Synthesis of the 4-aza cyclopentenone analogue of Δ12,14-15-deoxy-PGJ2 and S-cysteine adducts

Article abstract of DOI:10.1016/j.tetlet.2020.151969

The synthesis of a series of 4-aza cross-conjugated cyclopentenones, inspired by the natural prostaglandin Δ^12,14-15-deoxy-PGJ₂ (5) is described. Using the 4-aza cyclopentenone 7, the installation of the α-side chain was performed using N-functionalisation, following a Boc-deprotection. The ω-side chain was then installed through a Baylis-Hillman type aldol reaction with trans-2-octenal. This afforded 11, the aza-analogue of 5. With this prostaglandin analogue in hand, a series of thiol adducts (14–16) were prepared. Included are activities for compounds 11 and 14–16 in relation to inhibition of the transcription factor NF-κB.

Full text of DOI:10.1016/j.tetlet.2020.151969

Journal Pre-proofs
Synthesis of the 4-aza cyclopentenone analogue of Δ12,14-15-deoxy-PGJ and
2
S-cysteine adducts
Lorna Conway, Anna Riccio, M. Gabriella Santoro, Paul Evans
PII:
S0040-4039(20)30412-3
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151969
TETL 151969
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
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15 April 2020
21 April 2020
Please cite this article as: Conway, L., Riccio, A., Gabriella Santoro, M., Evans, P., Synthesis of the 4-aza
cyclopentenone analogue of Δ12,14-15-deoxy-PGJ and S-cysteine adducts, Tetrahedron Letters (2020), doi:
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Synthesis of the 4-aza cyclopentenone
Leave this area blank for abstract info.
1
2,14
analogue of 
cysteine adducts
-15-deoxy-PGJ2 and S-
Lorna Conway, Anna Riccio, M. Gabriella Santoro and Paul Evans
O
O
SH
O
R
R'
O
O
Et N, DMSO
rt, 15 h
3
NHBoc
N
S
N
H
R
H
OMe
OMe
R'
O
O

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis of the 4-aza cyclopentenone analogue of Δ12,14-15-deoxy-PGJ and S-
2
cysteine adducts
a
b
b
a
Lorna Conway, Anna Riccio, M. Gabriella Santoro and Paul Evans 
a
Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, Dublin 4, Ireland, email: paul.evans@ucd.ie
Department of Biology, University of Rome Tor Vergata, Italy, email: santoro@uniroma2.it
b
—
——
ARTICLE INFO
ABSTRACT

Corresponding author. Tel.: +353-1-716-2291; fax: +353-1-716-2501; e-mail: paul.evans@ucd.ie
Article history:
Received
Received in revised form
Accepted
The synthesis of a series of 4-aza cross-conjugated cyclopentenones, inspired by the
12,14
natural prostaglandin Δ -15-deoxy-PGJ
2
(5) is described. Using the 4-aza
cyclopentenone 7, the installation of the α-side chain was performed using N-
functionalisation, following a Boc-deprotection. The ω-side chain was then installed
through a Baylis-Hillman type aldol reaction with trans-2-octenal. This afforded 11,
the aza-analogue of 5. With this prostaglandin analogue in hand, a series of thiol
adducts (14-16) were prepared. Included are activities for compounds 11 and 14-16 in
relation to inhibition of the transcription factor NF-B.
Available online
Keywords:
Prostaglandin
Natural product analogue
Cross-conjugated cyclopentenone
Titanium aldol
2
009 Elsevier Ltd. All rights reserved.
S-Conjugate addition
Prostaglandins are members of the eicosanoid family, derived
from the essential fatty acid arachidonic acid. Prostaglandins
inhibitory effect of PGs towards NF-κB. This allows for the
binding of PGs to the β-subunit of the IKK complex, inactivating
1
1
0
have a wide range of roles in the body; including regulation of
the circulatory and respiratory systems as well as mediating
it and therefore blocking the activation of NF-κB. Recently,
additional members of the cross-conjugated cyclopentenone
prostaglandin family have been identified and synthesised (e.g.
2
tissue repair and the immune response. Interestingly,
1
1
prostaglandins can act as both pro-inflammatory modulators and
anti-inflammatory modulators, depending on their structure and
the receptors/systems upon which they act.1,2
6).
The early members of the prostaglandin family formed by the
cyclooxygenase pathway, for instance PGF2 (1), can undergo
further oxidation to prostanoids of the D and E series (e.g. 2).
These compounds are susceptible to elimination which produces
the cyclopentenone prostaglandins (cyPGs). Examples of these
OH
OH

