Identification and Structural Analysis of New Nrf2 Activators by Mechanism-Based Chemical Transformation of 15-Deoxy-Δ12, 14-PGJ2

Article abstract of DOI:10.1002/cbic.201600165

Mechanism-based chemical transformation of 15-deoxy-Δ^{12, 14}-PGJ₂ (15d-PGJ₂) resulted in a series of new NF-E2-related factor-2 (Nrf2) activators and detailed elucidation of the function of each electrophilic binding site. In addition, HO-1 expression resulting from Nrf2 activation through enhanced dissociation of the Keap1–Nrf2 complex by the new activators was proved.

Full text of DOI:10.1002/cbic.201600165

Accepted Article
Title: Identification and structural analysis of novel Nrf2 activators via mechanism-
based chemical transformation of 15 deoxy-PGJ2
Authors: Kyeojin Kim; Jong-Min Park; Nam-Jung Kim; Su-Jung Kim; Hyunyoung
Moon; Hongchan An; Jeeyeon Lee; Hyun-Ju Park; Young-Joon Surh; Young-
Ger Suh
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To be cited as: ChemBioChem 10.1002/cbic.201600165
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ChemBioChem
10.1002/cbic.201600165
COMMUNICATION
Identification and structural analysis of novel Nrf2 activators via
mechanism-based chemical transformation of 15-deoxy-Δ12,14
-
PGJ2
Kyeojin Kim,‡ [a] Jong-Min Park,‡ [c] Nam-Jung Kim,[d] Su-Jung Kim,[b] Hyunyoung Moon,[a] Hongchan
An,[a] Jeeyeon Lee,[a] Hyun-Ju Park,[e] Young-Joon Surh*[b] and Young-Ger Suh*[a]
Abstract: The mechanism-based chemical transformation of 15-
deoxy-Δ12,14-PGJ2 (15d-PGJ2) identified a series of novel NF-E2-
related factor-2 (Nrf2) activators and elucidated the detailed function
of each electrophilic binding site. In addition, HO-1 expression
resulting from Nrf2 activation through the dissociaton enhancement
of the Keap1-Nrf2 complex by the novel activators was proved via
our chemical approach.
regarding how Nrf2-activating molecules bind to the thiol groups
5]
of Keap1 cysteines,[4, although these studies have not fully
elucidated the mode of action responding to oxidative stresses.[6,
7]
Recently, endogenous 15d-PGJ2 has received much attention
due to its potent Nrf2-activating activity.[8] Its Nrf2 activation is
considered to be induced by a 1,4-nucleophilic addition of the
reactive thiols in Keap1 to the cyclopentenone core of 15d-PGJ2,
and a mutation study corroborated the evidence that Cys273 is
the major site for 15d-PGJ2 binding.[8a] Thus, these studies
evoked the importance of the electronic features of the thiol
binding sites[8a, 9] although the mechanistic questions about the
role of the thiol binding sites of 15d-PGJ2 remain unclear,
despite the significance of Keap1-Nrf2 as a chemopreventive
target. In addition, the limited structural information on the
Keap1-Nrf2 complex has complicated the development of
rationally designed Nrf2 activators based on 15d-PGJ2 and
confirmation of their interaction mode.[7] In this connection, we
have been intensively working on 15d-PGJ2 to elucidate its
structural features, focusing on its electrophilic binding sites, and
to confirm the proposed mechanism associated with the
interaction with Keap1. We herein report an unprecedented
chemical approach for the identification and structural analysis
of novel and potent Nrf2 activators.
Cells have evolved defense systems to survive under various
redox stresses, and understanding the molecular mechanisms
by which cells detect oxidative or electrophilic stresses and
transduce the signals to induce cytoprotective enzymes such as
hemeoxygenase-1 (HO-1) has been a central focus in biology.[1]
The induction of HO-1 is primarily mediated by the antioxidant
response element (ARE)/electrophile response elements
(EpREs) controlled by the transcription factor Nrf2.[2] Nrf2 activity
is regulated by the Keap1 protein, a cytoplasmic repressor of
Nrf2, through the formation of the Keap1-Nrf2 complex.[3] Under
oxidative stress, a disruption of the Keap1-Nrf2 complex induces
the release of Nrf2 and the translocation of active Nrf2 into the
nucleus, leading to ARE-dependent expression of HO-1.[4]
Keap1 is a cysteine-rich protein possessing twenty-seven
cysteine residues, and chemicals that react with the thiol groups
of cysteine are considered to be potential inducers of ARE
activity. Various experimental approaches have been reported
[a]
[b]
Dr. K. Kim, H. Moon, Dr. H. An, Prof. J. Lee, Prof. Y.-G. Suh
College of Pharmacy
Seoul National University
1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea
E-mail: ygsuh@snu.ac.kr
Dr. S.-J. Kim, Prof. Y.-J. Surh
Scheme 1. Strategy for enhancing Nrf2 activation based on the 15d-PGJ2
binding to Keap1.
Tumor Microenvironment Global Core Research Center, College of
Pharmacy
Seoul National University
1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea
E-mail: surh@plaza.snu.ac.kr
Dr. J.-M. Park
CHA Cancer Prevention Research Center
CHA University School of Medicine
Seoul, 135-081, Republic of Korea
Prof. N.-J. Kim
Department of Pharmacy, College of Pharmacy
Kyung Hee University
26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of
Korea
Prof. H.-J. Park
School of Pharmacy
Sungkyunkwan University
We pursued appropriate structural modification of endogenous
15d-PGJ2 to investigate the roles of each electrophilic carbon in
Nrf2 activation. Initially, rac-15d-PGJ2 (4) and rac-9,10-dihydro-
15d-PGJ2 (5) were prepared from rac-15d-PGJ2 methyl ester (3),
which was derived from known enone 2.[10] The Me3SnOH-
mediated hydrolysis of 3 afforded 4 and the chemoselective 1,4-
reduction of 3 with L-selectride followed by Me3SnOH-mediated
hydrolysis produced rac-9,10-dihydro-15d-PGJ2 (5). The
hydrolysis of 6, which was prepared from known enone via a
two-step sequence afforded rac-14,15-dihydro-15d-PGJ2 (7).
Next, rac-12,13,14,15-tetrahydro-15d-PGJ2 (8) was synthesized
by the Bu3SnH reduction of enone olefins of rac-14,15-dihydro-
15d-PGJ2 methyl ester (6) and a selective Saegusa oxidation to
yield the ring-olefin followed by ester hydrolysis.
[c]
[d]
[e]
Suwon 440-746, Republic of Korea
[‡]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))

