Design and synthesis of benzo-lipoxin A4 analogs with enhanced stability and potent anti-inflammatory properties

Article abstract of DOI:10.1016/j.bmcl.2008.01.013

A new class of chemically and metabolically stable lipoxin analogs featuring a replacement of the tetraene unit of native LXA₄ with a substituted benzo-fused ring system have been designed and studied. These molecules were readily synthesized v

Full text of DOI:10.1016/j.bmcl.2008.01.013

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 1382–1387
Design and synthesis of benzo-lipoxin A4 analogs with
enhanced stability and potent anti-inflammatory properties
Nicos A. Petasis,a,* Raquel Keledjian,a Yee-Ping Sun,b Kalyan C. Nagulapalli,a
Eric Tjonahen,b Rong Yanga,b and Charles N. Serhanb
aDepartment of Chemistry and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, CA
90089, USA
bCenter for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain
Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Received 9 November 2007; revised 31 December 2007; accepted 3 January 2008
Available online 9 January 2008
Abstract—A new class of chemically and metabolically stable lipoxin analogs featuring a replacement of the tetraene unit of native
LXA4 with a substituted benzo-fused ring system have been designed and studied. These molecules were readily synthesized via a
convergent synthetic route involving iterative palladium-mediated cross-coupling, and exhibit enhanced chemical stability, as well as
resistance to metabolic inactivation via eicosanoid oxido-reductase. These new LX analogs were evaluated in a model of acute
inflammation and were shown to exhibit potent anti-inflammatory properties, significantly decreasing neutrophil infiltration
in vivo. The most potent among these was compound 9 (o-[9,12]-benzo-15-epi-LXA4 methyl ester. Taken together, these findings
help identify a new class of stable and easily prepared LX analogs that may serve as novel tools and as promising leads for new
anti-inflammatory agents with improved therapeutic profile.
Ó 2008 Elsevier Ltd. All rights reserved.
The conventional strategy for the development of anti-
inflammatory therapeutics has been the inhibition of
pathways related to the biosynthesis and actions of
pro-inflammatory mediators, such as the prostaglandins
(PGs) and the leukotrienes (LTs) that are derived from
arachidonic acid (AA) and help amplify the inflamma-
tory response.1,2 An alternative approach for the discov-
ery of effective anti-inflammatory agents without the
usual adverse side-effects has been suggested from recent
investigations initiated in our laboratories3,4 based on
promoting the resolution of inflammation.5,6 Rather
than interfering with the biosynthesis and actions of
pro-inflammatory PGs and LTs, this novel strategy is
based on mimicking the actions of endogenous anti-
inflammatory and pro-resolution lipid mediators. The first
class of such compounds to be discovered were the
lipoxins (LX), which feature a unique trihydroxy-
E,E,Z,E-tetraene structure and are generated from AA
via lipoxygenase-mediated transcellular biosynthesis.
Lipoxin A4 (LXA4, 1) (Scheme 1) was shown to potently
suppress inflammation upon binding to its receptor
(ALXR or hFPRL1), a G-protein-coupled receptor
known to play a key role in modulating inflammation
that belongs to a phylogenetic cluster that includes
known receptors for other lipid mediators.7 Notably,
in a manner common to other eicosanoids, LXA4 is rap-
idly inactivated in vivo (>60% in 30 s),8 via a metabolic
enzyme system consisting of 15-prostaglandin dehydro-
genase (15-PGDH) and eicosanoid oxido-reductase
(EOR). The stereoselectivity of this inactivation was fur-
ther validated with the discovery of 15-epi-LXA4 (2),
which is generated via an alternative biosynthetic path-
Keywords: Lipoxin analogs; Benzo-analogs; Palladium; Suzuki cou-
pling; Heck reaction; Anti-inflammatory agents; Inflammation; Eicos-
anoid oxido-reductase; Neutrophil infiltration; Lipid mediators.
*
Corresponding author. Tel.: +1 213 740 6683; fax: +1 213 740
6684; e-mail: petasis@usc.edu
Scheme 1.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.01.013

