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Aging and disease    2016, Vol. 7 Issue (6) : 745-762     DOI: 10.14336/AD.2016.0505
Original Article |
Bioactive Flavonoids and Catechols as Hif1 and Nrf2 Protein Stabilizers - Implications for Parkinson’s Disease
Smirnova Natalya A.1,2, Kaidery Navneet Ammal3, Hushpulian Dmitry M.2,4, Rakhman Ilay I.1, Poloznikov Andrey A.2, Tishkov Vladimir I.5, Karuppagounder Saravanan S.1, Gaisina Irina N.6, Pekcec Anton7, Leyen Klaus Van7, Kazakov Sergey V.8, Yang Lichuan3, Thomas Bobby3, Ratan Rajiv R.1, Gazaryan Irina G.1,5,8,*
1Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, NY 10605, USA
2D. Rogachev Federal Scientific and Clinical Center for Pediatric Hematology, Oncology, and Immunology, Moscow 117997, Russia
3Departments of Pharmacology, Toxicology & Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
4ValentaPharm, Moscow 119530, Russia
5Department of Chemical Enzymology, Moscow State University, Moscow 119992, Russia
6Department of Medicinal Chemistry and Pharmacology, University of Illinois at Chicago, Chicago, IL 60612, USA
7Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
8Department of Chemistry and Physical Sciences, Dyson College, Pace University, Pleasantville, NY 10570, USA.
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Abstract  

Flavonoids are known to trigger the intrinsic genetic adaptive programs to hypoxic or oxidative stress via estrogen receptor engagement or upstream kinase activation. To reveal specific structural requirements for direct stabilization of the transcription factors responsible for triggering the antihypoxic and antioxidant programs, we studied flavones, isoflavones and catechols including dihydroxybenzoate, didox, levodopa, and nordihydroguaiaretic acid (NDGA), using novel luciferase-based reporters specific for the first step in HIF1 or Nrf2 protein stabilization. Distinct structural requirements for either transcription factor stabilization have been found: as expected, these requirements for activation of HIF ODD-luc reporter correlate with in silico binding to HIF prolyl hydroxylase. By contrast, stabilization of Nrf2 requires the presence of 3,4-dihydroxy- (catechol) groups. Thus, only some but not all flavonoids are direct activators of the hypoxic and antioxidant genetic programs. NDGA from the Creosote bush resembles the best flavonoids in their ability to directly stabilize HIF1 and Nrf2 and is superior with respect to LOX inhibition thus favoring this compound over others. Given much higher bioavailability and stability of NDGA than any flavonoid, NDGA has been tested in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-animal model of Parkinson’s Disease and demonstrated neuroprotective effects.

Keywords Parkinson’s disease model      glutathione depletion model      HIF prolyl hydroxylase      lipoxygenase      fisetin      luteolin      Keap1     
Corresponding Authors: Gazaryan Irina G.   
About author:

present address: Kunming Biomed International, Kunming, Yunnan, 650500, China

Issue Date: 01 December 2016
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Smirnova Natalya A.
Kaidery Navneet Ammal
Hushpulian Dmitry M.
Rakhman Ilay I.
Poloznikov Andrey A.
Tishkov Vladimir I.
Karuppagounder Saravanan S.
Gaisina Irina N.
Pekcec Anton
Leyen Klaus Van
Kazakov Sergey V.
Yang Lichuan
Thomas Bobby
Ratan Rajiv R.
Gazaryan Irina G.
Cite this article:   
Smirnova Natalya A.,Kaidery Navneet Ammal,Hushpulian Dmitry M., et al. Bioactive Flavonoids and Catechols as Hif1 and Nrf2 Protein Stabilizers - Implications for Parkinson’s Disease[J]. Aging and disease, 2016, 7(6): 745-762.
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2016.0505     OR     http://www.aginganddisease.org/EN/Y2016/V7/I6/745
Figure 1.  Schematic presentation of a luciferase-labeled surrogate transcription factor reporter. Ko, rate of fusion protein generation, “promoter capacity”, k1, rate constant for the recognition step, which has been shown to be rate-limiting for the reporters under discussion, Ki, inhibition constant for a stabilizer working at the first step; k2, ubiquitinylation rate constant; k3, proteasomal degradation rate constant.
