (Figure 2).
Quinones can induce cytoprotection through efficient
Figure 2 summarizes the close fundamental relation- induction of detoxification enzymatic pathways, anti-
ships between biomedical and technological applica- inflammatory activities, and modification of redox
tions of quinones. They are important molecular players status [22]. However, under other biomedical circum-
in the living world through acting as redox catalysts, as stances, these very same activities may lead to acute
antioxidants and pro-oxidants [16], and as dyes and cytotoxicity, immunotoxicity, and carcinogenesis
pigments [17], among others. Quinones are typical co- through mechanisms reported in Figure 4.
enzymes acting in electron transport chains to shuttle
electrons between many membrane proteins, but their A very typical ambivalent role of quinones, ranging from
reputed proficiency in biology for energy conservation/ highly positive to highly negative, depending on the
transduction stimulated interest for their application in quinone structure and its concentration [16], concerns
advanced Li/Na batteries [18, 19] or as catalysts in fuel their strong coupling as electron carriers with oxidative
biocells [20]. stress mechanisms leading to the production of reactive

Figure 1

Medicinal electrochemistry and interfaces.

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 Quinone-based molecular medicinal electrochemistry Silva et al. 81

Figure 2

Applications of quinones and precursors in several areas, with emphasis in life and health sciences (highlighted in red). General structures for ortho-
quinones (o-Q), para-quinones (p-Q), iminoquinones (IQ), metal complexes of quinones (QMetal), azoquinones (AzQ), and catechol (Ph(OH)2). Refer
Figure 3 for the actual structures of clinically relevant quinones and quinone derivatives.

oxygen species/reactive nitrogen species (ROS/RNS) two-electron transfer pathways, for example, by
and their follow-up products, as sketched in Figure 4A. NAD(P)H:quinone oxidoreductase 1 (NQO1), initia-
ROS/RNS are essential for redox signaling, cell ho- ting bioreductive cascades leading to alkylations
meostasis [36], and so on; however, their overexpression through the generation of electrophilic intermediates
can cause irreversible damage to macromolecules, (Figure 4B). Low oxygen tensioneactivated nano-
leading to beneficial medical outcomes when this is medicines [37] have precisely been designed to initiate
induced spontaneously or not inside unwanted cells (for such pathways in solid tumors placed in hypoxia.
instance, in tumors, bacteria, parasites, and so on) or
harmful ones when this occurs into functional cells of Quinones per se are electrophiles prone to undergo
the host [1]. Semiquinone radicals (SQ-) generated by Michael addition by several nucleophilic endobiotics.
enzymatic oxidation of phenols or reduction of quinones For instance, their spontaneous reaction with gluta-
catalyzed by enzymes such as cytochrome P450 can thione (Figure 4C) enforces their irreversible excretion
react with oxygen molecules to generate superoxide ions from cells, possibly leading to undesirable biologically
which lead to deadly ROS/RNS levels as soon as the active follow-up products.
antioxidant defenses of the host cell are overcome.
Among these detrimental species is H2O2 which readily They can also interact with multiple molecular targets,
produces the extremely damaging OH radicals by which elicit their intracellular effects, leading to
Fenton reaction, catalyzed by free transition metal changes in signal transduction, gene expression, and/or
traces. metabolism, which can, subsequently, affect the entire
cell and the host organisms (Figure 4D). There are
In many human tumors (ovarian, breast, colon cancer, varied biological targets of quinones including protein
and so on), quinones can also be reduced via direct sulfhydryls (heat shock proteins, P450s, cyclooxygenase-

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82 Organic and Molecular electrochemistry

Figure 3

a
Alvespimycin Apaziquone Atovaquone Banoxantrone BW-A 58C

Carboquone Coenzyme Q10 Daikenchuto TU-100 Daunorubicin Diacerein

2,5-diaziridinyl-3- 2,3-dichloro-5,6- 2,3-Dimethyl-1,4- Doxorubicin Duroquinone

[hydroxymethyl]-6- dicyanobenzoquinone naphthoquinone
methyl-1,4-
benzoquinone

Emodin EPI-A0001 Flaviolin Geldanamycin

Idebenone IPI-493 Iprazochrome KH-176 β-Lapachone

Lawsone Menadiol diphosphate Menadione Menaquinone Menaquinone 6

Menatetrenone Mitomycin Mitoquinone

Mitoxantrone Naftazone Nanaomycin D Napabucasin Ochromycinone

Current Opinion in Electrochemistry

Structures of the most clinically relevant quinones. (a): In use or in clinical trials; (b) with electrochemical studies relevant for their activity.

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 Quinone-based molecular medicinal electrochemistry Silva et al. 83

Figure 3

Phylloquinone (Vitamin K1) Porfiromycin Quinalizarin Retaspimycin

Rhein SkQ1 Seratrodast Tanespimycin

Troloxamide quinone Ubidecarenone Ubiquinol Ubiquinone Q1 Ubiquinone Q2

(EPI-589)

Vatiquinone

b
Biflorin Cationic anthraquinone LQB-118 Fluorescent lapachone-based BODIPY
analogs

Hydroxynaphthoquinone Naphthoquinone -aminophenol derivatives Naphthoquinone-containing triazoles

Nitro-substituted nor-β-lapachones 3-thio-substituted- Transition metal complexes containing quinone

nor-β-lapachone

Ru(II)-naphthoquinone complexes

Current Opinion in Electrochemistry

continued

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84 Organic and Molecular electrochemistry

Figure 4

Main mechanisms of molecular action of quinones. Adapted from the studies by Bolton and Dunlap et al [12, Bolton et al [13], and de Paiva et al [44]].
Meanings of the acronyms: ARE: antioxidant response element; BiP: binding immunoglobin protein; COX-2: cyclooxygenase-2; GSH: glutathione; GST:
glutathione S-transferase; HO-1: heme oxygenase-1; HSP: heat shock protein; IKK: IkB kinase; JNK: c-Jun N-terminal kinase; Keap1: kelch-like ECH-
associated protein 1; MAPK: mitogen-activated protein kinase; Nf-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf2: NF-E2-related
factor 2; NQO1: NAD(P)H:quinone oxidoreductase 1; P450: cytochrome P450; PDI: protein disulfide isomerase; RNS: reactive nitrogen species; ROS:
reactive oxygen species; SOD: superoxide dismutase.

