N -[1-Aryl-2-(1-imidazolo)ethyl]-guanidine derivatives as potent inhibitors of the bovine mitochondrial F 1 F 0 ATP hydrolase

Atwal, Karnail S.; Ahmad, Saleem; Ding, Charles Z.; Stein, Philip D.; Lloyd, John; Hamann, Lawrence G.; Green, David W.; Ferrara, Francis N.; Wang, Paulina; Rogers, W L; Doweyko, Lidia M.; Miller, Arthur V.; Bisaha, Sharon N.; Schmidt, Jenna Kropp; Li, Ling; Yost, K.J.; Lan, Hsi-Jung; Madsen, Cort S.

doi:10.1016/j.bmcl.2003.11.077

Cited by 15 publications

(15 citation statements)

References 21 publications

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“…Except for the mitochondrial inhibitor protein of ATP hydrolysis, IF 1 [55], we were only able to find one extant report of any other such inhibitor [56], with the compounds described being a series of substituted guanidine derivatives.…”

Section: Discussionmentioning

confidence: 99%

Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria

Bridges

Jones

Pollak

et al. 2014

Biochemical Journal

538

558

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The biguanide metformin is widely prescribed for Type II diabetes and has anti-neoplastic activity in laboratory models. Despite evidence that inhibition of mitochondrial respiratory complex I by metformin is the primary cause of its cell-lineage-specific actions and therapeutic effects, the molecular interaction(s) between metformin and complex I remain uncharacterized. In the present paper, we describe the effects of five pharmacologically relevant biguanides on oxidative phosphorylation in mammalian mitochondria. We report that biguanides inhibit complex I by inhibiting ubiquinone reduction (but not competitively) and, independently, stimulate reactive oxygen species production by the complex I flavin. Biguanides also inhibit mitochondrial ATP synthase, and two of them inhibit only ATP hydrolysis, not synthesis. Thus we identify biguanides as a new class of complex I and ATP synthase inhibitor. By comparing biguanide effects on isolated complex I and cultured cells, we distinguish three anti-diabetic and potentially anti-neoplastic biguanides (metformin, buformin and phenformin) from two anti-malarial biguanides (cycloguanil and proguanil): the former are accumulated into mammalian mitochondria and affect oxidative phosphorylation, whereas the latter are excluded so act only on the parasite. Our mechanistic and pharmacokinetic insights are relevant to understanding and developing the role of biguanides in new and existing therapeutic applications, including cancer, diabetes and malaria.

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Section: Discussionmentioning

confidence: 99%

Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria

Bridges

Jones

Pollak

et al. 2014

Biochemical Journal

538

558

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“…For example, during cardiac ischemia, cardioprotective benefit is thought to derive from preventing the destruction of ATP that leads to tissue damage by inhibiting the hydrolytic activity of pyran, guanidine, and benzodiazapines (69)(70)(71). Similarly, oligomycin, which inhibits F 1 F o -ATPase through its F o domain, preserves ATP and protects against or postpones injury during ischemia (72).…”

Section: Mechanism Of Inhibitionmentioning

confidence: 99%

Mechanism of inhibition of bovine F ₁ -ATPase by resveratrol and related polyphenols

Gledhill

Montgomery

Leslie

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

353

330

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The structures of F1-ATPase from bovine heart mitochondria inhibited with the dietary phytopolyphenol, resveratrol, and with the related polyphenols quercetin and piceatannol have been determined at 2.3-, 2.4-and 2.7-Å resolution, respectively. The inhibitors bind to a common site in the inside surface of an annulus made from loops in the three ␣-and three ␤-subunits beneath the ''crown'' of ␤-strands in their N-terminal domains. This region of F 1-ATPase forms a bearing to allow the rotation of the tip of the ␥-subunit inside the annulus during catalysis. The binding site is a hydrophobic pocket between the C-terminal tip of the ␥-subunit and the ␤TP subunit, and the inhibitors are bound via H-bonds mostly to their hydroxyl moieties mediated by bound water molecules and by hydrophobic interactions. There are no equivalent sites between the ␥-subunit and either the ␤DP or the ␤E subunit. The inhibitors probably prevent both the synthetic and hydrolytic activities of the enzyme by blocking both senses of rotation of the ␥-subunit. The beneficial effects of dietary resveratrol may derive in part by preventing mitochondrial ATP synthesis in tumor cells, thereby inducing apoptosis. mitochondria ͉ oxidative phosphorylation ͉ rotary mechanism ͉ crystal structure

