Antitumor quinol PMX464 is a cytocidal anti-trypanosomal inhibitor targeting trypanothione metabolism

König J, Wyllie S, Wells G, Stevens MF, Wyatt PG, Fairlamb AH (2011)
The Journal of biological chemistry 286(10): 8523-8533.

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Zeitschriftenaufsatz | Veröffentlicht | Englisch
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Abstract / Bemerkung
Better drugs are urgently needed for the treatment of African sleeping sickness. We tested a series of promising anticancer agents belonging to the 4-substituted 4-hydroxycyclohexa-2,5-dienones class ("quinols") and identified several with potent trypanocidal activity (EC(50) < 100 nM). In mammalian cells, quinols are proposed to inhibit the thioredoxin/thioredoxin reductase system, which is absent from trypanosomes. Studies with the prototypical 4-benzothiazole-substituted quinol, PMX464, established that PMX464 is rapidly cytocidal, similar to the arsenical drug, melarsen oxide. Cell lysis by PMX464 was accelerated by addition of sublethal concentrations of glucose oxidase implicating oxidant defenses in the mechanism of action. Whole cells treated with PMX464 showed a loss of trypanothione (T(SH)(2)), a unique dithiol in trypanosomes, and tryparedoxin peroxidase (TryP), a 2-Cys peroxiredoxin similar to mammalian thioredoxin peroxidase. Enzyme assays revealed that T(SH)(2), TryP, and a glutathione peroxidase-like tryparedoxin-dependent peroxidase were inhibited in time- and concentration-dependent manners. The inhibitory activities of various quinol analogues against these targets showed a good correlation with growth inhibition of Trypanosoma brucei. The monothiols glutathione and L-cysteine bound in a 2:1 ratio with PMX464 with K(d) values of 6 and 27 μM, respectively, whereas T(SH)(2) bound more tightly in a 1:1 ratio with a K(d) value of 430 nM. Overexpression of trypanothione synthetase in T. brucei decreased sensitivity to PMX464 indicating that the key metabolite T(SH)(2) is a target for quinols. Thus, the quinol pharmacophore represents a novel lead structure for the development of a new drug against African sleeping sickness.
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The Journal of biological chemistry
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286
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10
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8523-8533
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König J, Wyllie S, Wells G, Stevens MF, Wyatt PG, Fairlamb AH. Antitumor quinol PMX464 is a cytocidal anti-trypanosomal inhibitor targeting trypanothione metabolism. The Journal of biological chemistry. 2011;286(10):8523-8533.
König, J., Wyllie, S., Wells, G., Stevens, M. F., Wyatt, P. G., & Fairlamb, A. H. (2011). Antitumor quinol PMX464 is a cytocidal anti-trypanosomal inhibitor targeting trypanothione metabolism. The Journal of biological chemistry, 286(10), 8523-8533. doi:10.1074/jbc.M110.214833
König, J., Wyllie, S., Wells, G., Stevens, M. F., Wyatt, P. G., and Fairlamb, A. H. (2011). Antitumor quinol PMX464 is a cytocidal anti-trypanosomal inhibitor targeting trypanothione metabolism. The Journal of biological chemistry 286, 8523-8533.
König, J., et al., 2011. Antitumor quinol PMX464 is a cytocidal anti-trypanosomal inhibitor targeting trypanothione metabolism. The Journal of biological chemistry, 286(10), p 8523-8533.
J. König, et al., “Antitumor quinol PMX464 is a cytocidal anti-trypanosomal inhibitor targeting trypanothione metabolism”, The Journal of biological chemistry, vol. 286, 2011, pp. 8523-8533.
König, J., Wyllie, S., Wells, G., Stevens, M.F., Wyatt, P.G., Fairlamb, A.H.: Antitumor quinol PMX464 is a cytocidal anti-trypanosomal inhibitor targeting trypanothione metabolism. The Journal of biological chemistry. 286, 8523-8533 (2011).
König, Janine, Wyllie, Susan, Wells, Geoffrey, Stevens, Malcolm F, Wyatt, Paul G, and Fairlamb, Alan H. “Antitumor quinol PMX464 is a cytocidal anti-trypanosomal inhibitor targeting trypanothione metabolism”. The Journal of biological chemistry 286.10 (2011): 8523-8533.

6 Zitationen in Europe PMC

Daten bereitgestellt von Europe PubMed Central.

