Page 7 of 15
ACS Medicinal Chemistry Letters
Effect and Mechanism of Inhibiting Glucose-6-Phosphate
Corresponding Author
Dehydrogenase Activity on the Proliferation of Plasmodium
Falciparum. Biochim. Biophys. Acta - Mol. Cell Res. 2017, 1864
(5), 771–781.
1
2
3
4
5
6
7
8
9
(10)
(11)
Santos, C. D.; Toldo, M. P. A.; Santello, F. H.; Filipin, M. D. V.;
Brazão, V.; do Prado Júnior, J. C. Dehydroepiandrosterone
Increases Resistance to Experimental Infection by Trypanosoma
Cruzi. Vet. Parasitol. 2008, 153 (3–4), 238–243.
Domingues Santos, C.; Loria, R. M.; Rodrigues Oliveira, L. G.;
Collins Kuehn, C.; Alonso Toldo, M. P.; Albuquerque, S.; do
Prado Júnior, J. C. Effects of Dehydroepiandrosterone-Sulfate
(DHEA-S) and Benznidazole Treatments during Acute Infection
of Two Different Trypanosoma Cruzi Strains. Immunobiology
2010, 215 (12), 980–986.
Author Contributions
F.F.N.‡ and M.B. performed the synthesis; J.N.F.‡ produced the
purified enzymes and performed the enzymatic assays; A.G.E.
performed the cell-assays; A.T.C. designed and supervised the
biological assays; M.B. planned the target compounds; A.T.C. and
M.B. jointly designed the study and analyzed the results. The
manuscript was written through contributions of all authors. ‡These
authors contributed equally.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(20)
Kuehn, C. C.; Oliveira, L. G. R.; Santos, C. D.; Augusto, M. B.;
Toldo, M. P. A.; Do Prado, J. C. Prior and Concomitant
Dehydroepiandrosterone Treatment Affects Immunologic
Response of Cultured Macrophages Infected with Trypanosoma
Cruzi in Vitro? Vet. Parasitol. 2011, 177 (3–4), 242–246.
Romero-Hernández, L. L.; Merino-Montiel, P.; Meza-Reyes, S.;
Vega-Baez, J. L.; López, Ó.; Padrón, J. M.; Montiel-Smith, S.
Synthesis of Unprecedented Steroidal Spiro Heterocycles as
Potential Antiproliferative Drugs. Eur. J. Med. Chem. 2018, 143,
21–32.
Cui, H. W.; Peng, S.; Gu, X. Z.; Chen, H.; He, Y.; Gao, W.; Lv,
F.; Wang, J. H.; Wang, Y.; Xie, J.; Liu, M. Y.; Yi, Z.; Qiu, W. W.
Synthesis and Biological Evaluation of D-Ring Fused 1,2,3-
Thiadiazole Dehydroepiandrosterone Derivatives as Antitumor
Agents. Eur. J. Med. Chem. 2016, 111, 126–137.
Hamilton, N. M.; Dawson, M.; Fairweather, E. E.; Hamilton, N.
S.; Hitchin, J. R.; James, D. I.; Jones, S. D.; Jordan, A. M.; Lyons,
A. J.; Small, H. F.; Thomson, G. J.; Waddell, I. D.; Ogilvie, D. J.
Novel Steroid Inhibitors of Glucose 6-Phosphate Dehydrogenase.
J. Med. Chem. 2012, 55 (9), 4431–4445.
Cordeiro, A. T.; Thiemann, O. H. 16-Bromoepiandrosterone, an
Activator of the Mammalian Immune System, Inhibits Glucose 6-
Phosphate Dehydrogenase from Trypanosoma Cruzi and Is Toxic
to These Parasites Grown in Culture. Bioorganic Med. Chem.
2010, 18 (13), 4762–4768.
Funding Sources
This research was funded by the São Paulo Research Foundation
[FAPESP grants for M.B. (2013/16534-4), and A.T.C.
(2016/14271-4 and 2018/22202-8)] and by the Coordination for the
Improvement of Higher Education Personnel (CAPES 7775/2014-
98). The Brazilian Ministry of Science, Technology, Innovation
and Communication sponsored F.F.N. (PCI-DB 313424/2015-2).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors wish to thank Prof. Ronaldo Pilli and the Chemistry
Institute / UNICAMP for their support, as well as the Nuclear
Magnetic Resonance Laboratory at LNBio/CNPEM.
ABBREVIATIONS
NADP, nicotinamide adenine dinucleotide phosphate; G6PDH,
glucose-6-phosphate dehydrogenase; NFX, nifurtimox; BNZ,
benznidazole; PPP, pentose-phosphate pathway; NADPH,
dihydronicotinamide adenine dinucleotide phosphate; DHEA,
dehydroepiandrosterone; EA, epiandrosterone; BrEA, 16-
bromoepiandrosterone; DMSO, dimethyl sulfoxide; HIV, human
immunodeficiency virus.
Carrero, J. C.; Cervantes-Rebolledo, C.; Vargas-Villavicencio, J.