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Scheme 2. Design and syntheses of 15d-PGJ2 analogs.
sequential Nrf2 translocation, HO-1 expression and ARE
activation
by
15d-PGJ2
and
the
15d-PGJ2-based
cyclopentanones (or cyclopentenone) were evaluated. As shown
in Figures 1A and 1B, Nrf2 translocation and HO-1 expression in
non-tumorigenic human breast epithelial MCF10A cells were
effectively induced by 15d-PGJ2 (4) and 7, whereas they were
not induced by 5 or 8 at 1 μM. ARE luciferase activation (Figure
1C) and HO-1 expression (Figure 1D) in human breast
adenocarcinoma MCF7 cells were observed in a similar pattern.
These results indicate that both electrophlic sites are essential
for Nrf2 activation, ultimately leading to HO-1 expression. Of
interest, HO-1 expression was slightly induced upon treatment
with 8 at a high concentration (30 μM), although it was not
induced by 5 at the same concentration (Figure 1E). Again,
these results confirmed the crucial role of the intracyclic olefin as
a Michael acceptor for Nrf2 activation, with the exo-olefin being
beneficial. The key function of the intracyclic olefin for thiol
additions is also supported by the charge distribution (Supp.
Figure S1) and chemical shifts of the electrophilic carbons (Supp.
Synthesis Part) of both binding sites although the chemical shifts
sometimes do not support the correlation well. These findings
are consistent with the dienone moiety of prostaglandins
reacting with thiols at higher rates compared with the simple
enone.[13] Regarding the notably higher activity of 7 than 15d-
PGJ2, we assumed that the reduction of the 14,15-double bond
might induce C9 more reactive for 1,4-addition partly due to
decrease of the electronic density at C9, based on the charge
analysis by molecular modeling and 13C NMR analysis (160.6 to
161.6) although the enhanced activity of compound 7 might be
associated with other factors including cell permeability,
oxidative stress induction, and non-Keap1 mediated Nrf2
activation. To the best of our knowledge, this is the first report to
demonstrate the substantial role of the second binding site of
15d-PGJ2 in Nrf2 activation.
Figure 1. Effects of olefin-modified 15d-PGJ2 analogs on the Nrf2 pathway. A)
Nrf2 translocation in MCF10A cells (1 μM). B) HO-1 induction in MCF10A cells
(1 μM). C) ARE activation in MCF7 cells measured by luciferase assay (1 μM).
D) HO-1 induction in MCF7 cells (1 μM). E) HO-1 induction in MCF10A (10
and 30 μM, respectively). The data represent mean ± SD (n = 3). Significant
differences between the compared groups are indicated (*P < 0.05 vs. control).
To confirm the influence of the electronic character of the thiol
binding sites of 15d-PGJ2 on its chemopreventive effect,