Whole-organism high-throughput screening against Trypanosoma brucei brucei.
Jones AJ, Avery VM., Expert Opin Drug Discov 8(5), 2013
PMID: 23540598
Quinol derivatives as potential trypanocidal agents.
Capes A, Patterson S, Wyllie S, Hallyburton I, Collie IT, McCarroll AJ, Stevens MF, Frearson JA, Wyatt PG, Fairlamb AH, Gilbert IH., Bioorg Med Chem 20(4), 2012
PMID: 22264753
Peroxiredoxins in parasites.
Gretes MC, Poole LB, Karplus PA., Antioxid Redox Signal 17(4), 2012
PMID: 22098136
Chemical, genetic and structural assessment of pyridoxal kinase as a drug target in the African trypanosome.
Jones DC, Alphey MS, Wyllie S, Fairlamb AH., Mol Microbiol 86(1), 2012
PMID: 22857512

57 References

Daten bereitgestellt von Europe PubMed Central.

Kinetoplastids: related protozoan pathogens, different diseases.
Stuart K, Brun R, Croft S, Fairlamb A, Gurtler RE, McKerrow J, Reed S, Tarleton R., J. Clin. Invest. 118(4), 2008
PMID: 18382742
Melarsoprol versus eflornithine for treating late-stage Gambian trypanosomiasis in the Republic of the Congo.
Balasegaram M, Harris S, Checchi F, Ghorashian S, Hamel C, Karunakara U., Bull. World Health Organ. 84(10), 2006
PMID: 17128358
Effectiveness of melarsoprol and eflornithine as first-line regimens for gambiense sleeping sickness in nine Medecins Sans Frontieres programmes.
Balasegaram M, Young H, Chappuis F, Priotto G, Raguenaud ME, Checchi F., Trans. R. Soc. Trop. Med. Hyg. 103(3), 2008
PMID: 18947846
Trypanothione: a novel bis(glutathionyl)spermidine cofactor for glutathione reductase in trypanosomatids.
Fairlamb AH, Blackburn P, Ulrich P, Chait BT, Cerami A., Science 227(4693), 1985
PMID: 3883489
Ovothiol and trypanothione as antioxidants in trypanosomatids.
Ariyanayagam MR, Fairlamb AH., Mol. Biochem. Parasitol. 115(2), 2001
PMID: 11420105
Metabolism and functions of trypanothione in the Kinetoplastida.
Fairlamb AH, Cerami A., Annu. Rev. Microbiol. 46(), 1992
PMID: 1444271
Trypanothione-dependent synthesis of deoxyribonucleotides by Trypanosoma brucei ribonucleotide reductase.
Dormeyer M, Reckenfelderbaumer N, Ludemann H, Krauth-Siegel RL., J. Biol. Chem. 276(14), 2001
PMID: 11150302
Trypanothione as a target in the design of antitrypanosomal and antileishmanial agents.
Augustyns K, Amssoms K, Yamani A, Rajan PK, Haemers A., Curr. Pharm. Des. 7(12), 2001
PMID: 11472257
Glutathione and trypanothione in parasitic hydroperoxide metabolism.
Flohe L, Hecht HJ, Steinert P., Free Radic. Biol. Med. 27(9-10), 1999
PMID: 10569629
The parasite-specific trypanothione metabolism of trypanosoma and leishmania.
Krauth-Siegel RL, Meiering SK, Schmidt H., Biol. Chem. 384(4), 2003
PMID: 12751784
Trypanosomes lacking trypanothione reductase are avirulent and show increased sensitivity to oxidative stress.
Krieger S, Schwarz W, Ariyanayagam MR, Fairlamb AH, Krauth-Siegel RL, Clayton C., Mol. Microbiol. 35(3), 2000
PMID: 10672177
Trypanosoma brucei tryparedoxin, a thioredoxin-like protein in African trypanosomes.
Ludemann H, Dormeyer M, Sticherling C, Stallmann D, Follmann H, Krauth-Siegel RL., FEBS Lett. 431(3), 1998
PMID: 9714547
Molecular characterisation of mitochondrial and cytosolic trypanothione-dependent tryparedoxin peroxidases in Trypanosoma brucei.
Tetaud E, Giroud C, Prescott AR, Parkin DW, Baltz D, Biteau N, Baltz T, Fairlamb AH., Mol. Biochem. Parasitol. 116(2), 2001
PMID: 11522350
Kinetics and redox-sensitive oligomerisation reveal negative subunit cooperativity in tryparedoxin peroxidase of Trypanosoma brucei brucei.
Budde H, Flohe L, Hecht HJ, Hofmann B, Stehr M, Wissing J, Lunsdorf H., Biol. Chem. 384(4), 2003
PMID: 12751791
Trypanothione dependent peroxide metabolism in Crithidia fasciculata and Trypanosoma brucei.
