Review of Heterocyclic Scaffolds for the Inhibitors of ATP synthase

 

Saurabh Mehta*

Department of Applied Chemistry, Delhi Technological University, Bawana Road, Delhi, 110042 India

*Corresponding Author E-mail: saurabh.mehta@dtu.ac.in; saurabh.dtu@gmail.com

ATP synthase is an important enzyme and is an established drug target. The involvement of this enzyme has been attributed to various serious diseases and physiological conditions, such as cancer, obesity, neurodegenerative disorders, etc. It makes it an attractive drug target whose activity may be modulated by small molecules. A variety of inhibitors reported in the literature have been reviewed, and the important O- and N- containing heterocyclic scaffolds have been identified and are presented here. On examining the scaffolds, it is observed that a variety of 5-membered ring containing compounds to macrocycles inhibit ATP synthase. These include Flavones and Isoflavons, Catechins, Estrogen metabolites, Polyenic a-pyrones, Amphiphilic cationic dyes, Tertiary amine local anesthetics (TALAs), N-sulfonyl tetrahydrobenzodiazepines, N-[1-Aryl-2-(1-imidazolo)ethyl]-acylguanidine derivatives, O-[1-Aryl-2-(1-imidazolo)ethyl]-thiourethane derivatives and 4-amino benzopyrans.

 

 

 

INTRODUCTION:

ATP synthase (F₁F₀), also known as ATP phosphohydrolase (H⁺-transporting), is an important enzyme and a complex biomacromolecule. In most of the living organisms including the humans, the majority of ATP is synthesized from ADP and phosphate by the ATP synthase enzyme, using a transmembrane proton motive force, or sodium motive force as the source of energy.¹ The research work on this important enzyme resulted in the award of 1997 Nobel Prize in Chemistry to Professor Paul D. Boyer, Dr. John E. Walker and Professor Jens C. Skou.² ATP synthase is a membrane enzyme and is located in the membranes of chloroplast, bacteria, and mitochondria, where it is involved in energy transduction. From a structural viewpoint, the ATP synthase is composed of two rotary motors, the membrane-embedded F0 motor that translocates the coupling ions and the extrinsic F1 motor that synthesizes the ATP.³ The molecular machinery of ATP-synthase has been previously studied in detail.⁴ Furthermore, its catalytic and mechanic cycles have also been explored and reported before.^5,6 There is evidence about ATP synthase being associated with several human ailments. The examples include a neurodegenerative disease namely, Leigh syndrome which causes a neuromuscular disorder.⁷ Another neurodegenerative condition, Alzheimer’s disease, has been related to a deficiency of ATP synthase in mitochondria.⁸ Moreover, the ATP synthase has also been associated with the angiogenesis process in the process of tumor growth.⁹ Due to its involvement in various important physiological mechanisms, ATP synthase has emerged as an important drug target.^4,10 It has been successfully demonstrated^11,12 that the inhibition of the proton pump of Mtb ATP synthase using the drug Bedaquiline (Figure 1) can be used as a therapeutic strategy for the treatment of tuberculosis. Another drug, a mitochondrial ATP synthase inhibitor, 1,4-benzodiazepine, Bz-423, was developed for therapy of an autoimmune disorder systemic lupus erythematosus.⁹

Figure 1. Drugs known to inhibit ATP-synthase

 

 

Role of rotational mechanism has been studied using inhibitors and mechanisms.^13,14 Furthermore, various types of synthetic as well as natural inhibitors have been studied for ATP Synthase.^15,16,17 Moreover, it has been shown that during myocardial ischemia, the ATP synthase is switched to ATP hydrolase.¹⁸ It has been an established fact that the serious diseases like cancer can be treated using natural and synthetic molecules.¹⁹ Moreover, due to our continuous interest in the synthesis and biological evaluation of important heterocyclic compounds, we became interested in the biological profile of this important drug target.^20,21 Here various classes of compounds/scaffolds for the inhibition of ATP synthase and the related ATP hydrolase enzymes are discussed. Nevertheless, the discussion has been limited to the small molecules and heterocyclic compounds with Mole. Wt. <500, and therefore biomolecules, peptides, nucleotides, etc. have been skipped in this study.