-side chain
1
CO2H
CO H
2
12
HO
-side chain
O
15
1
2
include PGA
1
(3) and PGJ
2
(4), which contain a reactive α,β-
HO
HO
HO
3
unsaturated carbonyl unit (see Fig. 1). Evidence demonstrates
O
that the primary prostaglandins, e.g. 1, promote inflammation,
CO2H
4
CO2H
which the later cyPGs counteract. In recent years, there has been
significant interest in Δ12,14-15-deoxy-PGJ
identified in 1983 as a degradation product of PGD (2). While
2
(5), which was first
2
O
O
5
3
4
cyPGs are known generally to affect inflammation, cellular
proliferation and differentiation, evidence indicates that the
cross-conjugated cyclopentenone 5 is not only particularly active
in this regard but also induces apoptosis and inhibits cellular
growth. In part, this activity has been shown to be mediated
through inhibition of NF-κB.6 NF-κB (nuclear factor-kappaB) is
a transcription factor responsible for the regulation of the
immediate early pathogen response. It plays a key role in the
HO
1
1
CO2H
CO H
2
12
12
O
1
5
Figure 1:
cyclopentenones PGA
Δ12,14-15-deoxy-PGJ
(5), and Δ -PGJ (6).
3
5
Repre
s
6
entative prostaglandins: PGF
HO 2
(1), PGD2 (2), and
1
(3), PGJ (4) and cross-conjugated cyclopentenones
2
12
2
promotion of inflammation, the control of cell proliferation and
survival and in regulating viral gene expression.7 Due to its
Since their discovery by von Euler in the 1930s, much work has
been devoted to the synthesis of natural prostaglandins. The
ground-breaking work by Corey in the 1960s and 70s paved the
way for many elegant syntheses of such PGs exploring the
challenging installation of the two side chains as well as 3, or 4
frequent upregulation in many tumours, NF-κB is also an
8
important target for anti-cancer therapies and, consequently, its
inhibition is of interest.9 It has been shown that the electrophilic
α,β-unsaturated cyclopentenone moiety is responsible for the