Henderson GB, Fairlamb AH, Cerami A., Mol. Biochem. Parasitol. 24(1), 1987
PMID: 3614271
Trypanosoma brucei and Trypanosoma cruzi tryparedoxin peroxidases catalytically detoxify peroxynitrite via oxidation of fast reacting thiols.
Trujillo M, Budde H, Pineyro MD, Stehr M, Robello C, Flohe L, Radi R., J. Biol. Chem. 279(33), 2004
PMID: 15155760
A second class of peroxidases linked to the trypanothione metabolism.
Hillebrand H, Schmidt A, Krauth-Siegel RL., J. Biol. Chem. 278(9), 2002
PMID: 12466271
Catalytic mechanism of the glutathione peroxidase-type tryparedoxin peroxidase of Trypanosoma brucei.
Schlecker T, Comini MA, Melchers J, Ruppert T, Krauth-Siegel RL., Biochem. J. 405(3), 2007
PMID: 17456049
Substrate specificity, localization, and essential role of the glutathione peroxidase-type tryparedoxin peroxidases in Trypanosoma brucei.
Schlecker T, Schmidt A, Dirdjaja N, Voncken F, Clayton C, Krauth-Siegel RL., J. Biol. Chem. 280(15), 2005
PMID: 15664987
Mechanism of inhibition of trypanothione reductase and glutathione reductase by trivalent organic arsenicals.
Cunningham ML, Zvelebil MJ, Fairlamb AH., Eur. J. Biochem. 221(1), 1994
PMID: 8168518
Trypanothione is the primary target for arsenical drugs against African trypanosomes.
Fairlamb AH, Henderson GB, Cerami A., Proc. Natl. Acad. Sci. U.S.A. 86(8), 1989
PMID: 2704738
Trypanothione overproduction and resistance to antimonials and arsenicals in Leishmania.
Mukhopadhyay R, Dey S, Xu N, Gage D, Lightbody J, Ouellette M, Rosen BP., Proc. Natl. Acad. Sci. U.S.A. 93(19), 1996
PMID: 8816809
Dual action of antimonial drugs on thiol redox metabolism in the human pathogen Leishmania donovani.
Wyllie S, Cunningham ML, Fairlamb AH., J. Biol. Chem. 279(38), 2004
PMID: 15252045
Elucidation of thioredoxin as a molecular target for antitumor quinols.
Bradshaw TD, Matthews CS, Cookson J, Chew EH, Shah M, Bailey K, Monks A, Harris E, Westwell AD, Wells G, Laughton CA, Stevens MF., Cancer Res. 65(9), 2005
PMID: 15867391
4-Substituted 4-hydroxycyclohexa-2,5-dien-1-ones with selective activities against colon and renal cancer cell lines.
Wells G, Berry JM, Bradshaw TD, Burger AM, Seaton A, Wang B, Westwell AD, Stevens MF., J. Med. Chem. 46(4), 2003
PMID: 12570375
Cytotoxic and antiangiogenic activity of AW464 (NSC 706704), a novel thioredoxin inhibitor: an in vitro study.
Mukherjee A, Westwell AD, Bradshaw TD, Stevens MF, Carmichael J, Martin SG., Br. J. Cancer 92(2), 2005
PMID: 15655539
Induction of apoptosis without redox catastrophe by thioredoxin-inhibitory compounds.
Pallis M, Bradshaw TD, Westwell AD, Grundy M, Stevens MF, Russell N., Biochem. Pharmacol. 66(9), 2003
PMID: 14563480
A comparative study of methylglyoxal metabolism in trypanosomatids.
Greig N, Wyllie S, Patterson S, Fairlamb AH., FEBS J. 276(2), 2008
PMID: 19076214
Dissecting the essentiality of the bifunctional trypanothione synthetase-amidase in Trypanosoma brucei using chemical and genetic methods.
Wyllie S, Oza SL, Patterson S, Spinks D, Thompson S, Fairlamb AH., Mol. Microbiol. 74(3), 2009
PMID: 19558432
Chemical validation of trypanothione synthetase: a potential drug target for human trypanosomiasis.
Torrie LS, Wyllie S, Spinks D, Oza SL, Thompson S, Harrison JR, Gilbert IH, Wyatt PG, Fairlamb AH, Frearson JA., J. Biol. Chem. 284(52), 2009
PMID: 19828449
In vivo effects of difluoromethylornithine on trypanothione and polyamine levels in bloodstream forms of Trypanosoma brucei.
Fairlamb AH, Henderson GB, Bacchi CJ, Cerami A., Mol. Biochem. Parasitol. 24(2), 1987
PMID: 3114634
Protein production by auto-induction in high density shaking cultures.
Studier FW., Protein Expr. Purif. 41(1), 2005
PMID: 15915565