 

DISCUSSION:

Various classes of heterocyclic compounds have been explored against the ATP synthase. The generic structures/scaffolds of the inhibitors have been presented in the Table 1. Flavones and isoflavones are polyphenolic compounds and differ in the position of the phenyl group on the benzopyrone core. Flavone derivative quercetin inhibits the ATPase activities of F0 F1 (Table 1, A).²² On the other hand, Genistein inhibits both the ATP hydrolysis and ATP synthesis activities of mitochondrial ATP synthase, presumably by targeting F0 motor.²³ Among the Catechins [also known as flavan-3-ols (Table 1, B)], epicatechin gallate and epigallocatechin gallate inhibit the ATP hydrolysis activity of ATP synthase. Epigallocatechin gallate, exhibits about three times higher potency than epicatechin gallate for the inhibition of ATPase.²³

 

The micoestrogens, a-zearalenol and b-zearalenol (Table 1, C), are known to inhibit mitochondrial F₀F₁-ATPase enzyme activity. The I₅₀ value of a-zearalenol is about 50 mM, and the inhibitory potency of a-zearalenol is 3-4 times greater than that of b-zearalenol. While the mechanism of inhibition by the estrogen metabolites is not clear, the ATP synthase oligomycin sensitivity conferring protein (OSCP) subunit has been identified as an estradiol binding protein, and it has been reported that the inhibition is mediated by the binding of estrogens to this subunit.²⁴

 

a-Pyrone (Table 1, D) is a heterocyle containing a six-membered lactone ring. Its derivatives are prevalent in the nature, and some a-pyrone-containing mycotoxins, such as Aurovertin and Citreoviridin, are known to inhibit ATP synthase by targeting its F1 motor. Citreoviridin, is an a-Pyrone derivative, is a natural product, and it inhibits the ATPase activities of F1 from bacteria and mitochondria by binding to the b-subunit of ATP synthase.^25,26

 

Amphiphilic cationic dyes like Rhodamine 123 (Table 1, E) contain an amine group and another portion that is lipophilic in nature. These dyes are known to inhibit the ATPase activities. Many of these Rhodamines are considered to bind the target at more than one binding sites.²⁷

 

 

Table 1. Privileged Heterocyclic Scaffolds for the Inhibition of ATP synthase.

 

 

TALAs (Tertiary amine local anesthetics), e.g. Chlorpromazine and trifluoroperazine (Table 1, F), are made up of an aromatic portion, an intermediate chain, and an amine group at the terminal. The TALAs are known to inhibit bacterial ATP synthases selectively.^28,29 Furthermore, the binding sites may differ for different TALA derivatives. In some cases it has been found that the inhibitor forms covalent bonds with the ATP synthase, leading to its irreversible inhibition.³⁰ N-Sulfonyl-substituted tetrahydrobenzodiazepine analogues (Table 1, G) are also known to inhibit ATP synthase.³¹ 4-amino benzopyran derivatives (Table 1, H)  are inhibitors of ATP hydrolysis of mitochondrial ATP synthase.³² It was found that both the amino and benzopyran portions are necessary for inhibition. Other inhibitors of ATP synthase include Cyano- and acylguanidine derivatives (Table 1, I) containing imidazolo-ethyl and aryl groups and O-[1-Aryl-2-(1-imidazolo)ethyl]-thiourethane (Table 1, J) derivatives.³³

 

CONCLUSIONS:

Thus a variety of N- and O- containing heterocyclic scaffolds have been reviewed as inhibitors for ATP synthase enzyme. More advancements are expected in this important area of biochemical research.

 

CONFLICT OF INTEREST:

There is no conflict of interest.

