Controlled masking and targeted release of redox-cycling ortho-quinones via a C–C bond-cleaving 1,6-elimination

Dunsmore, Lavinia; Navo, Claudio D.; Becher, Julie; Montes, Enrique Gil de; Guerreiro, Ana; Hoyt, Emily A.; Brown, Libby; Zelenay, Viviane; Mikutis, Sigitas; Cooper, Jonathan; Barbieri, Isaia; Lawrinowitz, Stefanie; Siouve, Elise; Martin, Esther M.; Ruivo, Pedro; Rodrigues, Tiago; Cruz, Filipa P da; Werz, Oliver; Vassiliou, George S.; Ravn, Peter; Jiménez‐Osés, Gonzalo; Bernardes, Gonçalo J. L.

doi:10.1038/s41557-022-00964-7

Cited by 23 publications

(37 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to the cytotoxicity of o -quinone due to their reactivity with sulfhydryl compounds, there is another possible mechanism for o -quinone cytotoxicity ( Figure 2 ). o -Quinones may undergo one-electron reduction with reducing agents such as NAD(P)H and Fe 2+ to produce semi-quinone radicals, which disproportionately form the catechol and the o -quinone [ 78 , 79 ]. Catechols are converted back to o -quinones upon autoxidation, concomitantly producing ROS such as superoxide radical, hydrogen peroxide, and hydroxyl radical.…”

Section: Advances In Anti-melanoma Targeted Small Molecules and Mecha...mentioning

confidence: 99%

“…o -Quinones may also undergo two-electron reduction, with reducing enzymes such as NAD(P)H quinone dehydrogenase 1 (NQO1) or reducing compounds such as ascorbic acid, to produce catechols. Thus, both catechols and o -quinones can be a source of ROS generation through redox cycling [ 78 , 79 , 80 ]. In addition, the reactions of o -quinones with biological small thiols such as cysteine and GSH produce catechol derivatives that may produce ROS ( Figure 1 ).…”

Section: Advances In Anti-melanoma Targeted Small Molecules and Mecha...mentioning

confidence: 99%

See 1 more Smart Citation

Molecular Events in the Melanogenesis Cascade as Novel Melanoma-Targeted Small Molecules: Principle and Development

Wakamatsu

Ito

Tamura

et al. 2022

Cancers

View full text Add to dashboard Cite

Malignant melanoma is one of the most malignant of all cancers. Melanoma occurs at the epidermo–dermal interface of the skin and mucosa, where small vessels and lymphatics are abundant. Consequently, from the onset of the disease, melanoma easily metastasizes to other organs throughout the body via lymphatic and blood circulation. At present, the most effective treatment method is surgical resection, and other attempted methods, such as chemotherapy, radiotherapy, immunotherapy, targeted therapy, and gene therapy, have not yet produced sufficient results. Since melanogenesis is a unique biochemical pathway that functions only in melanocytes and their neoplastic counterparts, melanoma cells, the development of drugs that target melanogenesis is a promising area of research. Melanin consists of small-molecule derivatives that are always synthesized by melanoma cells. Amelanosis reflects the macroscopic visibility of color changes (hypomelanosis). Under microscopy, melanin pigments and their precursors are present in amelanotic melanoma cells. Tumors can be easily targeted by small molecules that chemically mimic melanogenic substrates. In addition, small-molecule melanin metabolites are toxic to melanocytes and melanoma cells and can kill them. This review describes our development of chemo-thermo-immunotherapy based on the synthesis of melanogenesis-based small-molecule derivatives and conjugation to magnetite nanoparticles. We also introduce the other melanogenesis-related chemotherapy and thermal medicine approaches and discuss currently introduced targeted therapies with immune checkpoint inhibitors for unresectable/metastatic melanoma.

show abstract

Section: Advances In Anti-melanoma Targeted Small Molecules and Mecha...mentioning

confidence: 99%

Section: Advances In Anti-melanoma Targeted Small Molecules and Mecha...mentioning

confidence: 99%

Molecular Events in the Melanogenesis Cascade as Novel Melanoma-Targeted Small Molecules: Principle and Development

Wakamatsu

Ito

Tamura

et al. 2022

Cancers

View full text Add to dashboard Cite

show abstract

“…This prodrug strategy of activation by C−C bond cleavage is potentially useful as a valuable addition to the existing prodrug strategies. Very recently, Bernardes and co‐workers reported similar C−C bond‐cleaving elimination and applied it for intracellular release of β‐lap ( 1 ) [42] …”