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 Quinone-based molecular medicinal electrochemistry Silva et al. 85

2, glutathione S-transferase, NQO1, kelch-like ECH- can be translated into meaningful in vivo and clinical
associated protein 1, IkB kinase, and aryl hydrocarbon results. Nonetheless, electrochemistry, possibly coupled
receptor) (Figure 4D) [12,13]. DNA is also an important with spectroelectrochemical and computational ana-
target for quinones, so, besides its medical applications, lyses, has proven successful for providing rational
this property has been used to design DNA-based mechanistic bases underlying the action of anticancer/
electrochemical sensors for detecting biomedically parasiticidal drugs, for instance, through revealing the
active quinones [38,39], as exemplified by studies with occurrence of highly reactive intermediates such as
biflorin (Figures 3B and 4E) [40] or with pter- quinonemethides [41,42], or for the design of better
ocarpanquinones [41,42] (Figure 3B). In Figure 4F, redox-active drugs activated in situ by intramolecular
quinones are shown to be carriers of active compounds, electron transfer [50].
released after a step of bioredox elimination (by
reduction or oxidation) [37,43]. Conclusions
We hope that this review will stimulate researchers to
Structure and electroactivity relation: a strategy for
become more involved in this fruitful interface between
the design and development of redox-selective drugs
molecular electrochemistry and life sciences. Future
Various human diseases, including different types of
studies need to be performed to better clarify relation-
cancer and tropical diseases, such as trypanosomiasis,
ships between in vivo reactivities and biological actions
leishmaniosis, and malaria, are associated with a
of endogenous and exogenous molecules such as qui-
disturbed intracellular redox balance and oxidative
nones, which possess electrophilic properties and a wide
stress [44]. Several types of cancer cells exhibit disturbed
panel of redox activities. Such new research lines will
intracellular redox balance, differentiating them from
undoubtedly provide new insights into the mechanisms
their noncancerous counterparts, having increased ROS
involved in cell damage [13] or protection, as well as in
levels compared with normal cells, because their accel-
stimulating new ideas for designing more specific and
erated metabolism generates high electron fluxes. The
more powerful drugs, taking advantage of natural or
levels of ROS are considerably closer to the critical redox
synthetic quinones.
threshold at which cell death by apoptosis would be
triggered in normal cellular counterparts. These
Nonetheless, as the result of academic efforts devel-
biochemical differences between healthy and malignant
oped in a few groups, the community has already been
tissues are significant and may be used in the design of
able to evidence promising views and offer new un-
selective drugs [45] to enforce these already critical ROS
derstanding based on the identification of new
levels. Several quinones are used as anticancer drugs
quinone-related targets linked to several diseases or
based on this concept [22]. For instance, this mechanism
pathologies. We have therefore no doubt that in a near
explains the high selectivity of b-lapachone (Figure 3A),
future, this knowledge will improve to the point that
nor-b-lapachone, and derivatives, such as nitrophenyl-
highly active pharmacological molecules will be
amine and thiolated ones (Figure 3B), toward several
designed with certainty based on natural or synthetic
cancer cell lines, in comparison with normal cells [22,46].
quinone moieties.
Electrochemical parameters (i.e. the less negative
reduction potential of the quinone, reactivity toward Declaration of competing interest
oxygen, in aprotic solvents) can be used as indicative of The authors declare that they have no known competing
quinones biological activity related to an easier forma- financial interests or personal relationships that could have
tion of SQ-, biochemical electrophilicity, and oxygen appeared to influence the work reported in this paper.
reactivity [47]. Despite the absence of linear correla-
tions and exceptions, such trends have been revealed in Acknowledgements
The Brazilian team gratefully acknowledges the financial support of the
several articles, concerning cytotoxicity and parasiti- Brazilian research funding agencies Conselho Nacional de Desenvolvimento
cidal activities [23,44,48]. Yet in other cases, no Cientı́fico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de
correlation could be obtained [49] presumably Pessoal de Nı́vel Superior (CAPES)/Rede Nordeste de Biotecnologia
(RENORBIO)/Programa de Apoio à Pós-graduação (PROAP), CAPES/
due to the interference of a multitude of other physi- Programa Nacional de Cooperação Acadêmica (PROCAD), Instituto
ological processes such as poor solubility, limited Nacional de Ciência e Tecnologia (INCT)-Bioanalysis, and Fundação de
bioavailability specific chelation under in vivo condi- Amparo à Pesquisa do Estado de Alagoas (FAPEAL). CA acknowledges
Centre Nationale de la Recherche Scientifique (CNRS), École Normale
tions, and so on. Supérieure (ENS), Sorbonne University, and PSL University (Unité Mixte
de Recherche (UMR) 8640 PASTEUR) for his Emeritus position, Xiamen
Among other difficulties, this evidences that expecting University for his position of Distinguished Visiting Professor, and the
Laboratoire International Associé (LIA) CNRS ‘NanoBioCatEchem’ for its
to fully understand or actually predict the biomedical financial support.
properties of a drug on the basis of data obtained in vitro,
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86 Organic and Molecular electrochemistry

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