Hydroxylated Rotenoids Selectively Inhibit the Proliferation of Prostate Cancer Cells

Russell, David A.; Bridges, Hannah R.; Serreli, Riccardo; Kidd, Sarah L.; Mateu, Natalia; Osberger, Thomas J.; Sore, Hannah F.; Hirst, Judy; Spring, David R.

doi:10.1021/acs.jnatprod.9b01224

Cited by 15 publications

(15 citation statements)

References 71 publications

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“…We thus propose that all the inhibitors of complex I formed by chains of aromatic rings are stabilized similarly by a permutation of π-stacking interactions with tunnel-lining residues, and bind in similar sites to IACS-2858, to block the entry of ubiquinone into the tunnel. Other hydrophobic complex I inhibitors with different chemical skeletons, such as the rotenoids, with three or more fused rings ( 13 ) still bind in the ubiquinone-binding site but in multiple binding locations, including in an overlapping site to IACS-2858 also stabilized by key π-stacking partners, Trp56 NDUFS7 and Phe224 ND1 ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

“…Metformin, a widely used drug for type 2 diabetes ( 7 ), is known to inhibit complex I, and the anthelmintic reagent nafuredin also targets complex I ( 8 ). A range of complex I inhibitors have also been investigated and developed as anticancer compounds, including BAY 87-2243 ( 9 ), IACS-010759 ( 10 ), mubritinib ( 11 ), carboxyamidotriazole ( 11 ), deguelin ( 12 ), hydroxylated rotenoids ( 13 ), and quinazoline diones ( 14 ), although often with limited knowledge about their modes of actions. At the same time, complex I is also a major contributor to drug-induced mitochondrial dysfunction, for example, by antipsychotics ( 15 ), through increased oxidative stress, impaired ATP synthesis, or imbalances in the NADH/NAD + ratio ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

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Cork-in-bottle mechanism of inhibitor binding to mammalian complex I

et al. 2021

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Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a major contributor of free energy for oxidative phosphorylation, is increasingly recognized as a promising drug target for ischemia-reperfusion injury, metabolic disorders, and various cancers. Several pharmacologically relevant but structurally unrelated small molecules have been identified as specific complex I inhibitors, but their modes of action remain unclear. Here, we present a 3.0-Å resolution cryo–electron microscopy structure of mammalian complex I inhibited by a derivative of IACS-010759, which is currently in clinical development against cancers reliant on oxidative phosphorylation, revealing its unique cork-in-bottle mechanism of inhibition. We combine structural and kinetic analyses to deconvolute cross-species differences in inhibition and identify the structural motif of a “chain” of aromatic rings as a characteristic that promotes inhibition. Our findings provide insights into the importance of π-stacking residues for inhibitor binding in the long substrate-binding channel in complex I and a guide for future biorational drug design.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cork-in-bottle mechanism of inhibitor binding to mammalian complex I

et al. 2021

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“…1 B) 27 . This lipophilic natural product has been used for centuries by indigenous peoples in South America to aid in catching fish and, more recently, broadly employed as a pesticide 28 or a candidate anticancer lead compound because it selectively inhibits proliferation of neoplastic cells 29 , 30 . The rotenone molecule contains five fused rings divided in two nearly flat regions (rings A+B and rings C+D+E).…”

Section: Introductionmentioning

confidence: 99%

Mechanism of rotenone binding to respiratory complex I depends on ligand flexibility

Pereira

Teixeira

Russell

et al. 2023

Sci Rep

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Respiratory complex I is a major cellular energy transducer located in the inner mitochondrial membrane. Its inhibition by rotenone, a natural isoflavonoid, has been used for centuries by indigenous peoples to aid in fishing and, more recently, as a broad-spectrum pesticide or even a possible anticancer therapeutic. Unraveling the molecular mechanism of rotenone action will help to design tuned derivatives and to understand the still mysterious catalytic mechanism of complex I. Although composed of five fused rings, rotenone is a flexible molecule and populates two conformers, bent and straight. Here, a rotenone derivative locked in the straight form was synthesized and found to inhibit complex I with 600-fold less potency than natural rotenone. Large-scale molecular dynamics and free energy simulations of the pathway for ligand binding to complex I show that rotenone is more stable in the bent conformer, either free in the membrane or bound to the redox active site in the substrate-binding Q-channel. However, the straight conformer is necessary for passage from the membrane through the narrow entrance of the channel. The less potent inhibition of the synthesized derivative is therefore due to its lack of internal flexibility, and interconversion between bent and straight forms is required to enable efficient kinetics and high stability for rotenone binding. The ligand also induces reconfiguration of protein loops and side-chains inside the Q-channel similar to structural changes that occur in the open to closed conformational transition of complex I. Detailed understanding of ligand flexibility and interactions that determine rotenone binding may now be exploited to tune the properties of synthetic derivatives for specific applications.

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“…While other complex I inhibitor classes have been proposed as possible therapeutic compounds ( 50 – 53 ), biguanides appear to offer a lower toxicity profile than neutral species like rotenone, with reduced risk of Parkinsonism ( 44 ). This could be influenced by the ready reversibility of biguanide inhibition seen here and previously ( 12 ), compared to the irreversibility of very hydrophobic, neutral compounds.…”

Section: Discussionmentioning

confidence: 99%

Structural Basis of Mammalian Respiratory Complex I Inhibition by Medicinal Biguanides

Bridges

Blaza

Yin

et al. 2022

Preprint

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The molecular mode of action of metformin, a biguanide used widely in the treatment of diabetes, is incompletely characterized. Here we define the inhibitory drug-target interaction(s) of a model biguanide with mammalian respiratory complex I by combining cryo-electron microscopy and enzyme kinetics. We explain the unique selectivity of biguanide binding to different enzyme states. The primary inhibitory site is in an amphipathic region of the quinone-binding channel and an additional binding site is in a pocket on the intermembrane space side of the enzyme. An independent local chaotropic interaction, not previously described for any drug, displaces a portion of a key helix in the membrane domain. Our data provide a structural basis for biguanide action and enable rational design of novel medicinal biguanides.

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Hydroxylated Rotenoids Selectively Inhibit the Proliferation of Prostate Cancer Cells

Cited by 15 publications

References 71 publications

Cork-in-bottle mechanism of inhibitor binding to mammalian complex I

Cork-in-bottle mechanism of inhibitor binding to mammalian complex I

Mechanism of rotenone binding to respiratory complex I depends on ligand flexibility

Structural Basis of Mammalian Respiratory Complex I Inhibition by Medicinal Biguanides

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