Section: Introductionmentioning

confidence: 96%

“…Very recently, Bernardes and co-workers reported similar CÀ C bond-cleaving elimination and applied it for intracellular release of β-lap (1). [42]…”

Section: Introductionmentioning

confidence: 99%

A Carbon‐Carbon Bond Cleavage‐Based Prodrug Activation Strategy Applied to β‐Lapachone for Cancer‐Specific Targeting

Gong

et al. 2022

Angewandte Chemie

View full text Add to dashboard Cite

Prodrugs are one of the most common strategies for the design of targeted anticancer agents. However, their application is often hampered by the modifiable groups available on parent drugs. Herein, a carbon-carbon (CÀ C) bond cleavage-based prodrug activation strategy is reported, which was successfully used to design prodrugs of β-lapachone (β-lap), an ortho-quinone natural product without traditional modifiable groups for the construction of CÀ N/CÀ O bond cleavage-based prodrugs. The designed β-lap prodrug with a reactive oxygen species-specific trigger was quickly activated, releasing β-lap. It exerted anticancer efficacy via NAD(P)H:quinone oxidoreductase 1 (NQO1)-mediated futile redox cycling, resulting in potent cytotoxicity that was highly selective for NQO1rich cancer cells over normal cells both in vitro and in vivo. This significantly amplified the therapeutic window of β-lap. This study provides a practical strategy for the design of prodrugs for parent drugs that do not contain traditional modifiable groups.

show abstract

“…[23, 26, 27] A recently developed prodrug-based delivery technique that improves tumor targeting demonstrates that systemic toxicity can be significantly reduced, rendering o -quinones a candidate compound family for targeted therapeutics. [28]…”

Section: Introductionmentioning

confidence: 99%

β-Lapachone Regulates Mammalian Inositol Pyrophosphate Levels in an NQO1- and Oxygen-dependent Manner

Eisenbeis

Qiu

Strotmann

et al. 2022

Preprint

View full text Add to dashboard Cite

Inositol pyrophosphates (PP-InsPs) are energetic signalling molecules with important functions in mammals. As their biosynthesis depends on ATP concentration, PP InsPs are tightly connected to cellular energy homeostasis. Consequently, an increasing number of studies involves PP InsPs in metabolic disorders, such as type 2 diabetes, aspects of tumorigenesis, and hyperphosphatemia. Research conducted in yeast suggests that the PP InsP pathway is activated in response to reactive oxygen species (ROS). However, the precise modulation of PP InsPs during cellular ROS signalling is unknown. Here, we report how mammalian PP InsP levels are changing during exposure to exogenous (H2O2) and endogenous ROS. Using capillary electrophoresis electrospray ionization mass spectrometry (CE-ESI MS), we found that PP-InsP levels decrease upon exposure to oxidative stressors in HCT116 cells. Application of quinone drugs, particularly β-lapachone (β-lap), under normoxic and hypoxic conditions enabled us to produce ROS in cellulo and to show that β lap treatment caused PP-InsP changes that are oxygen dependent. Experiments in MDA-MB-231 breast cancer cells deficient of NAD(P)H:quinone oxidoreductase-1 (NQO1) demonstrated that β-lap requires NQO1-bioactivation to regulate the cellular metabolism of PP InsPs. Critically, significant reductions in cellular ATP concentrations were not directly mirrored in reduced PP InsP levels as shown in NQO1-deficient MDA-MB-231 cells treated with β-lap. The data presented here unveil new aspects of β-lap pharmacology and its impact on PP-InsP levels. Our identification of different quinone drugs as modulators of PP-InsP synthesis will allow to better appreciate their overall impact on cellular function.

show abstract

Controlled masking and targeted release of redox-cycling ortho-quinones via a C–C bond-cleaving 1,6-elimination

Cited by 23 publications

References 85 publications

Molecular Events in the Melanogenesis Cascade as Novel Melanoma-Targeted Small Molecules: Principle and Development

Molecular Events in the Melanogenesis Cascade as Novel Melanoma-Targeted Small Molecules: Principle and Development

A Carbon‐Carbon Bond Cleavage‐Based Prodrug Activation Strategy Applied to β‐Lapachone for Cancer‐Specific Targeting

β-Lapachone Regulates Mammalian Inositol Pyrophosphate Levels in an NQO1- and Oxygen-dependent Manner

Contact Info

Product

Resources

About