A.; Hernández-Bello, R.; Dowding, C.; Frincke, J.; Reading, C.;
Morales-Montor,
J.
Parasiticidal
Effect
of
16α-
Bromoepiandrosterone (EpiBr) in Amoebiasis and Cysticercosis.
Microbes Infect. 2010, 12 (8–9), 677–682.
REFERENCES
Stickney, D. R.; Noveljic, Z.; Garsd, A.; Destiche, D. A.; Frincke,
J. M. Safety and Activity of the Immune Modulator HE2000 on
the Incidence of Tuberculosis and Other Opportunistic Infections
in AIDS Patients. Antimicrob. Agents Chemother. 2007, 51 (7),
2639–2641.
Frincke, J. M.; Stickney, D. R.; Onizuka-Handa, N.; Garsd, A.;
Reading, C.; Krudsood, S.; Wilairatana, P.; Looareesuwan, S.
Reduction of Parasite Levels in Patients with Uncomplicated
Malaria by Treatment with HE2000. Am. J. Trop. Med. Hyg.
2007, 76 (2), 232–236.
Reading, C.; Dowding, C.; Schramm, B.; Garsd, A.; Onizuka-
Handa, N.; Stickney, D.; Frincke, J. Improvement in Immune
Parameters and Human Immunodeficiency Virus-1 Viral
Response in Individuals Treated with 16α-Bromoepiandrosterone
(HE2000). Clin. Microbiol. Infect. 2006, 12 (11), 1082–1088.
Gordon, G.; Mackow, M. C.; Levy, H. R. On the Mechanism of
Interaction of Steroids with Human Glucose 6-Phosphate
Dehydrogenase. Arch. Biochem. Biophys. 1995, 318 (1), 25–29.
Zhao, Z. B.; Liu, Y.; Yao, Y. Computational Determination of
Binding Structures and Free Energies of Glucose 6-Phosphate
Dehydrogenase with Novel Steroid Inhibitors. J. Mol. Graph.
Model. 2014, 51, 168–172.
Ortiz, C.; Moraca, F.; Medeiros, A.; Botta, M.; Hamilton, N.;
Comini, M. A.; Schmidt, T. J. Binding Mode and Selectivity of
Steroids towards Glucose-6-Phosphate Dehydrogenase from the
Pathogen Trypanosoma Cruzi. Molecules 2016, 21 (3), 1–14.
Mercaldi, G. F.; Dawson, A.; Hunter, W. N.; Cordeiro, A. T. The
(1)
(2)
WHO. Chagas disease (American trypanosomiasis) fact sheet.
disease-(american-trypanosomiasis) (accessed Apr 8, 2020).
Pérez-Molina, J. A.; Pérez-Ayala, A.; Moreno, S.; Fernández-
González, M. C.; Zamora, J.; López-Velez, R. Use of
Benznidazole to Treat Chronic Chagas’ Disease: A Systematic
Review with a Meta-Analysis. J. Antimicrob. Chemother. 2009,
64 (6), 1139–1147.
(3)
Maya, J. D.; Cassels, B. K.; Iturriaga-Vásquez, P.; Ferreira, J.;
Faúndez, M.; Galanti, N.; Ferreira, A.; Morello, A. Mode of
Action of Natural and Synthetic Drugs against Trypanosoma
Cruzi and Their Interaction with the Mammalian Host. Comp.
Biochem. Physiol. - A Mol. Integr. Physiol. 2007, 146 (4), 601–
620.
(21)
(22)
(4)
(5)
Babior, B. M. Phagocytes and Oxidative Stress. Am. J. Med.
2000, 109 (1), 33–44.
Maugeri, D. A.; Cazzulo, J. J. The Pentose Phosphate Pathway in
Trypanosoma Cruzi. FEMS Microbiol. Lett. 2004, 234 (1), 117–
123.
(6)
(7)
Kovářová, J.; Barrett, M. P. The Pentose Phosphate Pathway in
Parasitic Trypanosomatids. Trends Parasitol. 2016, 32 (8), 622–
634.
Gupta, S.; Cordeiro, A. T.; Michels, P. A. M. Glucose-6-
Phosphate Dehydrogenase Is the Target for the Trypanocidal
Action of Human Steroids. Mol. Biochem. Parasitol. 2011, 176
(2), 112–115.
(23)
(24)
(25)
Structure of
a Trypanosoma Cruzi Glucose-6-Phosphate
(8)
(9)
Marks, P. A.; Banks, J. Inhibition of Mammalian Glucose-6-
Phosphate Dehydrogenase by Steroids. Proc. Natl. Acad. Sci.
1960, 46 (4), 447–452.
Dehydrogenase Reveals Differences from the Mammalian
Enzyme. FEBS Lett. 2016, 2776–2786.
Numazawa, M.; Nagaoka, M.; Osawa, Y. Stereospecific
Zhang, Z.; Chen, X.; Jiang, C.; Fang, Z.; Feng, Y.; Jiang, W. The
ACS Paragon Plus Environment