Gething M., Davidson B.., 1972
Quinols as novel therapeutic agents. 2.(1) 4-(1-Arylsulfonylindol-2-yl)-4-hydroxycyclohexa-2,5-dien-1-ones and related agents as potent and selective antitumor agents.
Berry JM, Bradshaw TD, Fichtner I, Ren R, Schwalbe CH, Wells G, Chew EH, Stevens MF, Westwell AD., J. Med. Chem. 48(2), 2005
PMID: 15658878
Antitumor quinols: role of glutathione in modulating quinol-induced apoptosis and identification of putative cellular protein targets.
Chew EH, Matthews CS, Zhang J, McCarroll AJ, Hagen T, Stevens MF, Westwell AD, Bradshaw TD., Biochem. Biophys. Res. Commun. 346(1), 2006
PMID: 16756956
PMX464, a thiol-reactive quinol and putative thioredoxin inhibitor, inhibits NF-kappaB-dependent proinflammatory activation of alveolar epithelial cells.
Callister ME, Pinhu L, Catley MC, Westwell AD, Newton R, Leaver SK, Quinlan GJ, Evans TW, Griffiths MJ, Burke-Gaffney A., Br. J. Pharmacol. 155(5), 2008
PMID: 18587424
The structure of reduced tryparedoxin peroxidase reveals a decamer and insight into reactivity of 2Cys-peroxiredoxins.
Alphey MS, Bond CS, Tetaud E, Fairlamb AH, Hunter WN., J. Mol. Biol. 300(4), 2000
PMID: 10891277
Antitumour properties of fluorinated benzothiazole-substituted hydroxycyclohexa-2,5-dienones ('quinols').
Lion CJ, Matthews CS, Wells G, Bradshaw TD, Stevens MF, Westwell AD., Bioorg. Med. Chem. Lett. 16(19), 2006
PMID: 16908135
Reaction mechanism of plant 2-Cys peroxiredoxin. Role of the C terminus and the quaternary structure.
Konig J, Lotte K, Plessow R, Brockhinke A, Baier M, Dietz KJ., J. Biol. Chem. 278(27), 2003
PMID: 12702727
Dimers to doughnuts: redox-sensitive oligomerization of 2-cysteine peroxiredoxins.
Wood ZA, Poole LB, Hantgan RR, Karplus PA., Biochemistry 41(17), 2002
PMID: 11969410
Structure, mechanism and regulation of peroxiredoxins.
Wood ZA, Schroder E, Robin Harris J, Poole LB., Trends Biochem. Sci. 28(1), 2003
PMID: 12517450
Crystal structure of the tryparedoxin peroxidase from the human parasite Trypanosoma cruzi.
Pineyro MD, Pizarro JC, Lema F, Pritsch O, Cayota A, Bentley GA, Robello C., J. Struct. Biol. 150(1), 2005
PMID: 15797726
The high resolution crystal structure of recombinant Crithidia fasciculata tryparedoxin-I.
Alphey MS, Leonard GA, Gourley DG, Tetaud E, Fairlamb AH, Hunter WN., J. Biol. Chem. 274(36), 1999
PMID: 10464297
Tryparedoxins from Crithidia fasciculata and Trypanosoma brucei: photoreduction of the redox disulfide using synchrotron radiation and evidence for a conformational switch implicated in function.
Alphey MS, Gabrielsen M, Micossi E, Leonard GA, McSweeney SM, Ravelli RB, Tetaud E, Fairlamb AH, Bond CS, Hunter WN., J. Biol. Chem. 278(28), 2003
PMID: 12707277
Comparative structural, kinetic and inhibitor studies of Trypanosoma brucei trypanothione reductase with T. cruzi.
Jones DC, Ariza A, Chow WH, Oza SL, Fairlamb AH., Mol. Biochem. Parasitol. 169(1), 2009
PMID: 19747949
2-Cys peroxiredoxin function in intracellular signal transduction: therapeutic implications.
Kang SW, Rhee SG, Chang TS, Jeong W, Choi MH., Trends Mol Med 11(12), 2005
PMID: 16290020
Can we rationally design promiscuous drugs?
Hopkins AL, Mason JS, Overington JP., Curr. Opin. Struct. Biol. 16(1), 2006
PMID: 16442279
Network pharmacology: the next paradigm in drug discovery.
Hopkins AL., Nat. Chem. Biol. 4(11), 2008
PMID: 18936753

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