2
Tetrahedron
stereogenic centres on the cyclopentane ring. Noyori has
described a three-component coupling strategy towards the
synthesis of primary prostaglandins.2 An efficient two-step
method for the preparation of cross-conjugated cyPGs via a
conjugate addition-Peterson olefination reaction was developed
by Iqbal and co-workers.4 In recent years there has been
significant interest in the synthesis of Δ12,14-15-deoxy-PGJ
.
11,12
2
However, these routes involve multi-step synthetic sequences and
do not allow for the straightforward synthesis of analogues.11,12
As a result of the range of interesting biological activities
coupled with the poor physiochemical properties of these natural
prostaglandins, the preparation of synthetically simpler and more
stable analogues have been reported.13-15 With this in mind, we
explored the presence of a suitably placed nitrogen atom to allow
for the facile derivatisation of analogues and, based on
Scheme 2: Synthesis of 4-aza analogue (11) of Δ12,14-15-deoxy-PGJ2.
Reagents and conditions: (i) trans-2-Octenal, TiCl , Ti(Oi-Pr) , PPh , CH Cl ,
-50 °C to rt; then K CO , 13% (54% recovery of 7); (ii) TFA, CH Cl , rt;
2 3(aq) 2 2
1
6
preliminary work, in this fashion we aimed to develop a direct
4
4
3
2
2
1
2,14
analogue of Δ -15-deoxy-PGJ
2
(see Scheme 1).
(
iii) mono-methyl adipate, EDCI (1.3 equiv.), Et
CH Cl , rt, 24%; (iv) TFA, CH Cl , rt, 86%; (v) methyl-6-chloro-6-
oxohexnoate, Et N (2 equiv.), CH Cl , 0 °C to rt, 72%; (vi) trans-2-octenal,
TiCl , Ti(Oi-Pr) , PPh , CH Cl , -50 °C to rt; then K CO3(aq), 12-22% (44%
recovery of 13).
3
N (3.5 equiv.), DMAP (cat.),
2
2
2
2
3
2
2
4
4
3
2
2
2
In an attempt to improve the overall yield of the target while also
showing the versatility of the Ti-mediated aldol reaction, we
decided to install the ω-side chain of the prostaglandin mimic
first. This involved the deprotection of the Boc protecting group
on the starting cyclopentenone 7. Ammonium salt 12 was
isolated with a yield of 86%. The coupling reaction with the
previously used acid chloride, and triethylamine (2 equiv.) at 0
Scheme 1: Planned 4-aza cross-conjugated cyclopentenone analogues (8) of
1
2,14
Δ
2
-15-deoxy-PGJ (5) and their S-conjugate addition.
While the susceptibility of the electrophilic, endocyclic alkene to
attack by “soft” nucleophilic thiol groups allows for the desirable
biological activities it can also lead to the undesirable attack of
circulating thiols such as glutathione.3,17 With this in mind,
masking of the thiol reactive endocyclic Michael acceptor was
also explored.
°
C successfully resulted in amide 13 with a yield of 72%. A
reaction time of 3 hours was used to avoid the formation of the β-
keto amide (for more details see ESI) observed upon leaving the
reaction for 15 hours. With the novel amide 13 in hand this was
subjected to Takanami’s α-alkylidenation reaction using freshly
distilled trans-2-octenal. Satisfyingly, the aldol-type reaction
successfully achieved the synthesis of the natural product mimic
Key enantioenriched (4R)-aza-cyclopentenone 7 was available
1
9
from a previously reported cycloaddition-enzymatic resolution
1
8
process. With the cyclopentenone core (7) in hand, we initially
focused on the installation of the α-side chain of the natural
prostaglandin (i.e. 7  9). Attempts at this transformation using
2
1
1
1 with an improved yield of up to 22%. Importantly, recovery
1
2
of the valuable amide 13 was also achievable (44%).
typical aldol conditions, as described for the synthesis of Δ -
1
1
12,14
12
PGJ
3
(6) and Δ -15-deoxy-PGJ
2
(5), resulted in no
Although the overall yields for the formation of 11 by the Ti-
aldol reaction are modest, due to its one-pot nature, its tolerance
for the aza-functional group, the recovery of starting material and
the failure of the direct aldol approach to this class of compound
means that this synthetic approach is a viable method to access
this compound.
discernable product. This observation is likely due to the
instability of the enolate derived from 7. With this in mind, a
Baylis-Hillman type aldol reaction, originally investigated by
Takanami and co-workers,19 was employed for the α-
alkylidenation (Scheme 2). Although these conditions afforded a
low yield of 9 (13%), this is arguably still an appealing approach
to achieve the direct α-alkylidenation step in the synthesis of this
type of prostaglandin. In this reaction a 54% recovery of starting
material 7 was also achieved. The desired E,E-stereochemistry of
With a stock of the direct analogue of the Δ12,14-15-deoxy-PGJ
-
2
analogue 11 - now in hand, the conjugation of various cysteine
adducts was investigated. A similar strategy for the preparation
of cross-conjugated cyclopentenone S-cysteine adducts has been
investigated previously and promising biological activities were
4
a
9
was evident from proton NMR spectroscopy. Additionally,
small amounts of the Z,E-isomer were isolated (3% - for details
see ESI). Next, the value of the key nitrogen substituent was
demonstrated. The Boc protecting group was cleaved using
trifluoroacetic acid to give 10. Due to its unstable nature the
intermediate was swiftly subjected to a coupling reaction with
methyl 6-chloro-6-oxohexanoate20 and triethylamine. In the event
the amide formation phase of this sequenceproved unsuccessful.
Since this result indicated the poor compatibility of the acid
chloride and 10 a carbodiimide coupling strategy was explored.
The reaction of the ammonium salt 10 with mono-methyl adipate
2
2
uncovered. Thus, reaction of 11 (1.2 equiv.) with N-acetyl-L-
cysteine methyl ester (1.0 equiv.) and triethylamine (1.0 equiv.)
in DMSO yielded the Michael-addition product 14 in a 16%
yield. Small quantities of the cis-addition product were also
isolated as a mixture with the trans-addition product and a 30%
1
recovery of the starting material (11) was achieved. H-NMR
spectroscopy of the crude reaction mixture indicated the
favourable addition to the less hindered face of the
cyclopentenone ring resulting in the trans-product being the
major diastereomer (see ESI). With mammalian compatibility in
mind the conjugate addition of (R)-ethyl 2-acetamido-3-
mercaptopropanoate to the cyclo-pentenone 11 was also
considered. Following the synthesis of (R)-ethyl 2-acetamido-3-
(0.9 equiv.), EDCI·HCl (1.3 equiv.), triethylamine (3.5 equiv.)
and catalytic DMAP resulted in a 24% yield of the target 11.
2
3
mercaptopropanoate using literature conditions, the conjugate
addition resulted in 15 with a yield of 29%. Finally, the conjugate
addition of N-(tert-butoxycarbonyl)-L-cysteine methyl ester
resulted in the formation of 16 with a yield of 34%. The
reasonably low yields for these conjugate addition reactions are
O
O
O
(i)
(ii)
O2CCF3
NHBoc
NHBoc
NH3
iii)
7
10
9
(
iv)
(
O
O
O
(v)
(vi)
O
O
OMe
N
H
NH3
N

