Quinones as Neuroprotective Agents

Abstract

Quinones can in principle be viewed as a double-edged sword in the treatment of neurodegenerative diseases, since they are often cytoprotective but can also be cytotoxic due to covalent and redox modification of biomolecules. Nevertheless, low doses of moderately electrophilic quinones are generally cytoprotective, mainly due to their ability to activate the Keap1/Nrf2 pathway and thus induce the expression of detoxifying enzymes. Some natural quinones have relevant roles in important physiological processes. One of them is coenzyme Q₁₀, which takes part in the oxidative phosphorylation processes involved in cell energy production, as a proton and electron carrier in the mitochondrial respiratory chain, and shows neuroprotective effects relevant to Alzheimer's and Parkinson's diseases. Additional neuroprotective quinones that can be regarded as coenzyme Q₁₀ analogues are idobenone, mitoquinone and plastoquinone. Other endogenous quinones with neuroprotective activities include tocopherol-derived quinones, most notably vatiquinone, and vitamin K. A final group of non-endogenous quinones with neuroprotective activity is discussed, comprising embelin, APX-3330, cannabinoid-derived quinones, asterriquinones and other indolylquinones, pyrroloquinolinequinone and its analogues, geldanamycin and its analogues, rifampicin quinone, memoquin and a number of hybrid structures combining quinones with amino acids, cholinesterase inhibitors and non-steroidal anti-inflammatory drugs.

Keywords: Keap1/Nrf2 pathway; coenzyme Q10; covalent drugs; embelin; idebenone; memoquin; multitarget drugs; oxidative stress; pyrroloquinolinequinone; vatiquinone.

Figure 1

Main mechanisms of action of the quinones described in this review. Abbreviations: T/B cells: the two main types of lymphocytes. BBB: blood brain barrier. AChE: acetylcholinesterase. BChE: butyrylcholinesterase. AChR: acetylcholine receptor. MMP-9: matrix metalloproteinase 9. Aβ: beta-amyloid protein. BACE-1: beta-secretase 1. GSK-3β: glycogen synthase kinase-3 beta. HSP90: Heat-shock protein 90. NQO1: NAD(P)H:quinone oxidoreductase 1. ROS: reactive oxygen species. MAO: monoamino oxidase. PTPm: mitochondrial permeability transition pore. 15-LOX: 15-lipooxygenase. NOX: nitric oxide. DAMPs: damage-associated molecular patterns. TLR4: Toll-like receptor 4. NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells. NRLP3: NLR family pyrin domain containing 3. JAK: Janus kinase. STAT: signal transducer and activator of transcription. TNF-α: tumor necrosis factor alpha. IL: interleukins.

Figure 2

General features of quinone chemistry of relevance to neuroprotection. Quinones may act as electrophiles, thereby alkylating proteins or nucleic acids. Additionally, they can accept one electron to give semiquinones, which can in turn be reduced to hydroquinones by one-electron transfer and protonation. Semiquinone formation can be reverted by molecular oxygen, leading to the generation of superoxide anion-radicals.

Figure 3

Toxic species derived from the oxidative metabolism of dopamine. Formation of dopamine-o-quinone (DAQ) from the one-electron or two-electron oxidation of dopamine and its evolution by intramolecular Michael additions and additional oxidation reactions.

Figure 4

Mechanisms explaining the generation of reactive oxygen species from doxorubicin.

Figure 5

Main molecular mechanisms involved in chemotherapy-induced cognitive impairment.

Figure 6

Cytoxic vs. cytoprotective responses to quinones, depending on their concentration and electrophilicity.

Figure 7

The Keap1/Nrf2 cytoprotective pathway. Basal state: Negative regulation of Nrf2 under normal conditions (“basal state”) and its activation under pathological conditions (“induced state” in the presence of reactive oxygen species (ROS) or covalent modifiers.

Figure 8

Structure of coenzyme Q₁₀ and generation of its three oxidation states by two successive one-electron reductions.

Figure 9

The role of coenzyme Q₁₀ in electron and proton transfer processes in the mitochondrial respiratory chain.

Figure 10

The lipid peroxidation process and mechanisms that protect against it involving the interplay of α-tocopherol and coenzyme Q₁₀.

Figure 11

Structure of ubisol-Q₁₀, a nanomicellar formulation combining coenzyme Q₁₀ with polyoxyethanyl α-tocopheryl sebacate (PTS).

Figure 12

Structures of idebenone, its active metabolite, QS-10 and the related hydroquinone D1.

Figure 13

Structures of decylubiquinone and its mitochondria-targeted phosphonium analogue mitoquinone mesylate.

Figure 14

Structure of plastoquinone and some of its synthetic analogues, namely the phosphonium derivative SkQ,1 designed for mitochondrial penetration and retention, and the fluorescent plastoquinone-rhodamine hybrid SkQR1.

Figure 15

Mechanism of the antioxidant activity of tocopherol in cell membranes and its metabolism to yield α-tocotrienol quinone (vatiquinone) and its α-tocotrienol hydroquinone.

Figure 16

Structures of neuroprotective vitamin K-related quinones.

Figure 17

Structures of embelin and its analogue, the embelin-donepezil hybrid SB-1448.

Figure 18

(A) Activation of transcription factors by the APE1/Ref-1 protein and its biological consequences. (B) Structures of the APE1/Ref-1 inhibitors APX-3330, APX-2009 and APX-2014. Abbreviations: APE1/Ref1: Apurinic/apyrimidinic endonuclease/redox-factor 1. TF: transcription factor. HIF-1α: Hypoxia-inducible factor 1-alpha. NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells. STAT3: Signal transducer and activator of transcription 3. Nrf2: nuclear factor erythroid 2–related factor 2.

Figure 19

Stages in the design of neuroprotective cannabinoid-derived quinones.

Figure 20

Neuroprotective asterriquinones and simpler indolylquinones.

Figure 21

Biosynthetic origin of PQQ and its redox equilibria with PQQ semiquinone and hydroquinone.

Figure 22

Products derived from the reaction of PQQ with amino acids such as free glutamate in the brain.

Figure 23

Geldanamycin and its neuroprotective analogues.

Figure 24

Structures of rifampicin and its quinone.

Figure 25

Miscellaneous neuroprotective benzoquinones, naphthoquinones and anthraquinones.

Figure 26

Structures of some neuroprotective heterocyclic quinones.

Figure 27

Structure and pharmacological profile of memoquin. Structures of a half-molecule simplified memoquin analogue 7 and memoquin-lipoic acid hybrids 8.

Figure 28

Memoquin analogues that include fragments corresponding to non-steroidal anti-inflammatory drugs.

Figure 29

Multitarget hybrid compounds with cholinesterase inhibitory activity.

Figure 30

Selected naphthoquinone-tryptophan and naphthoquinone-dopamine hybrids.

Figure 31

An indolequinone derivative acting as a bexarotene prodrug by a process initiated by NQO1 reduction of the quinone moiety.