#Trivial
and Chemical Names
Activation parameters at 10 µMIron chelationRedox properties
ODD-luc foldHRE-luc foldNeh2-luc fold
(EC50), µM
Iron complex Diss. Const, µMFC red Rate Const, mM-1s-1EHOMO,
eV [41]
I. Flavones
13-Hydroxy-1.5±0.21.5±0.2inactive2.0±0.2inactive
23,7-Dihydroxy-2.0±0.21.5±0.2Inactive2.5±0.3inactive
33,4’-Dihydroxy-InactiveInactiven.d.2.5±0.2Inactive
43-Hydroxy-4’-methoxy-4.0±0.4
53-Hydroxy-7-methoxy-InactiveInactiveInactive5.0±0.5n.d.
63,7-Dimethoxy-InactiveinactiveInactive-
73,5-Dihydroxy-1.3±0.22.0±0.2Inactive2.5±0.3inactive
8Galangin
3,5,7-Trihydroxy-
Inactive1.3±0.2Inactive3.5±0.448±6-8.90
9Kaempferol
3,5,7,4’-Tetrahydroxy-
Inactive1.5±0.215±2
(5±0.6)
2.5±0.3369±42-8.74
10Fisetin
3,7,3’,4’-Tetrahydroxy-
1.6±0.22.0±0.223±3
(2±0.2)
2.7±0.3301±34-8.69
11Quercetin
3,5,7,3’,4’-Pentahydroxy-
1.5±0.22.0±0.224±3
(2±0.2)
2.7±0.3366±39-8.72
12Morin
3,5,7,2’,4’-Pentahydroxy-
Inactive1.3±0.2Inactive2.5±0.3n.d.-8.81
13Myricetin
3,5,7,3’,4’,5’-Hexahydroxy
1.3±0.22.0±0.225±3
(2±0.2)
2.0±0.2n.d.-8.80
145-Hydroxy-InactiveInactiveinactiveInactiveInactive-9.12
15Chrysin
5,7-Dihydroxy-
Inactive1.2±0.15InactiveInactiveInactive-9.25
16Apigenin
5,7,4’-Trihydroxy-
Inactive1.3±0.15InactiveInactiveInactive-9.15
17Baicalein
5,6,7-Trihydroxy-
Inactive5.0±0.6Inactive2.5±0.325.5±3-8.99
18Luteolin
5,7,3’,4’-Tetrahydroxy-
2.5±0.32±0.255±0.6
(2±0.3)
3.5±0.4130±15-9.09
193’,4’-Dihydroxy-2.5±0.32±0.2515±2
(2±0.2)
2.5±0.3n.d.
207,8-Dihydroxy-1.5±0.23.6±0.4Inactive0.7±0.1n.d.-9.23
Table 1A  Comparison of flavones performance in reporter activation assays. Original data in the table represent Mean ± SD. Catechol (3’,4’-dihydroxy) motif on the freely rotating phenyl ring is shown in red.
#Trivial
and Chemical Names
Activation parameters at 10 µMIron chelationRedox properties
ODD-luc foldHRE-luc foldNeh2-luc fold
(EC50), µM
Iron complex Diss. Const, µMFC red Rate Const, mM-1s-1EHOMO,
eV [41]
II. Isoflavones
21Methoxyvone
5-Methyl-7-methoxy-
Inactive3.2±0.35InactiveInactiven.d.
22Ipriflavone
7-Isopropoxy-3-phenyl-
Inactive2.5±0.3InactiveInactiven.d.
23Genistein
6,7,4’-Trihydroxy-
Inactive1.5±0.2InactiveInactiven.d.
245-Hydroxy-daidzein
5,7,4’-Trihydroxy-
InactiveInactiveInactiveInactiven.d.
258-Hydroxy-daidzein
7,8,4’-Trihydroxy-
InactiveInactiveInactive1.5±0.3n.d.
26Daidzein
7,4’-Dihydroxy-
InactiveInactiveInactiveInactiven.d.