 

REFERENCES:

(1)       Hong, S; Pedersen, PL. ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas. Microbiology and Molecular Biology Reviews 2008, 72 (4), 590–641.

(2)       Press Release: The 1997 Nobel Prize in Chemistry. https://www.nobelprize.org/nobel_prizes/chemistry/laureates/1997/press.html.

(3)       Capaldi, RA, Aggeler, R. Mechanism of the F1F0-Type ATP Synthase, a Biological Rotary Motor. Trends in Biochemical Sciences 2002, 27 (3), 154–160.

(4)       Boyer, PD. The ATP Synthase—A Splendid Molecular Machine. Annual Review of Biochemistry 1997, 66 (1), 717–749.

(5)       Dimroth P, von Ballmoos C, Meier T. Catalytic and Mechanical Cycles in F-ATP Synthases: Fourth in the Cycles Review Series. EMBO reports 2006, 7 (3), 276–282.

(6)       Nakamoto RK, Baylis Scanlon JA, Al-Shawi MK. The Rotary Mechanism of the ATP Synthase. Archives of Biochemistry and Biophysics 2008, 476, 43–50.

(7)       de Vries DD, et al. A Second Missense Mutation in the Mitochondrial ATPase 6 Gene in Leigh’s Syndrome. Annals of Neurology 1993, 34 (3), 410–412.

(8)       Schägger H, Ohm TG. Human Diseases with Defects in Oxidative Phosphorylation. European Journal of Biochemistry 2008, 227 (3), 916–921.

(9)       Moser TL, et al. Endothelial Cell Surface F1-F0 ATP Synthase Is Active in ATP Synthesis and Is Inhibited by Angiostatin. Proceedings of the National Academy of Sciences of the United States of America 2001, 98 (12), 6656–6661.

(10)    Capaldi RA, Aggeler R. Mechanism of the F1F0-Type ATP Synthase, a Biological Rotary Motor. Trends in Biochemical Sciences 2002, 27 (3), 154–160.

(11)    Andries K et al. A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium Tuberculosis. Science (New York, N.Y.) 2005, 307 (5707), 223–227.

(12)    Huitric E et al. In Vitro Antimycobacterial Spectrum of a Diarylquinoline ATP Synthase Inhibitor. Antimicrobial agents and chemotherapy 2007, 51 (11), 4202–4204.

(13)    Sekiya M, et al. Role of a/b Interface in F1 ATPase Rotational Catalysis Probed by Inhibitors and Mutations. International Journal of Biological Macromolecules 2017, 99, 615–621.

(14)    Nakanishi-Matsui M, Sekiya M, Futai, M. ATP Synthase from Escherichia Coli: Mechanism of Rotational Catalysis, and Inhibition with the ε Subunit and Phytopolyphenols. Biochimica et Biophysica Acta 2016, 1857, 129–140.

(15)    Sekiya M, et al. Mayumi Nakanishi-Matsui a. A Unique Mechanism of Curcumin Inhibition on F1 ATPase. Biochemical and Biophysical Research Communications 2014, 452, 940–944.

(16)    Lebowitz MS, Pedersen PL. Protein Inhibitor of Mitochondrial ATP Synthase: Relationship of Inhibitor Structure to pH-Dependent Regulation. Archives of Biochemistry and Biophysics 1996, 330 (2), 342–354.

(17)    Moreno AJM et al. Mechanism of Inhibition of Mitochondrial ATP Synthase by 17β−Estradiol. Journal of Bioenergetics and Biomembranes 2013, 45 (3), 261–270.

(18)    Grover GJ, Malm, J. Pharmacological Profile of the Selective Mitochondrial F1F0 ATP Hydrolase Inhibitor BMS-199264 in Myocardial Ischemia. Cardiovascular Therapeutics 2008, 26 (4), 287–296.

(19)    Sharma B. Synthetic and Natural Compounds as Anti-Cancer Agents – A Review. Asian Journal of Research in Chemistry 2017, 10 (5), 699–707.