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“…The toxicological modulation of F0-ATP hydrolase-based inhibition may provide a novel mechanism to prevent different pathological conditions where mitochondrial ATP-hydrolysis mechanisms are exacerbated. Recent experimental evidence suggest that the mitochondrial Oligomycin A-sensitive F0-ATPase subunit is an uncoupling channel within the mitochondrial permeability transition pore, which is responsible for inducing mitochondrial dysfunction linked to apoptosis. − This in turn can thus be an interesting mitotoxic-targeting therapy based on the F0-ATP hydrolase inhibition under pathological conditions, as has been suggested in previous investigations using experimental in vitro assays combined with traditional approach-based quantitative structure–activity relationship models (SAR/QSAR). ,,, …”

Section: Introductionmentioning

confidence: 97%

“…The H + proton flux through the membrane-embedded F0-ATPsynthase subunit of mitochondrial F0F1-ATP synthase favors mechanical rotation coupled to the γ and the ε subunits co-rotating within the F1-ATP synthase subunit, which induces synchronized conformational changes resulting in the synthesis and release of ATP. − However, under pathological conditions like cancer, heart ischemia/reperfusion, cerebrovascular events, and mitochondrial encephalomyopathy, the membrane-embedded F0-ATPsynthase subunit paradoxically hydrolyzes ATP associated with the reverse biochemical reaction consuming the ATP reserves and quickly compromising the cellular homeostasis and viability …”

Section: Introductionmentioning

confidence: 99%

MitoTarget Modeling Using ANN-Classification Models Based on Fractal SEM Nano-Descriptors: Carbon Nanotubes as Mitochondrial F0F1-ATPase Inhibitors

González-Durruthy

Nunes²,

Ventura‐Lima

et al. 2018

J. Chem. Inf. Model.

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Recently, it has been suggested that the mitochondrial oligomycin A-sensitive F0-ATPase subunit is an uncoupling channel linked to apoptotic cell death, and as such, the toxicological inhibition of mitochondrial F0-ATP hydrolase can be an interesting mitotoxicity-based therapy under pathological conditions. In addition, carbon nanotubes (CNTs) have been shown to offer higher selectivity like mitotoxic-targeting nanoparticles. In this work, linear and nonlinear classification algorithms on structure−toxicity relationships with artificial neural network (ANN) models were set up using the fractal dimensions calculated from CNTs as a source of supramolecular chemical information. The potential ability of CNT-family members to induce mitochondrial toxicity-based inhibition of the mitochondrial H + -F0F1-ATPase from in vitro assays was predicted. The attained experimental data suggest that CNTs have a strong ability to inhibit the F0-ATPase active-binding site following the order oxidized−CNT (CNT−COOH > CNT−OH) > pristine−CNT and mimicking the oligomycin A mitotoxicity behavior. Meanwhile, the performance of the ANN models was found to be improved by including different nonlinear combinations of the calculated fractal scanning electron microscopy (SEM) nanodescriptors, leading to models with excellent internal accuracy and predictivity on external data to classify correctly CNT-mitotoxic and nonmitotoxic with specificity (Sp > 98.9%) and sensitivity (Sn > 99.0%) from ANN models compared with linear approaches (LNN) with Sp ≈ Sn > 95.5%. Finally, the present study can contribute toward the rational design of carbon nanomaterials and opens new opportunities toward mitochondrial nanotoxicology-based in silico models.

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N -[1-Aryl-2-(1-imidazolo)ethyl]-guanidine derivatives as potent inhibitors of the bovine mitochondrial F 1 F 0 ATP hydrolase

Cited by 15 publications

References 21 publications

Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria

Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria

Mechanism of inhibition of bovine F ₁ -ATPase by resveratrol and related polyphenols

MitoTarget Modeling Using ANN-Classification Models Based on Fractal SEM Nano-Descriptors: Carbon Nanotubes as Mitochondrial F0F1-ATPase Inhibitors

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N -[1-Aryl-2-(1-imidazolo)ethyl]-guanidine derivatives as potent inhibitors of the bovine mitochondrial F 1 F 0 ATP hydrolase

Cited by 15 publications

References 21 publications

Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria

Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria

Mechanism of inhibition of bovine F 1 -ATPase by resveratrol and related polyphenols

MitoTarget Modeling Using ANN-Classification Models Based on Fractal SEM Nano-Descriptors: Carbon Nanotubes as Mitochondrial F0F1-ATPase Inhibitors

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Mechanism of inhibition of bovine F ₁ -ATPase by resveratrol and related polyphenols