Small Molecule Mitochondrial F1F0ATPase Hydrolase Inhibitors as Cardioprotective Agents. Identification of 4-(N-Arylimidazole)-Substituted Benzopyran Derivatives as Selective Hydrolase Inhibitors

Atwal, Karnail S.; Wang, Paulina; Rogers, W L; Sleph, Paul G.; Monshizadegan, Hossain; Ferrara, Francis N.; Traeger, Sarah C.; Green, David W.; Grover, Gary J.

doi:10.1021/jm030291x

Cited by 46 publications

(30 citation statements)

References 15 publications

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“…The inhibition of ATP synthesis by these derivatives is about an order of magnitude less potent than that of ATP hydrolysis (21). Both the N-arylimidazole ring and benzopyran seem to be required for inhibition, since the removal of either from the structure causes a dramatic loss of inhibitory potency.…”

Section: Miscellaneous Inhibitorsmentioning

confidence: 97%

“…A series of derivatives of benzodiazepine, 4-(N-arylimidazole)-substituted benzopyran, and N-[1-aryl-2-(1-imidazolo) ethyl]-guanidine have been synthesized and tested for the treatment of ischemic heart disease as cardioprotective agents (Table 24) (20,21,166). During ischemia, ATP is hydrolyzed by mitochondrial ATP synthase, leading to depletion of ATP.…”

Section: Miscellaneous Inhibitorsmentioning

confidence: 99%

“…4-(N-Arylimidazole)-substituted benzopyran derivatives are inhibitors of ATP hydrolysis of mitochondrial ATP synthase (21,156). The inhibition of ATP synthesis by these derivatives is about an order of magnitude less potent than that of ATP hydrolysis (21).…”

Section: Miscellaneous Inhibitorsmentioning

confidence: 99%

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ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas

Hong

Pedersen

2008

Microbiol Mol Biol Rev

276

302

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SUMMARY ATP synthase, a double-motor enzyme, plays various roles in the cell, participating not only in ATP synthesis but in ATP hydrolysis-dependent processes and in the regulation of a proton gradient across some membrane-dependent systems. Recent studies of ATP synthase as a potential molecular target for the treatment of some human diseases have displayed promising results, and this enzyme is now emerging as an attractive molecular target for the development of new therapies for a variety of diseases. Significantly, ATP synthase, because of its complex structure, is inhibited by a number of different inhibitors and provides diverse possibilities in the development of new ATP synthase-directed agents. In this review, we classify over 250 natural and synthetic inhibitors of ATP synthase reported to date and present their inhibitory sites and their known or proposed modes of action. The rich source of ATP synthase inhibitors and their known or purported sites of action presented in this review should provide valuable insights into their applications as potential scaffolds for new therapeutics for human and animal diseases as well as for the discovery of new pesticides and herbicides to help protect the world's food supply. Finally, as ATP synthase is now known to consist of two unique nanomotors involved in making ATP from ADP and Pi, the information provided in this review may greatly assist those investigators entering the emerging field of nanotechnology.

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Section: Miscellaneous Inhibitorsmentioning

confidence: 97%

Section: Miscellaneous Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas

Hong

Pedersen

2008

Microbiol Mol Biol Rev

276

302

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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.

357

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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“…13 Interestingly, a benzopyran analog BMS-199264 capable of selective inhibition of F 0 F 1 ATP hydrolase but not F 0 F 1 ATP synthase has been reported. 14,15 This switch of the enzymatic function was beneficial under the conditions of ischemia, because the drug reduced the ATP decrease during ischemia. Although the chemical structure of BMS-199264 is unrelated to oligomycins or apoptolidin, these findings raise the idea of the design of drugs that modulate particular functions of the complex energy-controlling machinery.…”

Section: Resultsmentioning

confidence: 99%

A novel acyclic oligomycin A derivative formed via retro-aldol rearrangement of oligomycin A

et al. 2012

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The antibiotic oligomycin A in the presence of K 2 CO 3 and n-Bu 4 NHSO 4 in chloroform in phase-transfer conditions afforded a novel derivative through the initial retro-aldol fragmentation of the 8,9 bond, followed by further transformation of the intermediate aldehyde. NMR, MS and quantum chemical calculations showed that the novel compound is the acyclic oligomycin A derivative, in which the 8,9 carbon bond is disrupted and two polyfunctional branches are connected with spiroketal moiety in positions C-23 and C-25. The tri-O-acetyl derivative of the novel derivative was prepared. The acyclic oligomycin A derivative retained the ability to induce apoptosis in tumor cells at low micromolar concentrations, whereas its antimicrobial potencies decreased substantially. The derivative virtually lost the inhibitory activity against F 0 F 1 ATP synthasecontaining proteoliposomes, strongly suggesting the existence of the target(s) beyond F 0 F 1 ATP synthase that is important for the antitumor potency of oligomycin A. INTRODUCTIONThe macrolide antibiotic oligomycin A (1) has long been considered a valuable experimental tool for studies of energy metabolism. The major pharmacological activity of 1 is the suppression of oxidative phosphorylation and a decrease of intracellular ATP content due to interaction with the oligomycin-sensitivity-conferring protein component of F 0 F 1 ATP synthase. 1 These effects of 1 are of particular importance for the interference with ATP-dependent outward transport and the reversal of drug-resistant phenotypes in bacterial and mammalian cells. 2,3 Furthermore, growing interest in the mechanisms of energy disbalance in disease, to the most part (but not limited to) of cancer, opened the way to the application of 1 as a potent cytotoxic agent. Design of new compounds based on 1 scaffold is of interest, as F 0 F 1 ATP synthase inhibitors are drug candidates for the treatment of bacterial infections and cancer. 4 Recently, we reported the modifications at the C 7 carbonyl group and the C 2 ¼ C 3 double bond of the antibiotic. 5 Search for rather selective methods of modifications of 1 prompted us to study the behavior of the molecule in the conditions of phase-transfer reactions.

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Small Molecule Mitochondrial F₁F₀ATPase Hydrolase Inhibitors as Cardioprotective Agents. Identification of 4-(N-Arylimidazole)-Substituted Benzopyran Derivatives as Selective Hydrolase Inhibitors

Cited by 46 publications

References 15 publications

ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas

ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas

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

A novel acyclic oligomycin A derivative formed via retro-aldol rearrangement of oligomycin A

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Small Molecule Mitochondrial F1F0ATPase Hydrolase Inhibitors as Cardioprotective Agents. Identification of 4-(N-Arylimidazole)-Substituted Benzopyran Derivatives as Selective Hydrolase Inhibitors

Cited by 46 publications

References 15 publications

ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas

ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas

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

A novel acyclic oligomycin A derivative formed via retro-aldol rearrangement of oligomycin A

Contact Info

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Small Molecule Mitochondrial F₁F₀ATPase Hydrolase Inhibitors as Cardioprotective Agents. Identification of 4-(N-Arylimidazole)-Substituted Benzopyran Derivatives as Selective Hydrolase Inhibitors

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