3
partly due to instability of the cross-conjugated triene 11 under
the reaction conditions. Furthermore, this type of S-adduct
proved to be only partially stable during silica-gel
chromatographic purification and variable levels of retro-
conjugate addition (reforming 11), and decomposition, were
observed. It should be mentioned that no adducts resulting from
S-addition at the exocyclic enone were detected.
their support. Finally, Prof. Stan Roberts is warmly thanked for
his friendship, advice and guidance.
References and notes
1
2
.
.
Funk, C. Science 2001, 294, 1871-1875.
Noyori, R.; Suzuki, M. Science 1993, 259, 44-45. For reviews
concerning the synthesis of prostaglandins, see: (a) Collins, P. W.;
Djuric, S. W. Chem. Rev. 1993, 93, 1533-1564; (b) Das, S.;
Chandrasekhar, S.; Yadav, J. S.; Grée, R. Chem. Rev. 2007, 107,
3286-3337; Peng, H.; Chen, F. -E. Org. Biomol. Chem. 2017, 15,
O
O
(i)
O
O
6
281-6301.
S
N
N
R
H
SH
3. Oeste, C.; Pérez-Sala, D. Mass Spectrom. Rev. 2014, 33, 110-125.
H
OMe
OMe
R
R'
4
5
.
.
(a) Iqbal, M.; Duffy, P.; Evans, P.; Cloughley, G.; Allan, B.;
Lledó, A.; Verdaguer, X.; Riera, A. Org. Biomol. Chem. 2008, 6,
649-4661; (b) Willoughby, D.A.; Moore, A.R.; Colville-Nash,
11
R'
O
O
1
1
1
4: R = NHAc, R' =CO Me, 16%
2
4
5: R = NHAc, R' = CO Et, 29%
2
P.R. Nature Med. 2000, 6, 137–138.
Powell, W. J. Clin. Invest. 2003, 112, 828-830.
6: R = NHBoc, R' = CO Me, 34%
2
Scheme 3: The synthesis of S-Michael-type adducts 14-16. Reagents and
conditions: (i) RR’CHCH SH (1 equiv.), Et N (1.0 equiv.), DMSO, rt
6.
(a) Piva, R.; Gianferretti, P.; Ciucci, A.; Taulli, R.; Belardo, G.;
Santoro, M.G. Blood 2005, 105, 1750-1758: (b) Bell-Parikh, L.C.;
Ide, T.; Lawson, J.; McNamara, P.; Reilly, M.; FitzGerald, G. J.
Clin. Invest. 2003, 112, 945-955.
2
3
The ability of synthetic compounds: 11 and 14-16, to inhibit
the transcription factor NF-B was investigated using a gene
reporter, HeLa cell-based assay system (Table 1). The data
generated was compared with that measured for 12,14-15-deoxy-
7. (a) Santoro, G.; Rossi, A.; Amici, C. EMBO J. 2003, 22, 2552-
560; (b) Caselli, E.; Fiorentini, S.; Amici, C.; Di Luca, D.;
2
Caruso, A.; Santoro, M. Blood 2007, 109, 2718-2726.
Taniguchi, K.; Karin, M. Nat. Rev. Immunol. 2018, 18, 309-324.
Duplan, V.; Serba, C.; Garcia, J.; Valot, G.; Barluenga, S.; Hoerle,
M.; Cuendet, Winssinger, N. Org. Biomol. Chem. 2014, 12, 370-
375.
8
.
PGJ (5). It was found that at concentrations between 3-12 M
2
9
.
compounds 11 and 14-16 all blocked TPA (12-O-
tetradecanoylphorbol-13-acetate) challenged NF-B activation
®
10. Rossi, A.; Kapahi, P.; Natoli, G.; Takahashi, T.; Chen, Y.; Karin,
by half (ED50). Furthermore, an Alamar blue cell viability assay
M.; Santoro, M.G. Nature 2000, 403, 103-108.
demonstrated that toxicity (measured as an LD50 value in HeLa
cells) was only observed at doses significantly higher than the
ED50 of the individual compounds. As a trend, the S-adducts, 14-
1
1. (a) Nicolaou, K.C.; Pulukuri, K.K.; Yu, R.; Rigol, S.; Heretsch, P.;
Grove, C.; Hale, C.; ElMarrouni, A. Chem. Eur. J. 2016, 22, 8559-
8570; (b) Nicolaou, K.C.; Pulukuri, K.K.; Rigol, S.; Heretsch, P.;
Yu, R.; Grove, C.; Hale, C.; ElMarrouni, A.; Fetz, V.; Brönstrup,
M.; Aujay, M.; Sandoval, J.; Gavrilyuk, J. J. Am. Chem. Soc.
1
6, proved slightly less active than the cyclopentenone 11, which
proved more active in this assay than the natural prostanoid, 5.