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chloro-14,15-dihydro-15d-PGJ2 were prepared from rac or (R)-2.
Ketone 2 was first converted to α-chloro ketone 12 via
epoxidation and chlorination. The synthesis of -chloro analogs
were completed by the same manner above.
Scheme 3. Synthesis of α halogenated 15d-PGJ2 analogs
Modifying the α-position of an α,β-unsaturated carbonyl system
is quite attractive for enhancing the 1,4-additions of thiol,
although it is not a common strategy.[14] Thus, we designed 
halogenated analogs of 15d-PGJ2 to evaluate with regard to the
production of chemopreventive HO-1. The α-halo-15d-PGJ2, 11a
and 11b were synthesized via the epoxidation of 3, the
regioselective halogenation of the resulting epoxide, and
dehydration and ester hydrolysis.[12]
Scheme 4. Synthesis of α chloro 14, 15 dihydro-PGJ2 analogs
As anticipated, 15 exhibited the most potent ARE activation
(Figure 3A), resulting in the highest HO-1 induction (Figure 3B)
among the racemic compounds. Cyclopentenone 15 also
showed dose-dependent HO-1 expression (Figure 3C). In
addition, it was confirmed that the stereochemistry of 15d-PGJ2
importantly influences the HO-1 inducing effect in favor of the
(S)-configuration, as shown in Figures 3A and 3B. The improved
activities of 11b and 15 (or 16) are obviously associated with
electronegativity of the chlorine atom, and 16 appears to form
the most energetically favorable complex with Keap1. The
higher activity of 11b versus 11a (X= F; See Supp. Figure S3), in
spite of the lower electronegativity of chlorine compared to
fluorine, is not clearly explained. However, the higher biological
activities of the chlorinated enones seem partly due to the lower
electrophilic activity of fluoroenone 11a caused by the overall
electron-donating effect of fluorine, resulted from its strong
resonance effect which can overrule its inductive effect.[15] The
higher biological activities of 11b was further supported by
comparison of the binding and total free energies of the docked
complexes between the Nrf2 activators and Keap1. (See Supp.
Table S1 and S2). It was also predicted that the Keap1 complex
with the most active chlorinated analog 16 was more stable than
the Keap1 complex with any other halogenated analogs in terms
of the total free energy of the ligand-receptor complex. (See
Supp. Table S2).
Figure 2. Effects of α-Cl-15d-PGJ2 (11b) on the Nrf2 pathway. A) Nrf2
translocation (1 μM) in MCF10A cells. B) HO-1 induction in MCF10A cells (1
μM). C) ARE activation in MCF7 cells measured by luciferase assay (1 μM). D)
HO-1 induction in MCF7 cells (1 μM). The data represent mean ± SD (n = 3).
Significant differences between the compared groups are indicated (*P < 0.05
vs. control).
As anticipated, Nrf2 translocation (Figure 2A) and HO-1
expression (Figure 2B) in MCF-10A cells were highly induced by
11b compared to the parent 15d-PGJ2. In addition, 11b
significantly enhanced the ARE-luciferase activity (Figure 2C)
and HO-1 expression (Figure 2D) in MCF7 cells. Based on the
analysis of the chlorine substitution and 14,15-olefin effects on
Nrf2 activation, we further prepared cyclopentenone 15, which
reflects the structural optimization of 15d-PGJ2 for enhanced
Nrf2 activation. Both racemic (15) and optically active (16) α-