N. A. Petasis et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1382–1387
1383
way originating in endothelial or epithelial cells that in-
volves the initial mono-oxygenation of AA via the ac-
tion of COX-2 in the presence of aspirin.9 The aspirin-
triggered lipoxin (ATL) 2 retains the potent biological
actions of LXA4, but exhibits a longer half-life
in vivo,10 apparently because it is a less effective sub-
strate for the metabolizing enzymes, due to its 15(R)
configuration. The ATL pathway was recently shown
to operate in humans taking low dose aspirin11 and pro-
vides a novel mechanism for aspirin’s many health
benefits.12
tures: (a) a free acid, carboxylate salt, or ester at C1, (b)
a diol moiety at C5–C6 having the native 5(S),6(R) con-
figuration, and (c) a hydroxyl group at C15 having the
15(R) configuration (15-epi). It is also known that the
LX isomer with an all-trans tetraene moiety is much less
active than molecules having the native 7E,9E,11Z,13E
stereochemistry, suggesting the critical importance of
the 11Z C@C bond. Since this bond can be readily isom-
erized to the corresponding E-isomer under a variety of
chemical or biological conditions,26 this limits the over-
all chemical and in vivo stability of LX analogs. More-
over, the synthesis of LX analogs containing a Z-alkene
is more challenging, because this must be done in a ste-
reospecific manner and at a later stage of the synthesis in
order to avoid pre-mature isomerization. Therefore, it
would be preferable to replace the native tetraene unit
with an equivalent moiety that is more stable and easier
to synthesize, while retaining the other desired structural
characteristics needed for bioactivity.
In order to increase the half-life of LX, we have previ-
ously developed4,10 the first metabolically stable LXA4
analogs that retain all of the potent actions of LX but
are not susceptible to enzymatic inactivation. The initial
LX analogs10 were based on modifying the C15–C20 por-
tion of LX, thereby suppressing EOR-mediated meta-
bolic inactivation. Using such long acting synthetic
molecules we were able to systematically investigate a
number of important biological actions of LX, and have
demonstrated their potential anti-inflammatory role.3,4
Among the several LXA4 analogs designed, synthesized,
and studied, the aspirin-triggered lipoxin analog (ATLa)
16-p-fluorophenoxy-15-epi-LXA4 methyl ester (3)
turned out to be the most effective,13 and has served as
the gold standard for studying a wide range of LX-asso-
ciated actions.3,4 Compound 3 also led to the discovery
of the 3-oxa LX analog ZK-142 (4) and its 11-dehydro
analog ZK-994, which are topically and orally active
Using the above principles, we designed a new series of
benzo-LXA4 analogs27 of the general structure 5
(Scheme 2) and explored the potential use of such com-
pounds as anti-inflammatory agents. Herein, we present
the synthesis and study of selected examples shown in
Scheme 3. An added advantage of molecules of this type
is that they can be readily prepared in large scale from
three readily available building blocks (6–8) using itera-
tive Pd-mediated coupling processes. Overall, therefore,
such benzo-LXA4 analogs could benefit both from en-
hanced chemical and biological stability as well as sim-
anti-inflammatory
development.14,15
agents
currently
under
Lipoxins and their stable analogs were recently shown to
simultaneously dampen the adverse effects of inflamma-
tion in addition to promoting its resolution.3,4 More-
over, the therapeutic potential of these molecules was
demonstrated for a number of major inflammatory dis-
orders, including: vascular injury,15,16 dermal inflamma-
tion,14,15,17 gastrointestinal disease,18 colitis,19 asthma,20
arthritis,21 ocular inflammation,22 kidney disease,23 peri-
odontal disease,24 and cystic fibrosis.25 The development
of pharmacologically active stable LX analogs that mi-
mic the actions of LX, therefore, is of great interest
for the development of new anti-inflammatory therapeu-
tics for a variety of applications.
Scheme 2. Strategy for the design and synthesis of benzo-LXA4
analogs.
Herein, we report the design, synthesis, and evaluation
of several benzo-LXA4 analogs that involve the modifi-
cation of the tetraene portion of the LX molecule. In
addition to enhanced chemical stability, these new LX
analogs are much easier to synthesize through a highly
convergent and efficient strategy, and exhibit potent
anti-inflammatory actions in vivo, while resisting meta-
bolic inactivation by eicosanoid oxido-reductase.
Since the detailed three-dimensional molecular structure
of ALXR is not known, the design of LX analogs has
been substrate-driven and guided by considerations
linked to LX biological function. Based on known struc-
ture–function studies of LX and LX analogs to date, it
can be concluded that the most active and longer acting
LX analogs have the following minimum structural fea-
Scheme 3. Selected benzo-LXA4 analogs synthesized and studied.