However, the S-adducts were also markedly less toxic.
2
016, 138, 6550-6560; (c) Nicolaou, K. C.; Pulukuri, K. K.; Rigol,
S.; Peitsinis, Z.; Yu, R.; Kishigami, S.; Cen, N.; Aujay, M.;
Sandoval, J.; Zepeda, N.; Gavrilyuk, J. J. Org. Chem. 2019, 84,
Table 1: NF-B inhibition and toxicity of compounds 5, 11 and 14-16.
3
65-378.
Alamar blue®
12.
(a) Bickley, J. F.; Jadhav, V.; Roberts, S. M.; Santoro, M. G.;
Steiner, A.; Sutton, P. W. Synlett 2003, 8, 1170-1174; (b)
Brummond, K. M.; Sill, P. C.; Chen, H. Org. Lett. 2004, 6, 149-
152; (c) Jung, M. E.; Berliner, J. A.; Koroniak, L.; Gugiu, B. G.;
Watson, A. D. Org. Lett. 2008, 10, 4207-4209; (d) Egger, J.;
Fischer, S.; Bretscher, P.; Freigang, S.; Kopf, M.; Carreira, E. M.
Org. Lett. 2015, 17, 4340-4343; (e) Li, J.; Stoltz, B. M.; Grubbs,
R. H. Org. Lett. 2019, 21, 10139-10142.
Entry
Compound
NF-B ED50
7 M
LD50
5 (12,14-15-
deoxyPGJ )
2
1
400 M
2
3
4
5
11
14
15
16
3 M
10 M
12 M
7.5 M
210 M
400 M
800 M
600 M
1
3. (a) Furuta, K.; Maeda, M.; Hirata, Y.; Shibata, S.; Kiuchi, K.;
Masaaki, S. Bioorg. Med. Chem. Lett. 2007, 17, 5487-5491; (b)
Furuta, K.; Tomokiyo, K.; Satoh, T.; Watanabe, Y.; Suzuki, M.
ChemBioChem 2000, 1, 283-286.
14. Ladin, D.A.; Soliman, E.; Escobedo, R.; Fitzgerald, T.L.; Yang,
L.V.; Burns, C.; Van Dross, R. Mol. Cancer Ther. 2017, 16, 838-
8
49.
In conclusion, this manuscript describes a flexible synthesis
15. Roulland, E.; Monneret, C.; Florent, J. -C.; Bennejean, C.; Renard,
P.; Léonce, S. J. Org. Chem. 2002, 67, 4399-4406.
16. Dauvergne, J.; Happe, A. M.; Roberts, S. M. Tetrahedron 2004,
of 11, the methyl ester analogue of the cross-conjugated natural
1
2,14
2
product Δ -15-deoxy-PGJ (5). In addition, the more reactive
6
0, 2551-2557.
endocyclic double bond of 11 was reacted with three protected
forms of cysteine forming S-adducts 14-16. Compounds 11 and
4-16 were shown to inhibit NF-B at comparable levels to the
1
1
7. Suzuki, M.; Mori, M.; Niwa, T.; Hirata, R.; Furuta, K.; Ishikawa,
T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 2376-2385.
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McCormack, P.J.; Pitts, M.R.; Roberts, S.M.; Singh, S.K.; Snape,
T.J.; Whittall, J. Tetrahedron 2004, 60, 2559-2567.
1
natural prostanoid 5. The S-adducts (particularly 15)
demonstrated diminished toxicity in comparison to 5 and 11. The
emergence of the irreversible kinase inhibitors,24 amongst other
examples, has renewed interest in the biological possibilities for
compounds that can (selectively) react covalently with a range of
19. Takanami, T.; Suda, K.; Ohmori, H. Tetrahedron Lett. 1990, 31,
677-680.
2
2
0. Uno, T.; Ku, J.; Prudent, J. R.; Huang, A.; Schultz, P. G. J. Am.
Chem. Soc. 1996, 118, 3811-3817.
1. Attempts to further optimise the Ti-mediated alkylidenation by
adjusting the relative amounts of the reagents and adjusting
reaction temperatures were not found to improve yields.
2
5
disease relevant biomolecules.
Acknowledgments
2
2. (a) Bickley, J. F.; Ciucci, A.; Evans, P.; Roberts, S. M.; Ross, N.;
Santoro, M. G. Bioorg. Med. Chem. 2004, 12, 3221-3227; (b)
Escobar, Z.; Bjartell, A.; Canesin, G.; Evans-Axelsson, S.; Sterner,
O.; Hellsten, R.; Johansson, M. J. Med. Chem. 2016, 59, 4551-
We thank the Irish Research Council (LC) for a postgraduate
scholarship (GOIPG/2017/1702). PentaRES BioPharma s.r.l.,
Biogem Scarl, Araiano Irpino (AV) Italy and Fondazione Maria
Antonia Gervasio, Bisaccia (AV) Italy are acknowledged for
4
562.