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Figure 3. Effects of analogs 4, 15 and 16 on the Nrf2 pathway. A) ARE
activation in MCF7 cells measured by luciferase assay (1 μM). B) HO-1
induction in MCF10A cells (1 μM). C) Dose-dependent HO-1 induction in
MCF10A cells. The data represent mean ± SD (n = 3). Significant differences
between the compared groups are indicated (*P < 0.05 vs. control).
resulted in HO-1 expression (Figure 5B). Finally, the binding of
biotin conjugates 17 and 18 with Keap1 was confirmed via
immunoprecipitation of cellular Keap1 and
a subsequent
immunoblot analysis (Figure 5C). In addition, the analysis well
revealed better interaction of analog 18 with Keap1 than analog
17. Again, these results suggested a direct interaction between
15d-PGJ2 and its analogs and Keap1, which subsequently
results in Nrf2 activation.
A hypothetical model of covalent adducts was established to
examine the molecular interactions of 1 and 16 with Keap1.
Previously, Kobayashi et al identified the covalent adduct of 1
with Cys273 of mouse Keap1 by MALDI-TOF MS analysis.[8a]
Based on this result, we built covalent adduct models for 1 and
16 attached at Cys273, using a homology model of the IVR
domain of mouse Keap1. In agreement with our experimental
data showing that optically pure 1 and 16 are more active than
racemate 4 (See Supp. Figure S2) and 15 (shown in Figure 3),
only (S)-1 and (S)-16 fit well into the binding pocket to form a
covalent bond with the sulfur atom of Cys273. The terminal
carboxylic acid group forms hydrogen bonds with Arg240, and
the hydrophobic ω-chain is positioned at the hydrophobic pocket,
as shown in Figure 4. The low activity of 15d-PGJ2 methyl ester
3 is likely due to the prevention of hydrogen bonding with
Arg240. (See Supp. Figure S2) In addition, the 1,4-addition of
the Cys273 thiol group to the cyclopentenone of 1 or 16 led to
adducts with an S configuration at the electrophilic carbon C9,
while the adduct with an opposite configuration was not able to
be formed in the same binding pocket.
Figure 5. Immunoprecipitation of Keap1-biotin complex. A) Structures of
biotin-conjugated probes 17, 18 and 19. B) HO-1 induction in MCF10A cells by
the prepared probes at 30 μM. C) Immunoprecipitation and subsequent
immunoblot analysis. The data represent mean ± SD (n = 3). Significant
differences between the compared groups are indicated (*P < 0.05 vs. control).
In summary, we identified and structurally analysed novel Nrf2
activators via a chemical approach based on the interaction of
15d-PGJ2 with Keap1. Our systematic investigation on the
binding of 15d-PGJ2 enabled us to elucidate the key roles of
each binding site of 15d-PGJ2 with regard to Nrf2 activation and
to develop novel 15d-PGJ2-based Nrf2 activators. The rationally
designed chemical probes also supported that the concise
tuning of the electronic states of the 15d-PGJ2 binding sites
could ultimately enhance HO-1 expression. Homology modeling
also predicted that the covalent adduct of α-chloro-15d-PGJ2
with Keap1 IVR is more stable than the 15d-PGJ2 adduct. Our
systematic studies on Nrf2 activation associated with 15d-PGJ2
Figure 4. Modeling of covalent adduct of 1 and 16 with Cys273 in the Keap1
IVR domain. A) Covalently-bound 1 (space-fill atom type) in the binding site.
The surface of the protein is represented by lipophilicity, which increases from
blue (hydrophilic) to brown (lipophilic). B) and C) Covalent adducts of 1 and 16
in the binding site of Keap1. White carbon- capped sticks are the amino acids
of Keap1. The ligand is rendered as a ball and stick models. Red dashed lines
represent hydrogen bonding interactions.
To confirm the binding of 15 with Keap1, biotin-conjugates of
15 were prepared using amide coupling of the corresponding
analogs with commercially available biotin cadaverine in the
presence of 1,1’-carbodiimidazole (See Supp. Synthesis Part).[16]
Initially, the induction of HO-1 expression by treatment of
MCF10A cells with the biotin conjugates was examined. The
biotin conjugates 17 and 18, which were prepared from 4 and 15
is anticipated to provide
chemopreventive therapeutics.
a
facile access to novel
Experimental Section

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Detailed procedures for chemical synthesis, cellular analysis, and
docking study of the identified Nrf2 activators are described in
Supplemental Experimental Methods.
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Acknowledgements
This work was supported by the National Research Foundation
of Korea (NRF) grant for the Global Core Research Center
(GCRC) funded by the Korea government (MSIP) (No. 2011-
0030001)
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Keywords: Nrf2 • Keap1 • Michael addition • 15 deoxy-PGJ2 •
Chemical approach
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COMMUNICATION
Kyeojin Kim, ‡ Jong-Min Park, ‡ Nam-
Jung Kim, Su-Jung Kim, Hyunyoung
Moon, Hongchan An, Jeeyeon Lee,
Hyun-Ju Park, Young-Joon Surh,* and
Young-Ger Suh*
Page No. – Page No.
The mechanism-based chemical transformation of 15 deoxy-PGJ2 identified a
series of novel NF-E2-related factor-2 (Nrf2) activators and elucidated the detailed
function of each electrophilic binding sites. In addition, the HO-1 expression
resulting from the Nrf2 activation through the dissociaton enhancement of the
Keap1-Nrf2 complex by the novel activators was proved via our chemical approach.
Identification and structural analysis
of novel Nrf2 activators via
mechanism-based chemical
transformation of 15 deoxy-PGJ2