273’-Hydroxy-daidzein
7,3’,4’-Trihydroxy-
2.5±0.32.5±0.315±2
5±0.6
3.5±0.4n.d.
III. Catechols
28NDGA 4,4'-(2,3-dimethylbutane-1,4-diyl)dibenzene-1,2-diol2.5±0.32±0.215±1.8
(2±0.3)
2.5±0.3n.d.
29Levodopa
3,4-Dihydroxy-L-phenylalanine
2.0±0.251.7±0.2Inactive
(20±3)
2.5±0.3n.d.
30D-DOPA
3,4-Dihydroxy-D-phenylalanine
InactiveInactiveInactive
(20±3)
2.5±0.3n.d.
31Carbidopa
N-Aminomethyldopa
InactiveInactiveInactive
(20±3)
2.5±0.3n.d.
32DHB
Ethyl 3,4-dihydroxybenzoate
Active above 50 µMActive above 20 µMInactive
(20±3)
2.5±0.3n.d.
33Didox
3,4-Dihydroxy-benzohydroxamate
Active above 100 µMActive above 100 µMInactive
(100±5)
1.5±0.3n.d.
IV. Other
34Calcein2.0±0.251.7±0.2Inactive0.05±0.01n.d.
Table 1B  Comparison of isoflavones and catechols performance in reporter activation assays. Original data in the table represent Mean ± SD.
Figure 2.  Specificity for the flavone structure in HIF1 ODD-reporter activation. A) Independence of activation amplitude from iron binding constant, and B) Independence of activation amplitude from ferricyanide (FC) reduction rate constant (The protocols for the determination of the constants under Materials and Methods).
Figure 3.  Structural requirements for activating HIF1 ODD-luc reporter correspond to those for inhibiting HIF PHD2. A) 3,7-hydroxyflavone docking into PHD2 active site illustrating bi-ligand iron chelation via carbonyl oxygen and 3-hydroxygroup and interaction of 5-hydroxygrop with Met299; B) docking of luteolin, active center view, and C) overall view; D) docking of 3’-hydroxydaidzein, and E) NDGA.
Figure 4.  Comparison of NDGA with flavonoids. A) Inhibition of rabbit reticulocyte 15-LOX-1 activity; B) Induction of VEGF mRNA. C1, fisetin, C2, luteolin, C3, kaempferol, C4, genistein, C5, NDGA, C6, quercetin, C7, 3’4’-dihydroxyflavone, C8, FG-4592, used as a control HIF PHD inhibitor. For LOX inhibition compounds were used at 25 µM; for VEGF induction pretreatment was performed at concentrations shown in brackets in µM.
Figure 5.  Comparison of effects of flavonoids and catechols in glutathione depletion model. Neuroprotective effects in HCA model correspond to compounds ranking in HIF ODD-luc screen (A, fisetin, B, luteolin, C, 3’-hydroxydaidzein, D, daidzein, E, NDGA).
Figure 6.  Independence of Neh2-luc reporter activation from redox potential (EHOMO) of flavones.
Treatment groupsNDOPAMINEDOPACHVA
CONTROL589.9 ± 6.18.5 ± 0.767.8 ± 1.2
NDGA588.4 ± 6.27.59 ± 1.357.5 ± 1.66
MPTP1035.4 ± 3.45*3.92 ± 0.35*4.7 ± 0.63*
NDGA+MPTP1055.3 ± 5.7#6.04 ± 1.14#7.4 ± 0.96#
Table 2  Striatal levels of Dopamine and its metabolites
Figure 7.  Neuroprotective effects of NDGA in the MPTP model of Parkinson's disease. (A) Immunohistochemical staining for TH and (B) stereological analysis of total (NISSL) and TH+-neurons in the SNpc in the acute MPTP model on the 7th day after treatment with NDGA. Bars represent mean ± SEM. *p < 0.05 compared to Vehicle controls, and #p < 0.05 compared to MPTP (n=8 mice per group).
Treatment groupsMPP+
MPTP8.1 ± 0.14
NDGA+MPTP8.4 ± 0.22
Table 3  Striatal MPP+ levels
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