4
Tetrahedron
2
3. Uhrig, R.; Picard, M.; Beyreuther, K.; Wiessler, M. Carbohydr.
Res. 2000, 325, 72-80.
Synthesis of the 4-aza cyclopentenone analogue of
1
2,14
2
2
4. Gilbert, A. M. Pharm. Pat. Anal. 2014, 3, 375-386.

-15 -deoxy-PGJ and S-cysteine adducts
2
5. For general reviews concerning the covalent derivatisation of
biomolecules by electrophilic natural products and drugs, see: (a)
Robertson, J. G. Biochem. 2005, 44, 5561-5571; (b) Conti, M.
Exp. Opin. Drug Discov. 2007, 2, 1153-1159; (c) Potashman, M.
H.; Duggan, M. E. J. Med. Chem. 2009, 52, 1231-1246; (d) Singh,
J.; Petter, R. C.; Baillie, T. A.; Whitty, A. Nat. Rev. Drug Discov.
Lorna Conway, Anna Riccio, M. Gabriella Santoro and
Paul Evans
2
011, 10, 307-317; (e) Flanagan, M. E.; Abramite, J. A.;
•
Preparation of a new type of cross-conjugated
cyclopentenone prostaglandin analogue
Masking of the endocyclic enone by S-cysteine
conjugate addition
Anderson, D. P.; Aulabaugh, A.; Dahal, U. P.; Gilbert, A. M.; Li,
C.; Montgomery, J.; Oppenheimer, S. R.; Ryder, T.; Schuff, B. P.;
Uccello, D. P.; Walker, G. S.; Wu, Y.; Brown, M. F.; Chen, J. M.;
Hayward, M. M.; Noe, M. C.; Obach, R. S.; Phillippe, L.;
Shanmugasundaram, V.; Shapiro, M. J.; Starr, J.; Stroh, J.; Che, Y.
J. Med. Chem. 2014, 57, 10072-10079; (f) Jackson, P. A.; Widen,
J. C.; Harki, D. A.; Brummond, K. M. J. Med. Chem. 2017, 60,
•
•
Comparable inhibition of nuclear factor kappa B
1
2,14
8
39-885; (g) De Cesco, S.; Kurian, J.; Dufresne, C.; Mittermaier,
(NF-kB) to natural prostanoid 
-15-deoxy-PGJ2
A. K.; Moitessier, N. Eur. J. Med. Chem. 2017, 138, 96-114; (h)
Lagoutte, R.; Patouret, R.; Winssinger, N. Curr. Opin. Chem. Biol.
2
5
017, 39, 54-63; (i) Ray, S.; Murkin, A. S. Biochem. 2019, 58,
234-5244.
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Supplementary Material
Supplementary material (experimental procedures, including
the determination of biological activity, proton and carbon NMR
spectra) are available free-of-charge via the internet.
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Declaration of interests
☒
The authors declare that they have no known
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competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
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☐
The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
Paul Evans
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