(20)    Allen BK et al. Large-Scale Computational Screening Identifies First in Class Multitarget Inhibitor of EGFR Kinase and BRD4. Scientific Reports 2015, 5, 16924.

(21)    Huang Q et al. Design, Synthesis, and Evaluation of NO-Donor Containing Carbonic Anhydrase Inhibitors To Lower Intraocular Pressure. J. Med. Chem. 2015, 58 (6), 2821–2833.

(22)    Lang DR, Racker E. Effects of Quercetin and F1 Inhibitor on Mitochondrial ATPase and Energy-Linked Reactions in Submitochondrial Particles. Biochimica et Biophysica Acta (BBA) - Bioenergetics 1974, 333 (2), 180–186.

(23)    Zheng J, Ramirez VD. Inhibition of Mitochondrial Proton F0F1-ATPase/ATP Synthase by Polyphenolic Phytochemicals. British Journal of Pharmacology 2000, 130 (5), 1115–1123.

(24)    Zheng J, Ramirez VD. Purification and Identification of an Estrogen Binding Protein from Rat Brain: Oligomycin Sensitivity-Conferring Protein (OSCP), a Subunit of Mitochondrial FOF1-ATP synthase/ATPase. Journal of Steroid Biochemistry and Molecular Biology 1999, 68 (1–2), 65–75.

(25)    Gause E, Buck M, Douglas M. Binding of Citreoviridin to the Beta Subunit of the Yeast F1-ATPase. J Biol Chem. 1981, 256 (2), 557–559.

(26)    Satre M, Bof M, Vignais P. Interaction of Escherichia Coli Adenosine Triphosphatase with Aurovertin and Citreoviridin: Inhibition and Fluorescence Studies. J. Bacteriol. 1980, 142, 768–776.

(27)    Bullough DA et al. Inhibition of the Bovine-Heart Mitochondrial F1-ATPase by Cationic Dyes and Amphipathic Peptides. Biochimica et Biophysica Acta (BBA) - Bioenergetics 1989, 975 (3), 377–383.

(28)    Chazotte B, Vanderkooi G, Chignell D. Further Studies on F1-ATPase Inhibition by Local Anesthetics. BBA - Bioenergetics 1982, 680 (3), 310–316.

(29)    Vanderkooi G et al. On the Mechanism of Action of Anesthetics. Direct Inhibition of Mitochondrial F1-ATPase by N-Butanol and Tetracaine. Biochimica et Biophysica Acta (BBA) - Bioenergetics 1981, 635 (1), 200–203.

(30)    Dabbeni-Sala, F, Schiavo G, Palatini P. Mechanism of Local Anesthetic Effect on Mitochondrial ATP Synthase as Deduced from Photolabelling and Inhibition Studies with Phenothiazine Derivatives. Biochimica et Biophysica Acta (BBA) - Biomembranes 1990, 1026, 117–125.

(31)    Hamann LG at al. Benzodiazepine-Based Selective Inhibitors of Mitochondrial F1F0 ATP Hydrolase. Bioorganic and Medicinal Chemistry Letters 2004, 14, 1031–1034.

(32)    Atwal KS et al. Small Molecule Mitochondrial F 1F 0 ATPase Hydrolase Inhibitors as Cardioprotective Agents. Identification of 4-(N-Arylimidazole)-Substituted Benzopyran Derivatives as Selective Hydrolase Inhibitors. Journal of Medicinal Chemistry 2004, 47 (5), 1081–1084.

(33)    Atwal KS et al. N-[1-Aryl-2-(1-Imidazolo)ethyl]-Guanidine Derivatives as Potent Inhibitors of the Bovine Mitochondrial F1F0 ATP Hydrolase. Bioorganic and Medicinal Chemistry Letters 2004, 14, 1027–1030.

 

 

Received on 25.12.2017         Modified on 13.01.2018

Accepted on 06.02.2018         © AJRC All right reserved