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N. A. Petasis et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1382–1387
plified synthesis, while having structures that can mimic
ATL and their actions.
The naming of these analogs, shown in Scheme 3, was
based on the native LXA4 structure and the incorpora-
tion of a fused o- or m-substituted benzo-ring between
two positions of the tetraene. This naming suggests a
more direct co-relation between the analogs and the na-
tive LX structure. Among these, LX analogs 9, 10, 12,
and 13 have the two key LX fragments in a proximal
o-orientation, while LX analog 11 has a more angular
m-configuration. The 15-deoxy analog 10 lacking a third
hydroxyl group at C15 would constitute a negative con-
trol for LX actions, since the corresponding 15-deoxy-
LXA4 analog is generally inactive. The more extended
LX analog 12 was designed to provide an insight into
the acceptable length of LX agonists, while analog 13
has a more condensed structure, generated simply by
joining atoms C9 and C14 of the tetraene.
Scheme 5. Reagents and conditions: (a) Cp2TiMe2, THF, 80 °C (67–
72%); (b) nBuLi, CuI, THF (70%); (c) tBuMe2SiCl, imidazole, DMAP,
CH2Cl2 (86%); (d) CSA, MeOH/CH2Cl2 (97%); (e) oxalyl chloride,
DMSO, Et3N, CH2Cl2 (75%); (f) Pd(OAc)2, Cs2CO3, MeCN, 85 °C
(62%); (g) Pd(OAc)2, NaHCO3, Bu4NCl, PPh3, MeCN, 60 °C (47%).
As outlined in Scheme 2, our synthetic strategy for all of
these LX analogs was based on Pd-mediated coupling
procedures.28 The detailed syntheses of compounds 9–
13 are shown in Schemes 4–8.
For the synthesis of the o-analog 9 we investigated two
alternative strategies starting with o-bromophenyl boro-
nic acid 21, one relying on the Suzuki–Miyaura coupling
Scheme 6. Reagents and conditions: (a) Pd(PPh3)4, K2CO3, dioxane,
60 °C (70%); (b) Pd(PPh3)4, K2CO3, dioxane/H2O, 80 °C (44%); (c)
Bu4NF, THF (95%).
Scheme 7. Reagents and conditions: (a) BCl3, Et3SiH, 0 °C, then
NaOH, then HCl (50%); (b) Pd(PPh3)4, K2CO3, dioxane, 60 °C (65%);
(c) bis-pinacolato diboron, PdCl2(dppf), dppf, AcOK, DMSO, 80 °C
(40%); (d) PdCl2(dppf), K3PO4, DMF, 60 °C (45%); (e) Bu4NF, THF
(96%).
Scheme 4. Reagents and conditions: (a) CHI3, CrCl2, THF, 0 °C to rt
(40%); (b) catecholborane, 60 °C; (c) N-bromosuccinimide, rt (80%);
(d) Pd(PPh3)4, K2CO3, dioxane, 60 °C (70%); (e) Pd(PPh3)4, K2CO3,
dioxane/H2O, 80 °C (40–45%); (f) Bu4NF, THF (95–97%).

N. A. Petasis et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1382–1387
1385
condensed analog 13 was prepared from racemic bro-
mide 38, which was prepared from acyl chloride 37.
Conversion of 38 to the boronate 39 using bis-pinacola-
to diboron under Pd-catalysis,35 followed by Suzuki–
Miyaura Pd-mediated coupling28 with iodide 15 and a fi-
nal desilylation, gave LX analog 13.
In order to determine whether these new LX analogs
were resistant to rapid enzymatic catalysis,10 each of
these compounds (ꢀ15 lM) was incubated with recom-
binant EOR (0.05 lg) and their rates of conversion were
calculated by monitoring formation of NADH, an
essential cofactor in this process (Table 1). Native
LXA4 (1) was converted most readily (3.1 lM/min),
while the 15-epi-LXA4 methyl ester 2-Me (ATL-Me),
used here as a positive control, as well as the benzo-
LX analogs (9–13) were not readily converted, in com-
parison with LXA4. As expected, the initial rate of con-
version for the deoxy LX analog 10, used as a negative
control, was the slowest.
Scheme 8. Reagents and conditions: (a) MeNHOMeÅHCl, Et3N,
CH2Cl2, then C5H11MgBr, THF (70%); (b) NaBH4, MeOH (90%);
(c) tBuMe2SiOTf, 2,6-lutidine, CH2Cl2 (95%); (d) bis-pinacolato
diboron, PdCl2(dppf), dppf, AcOK, DMSO, 80 °C (40%); (e)
PdCl2(dppf), K3PO4, DMF, 60 °C (46%); (f) Bu4NF, THF (95%).
(Scheme 4), and one featuring a novel boronic acid
Heck-type coupling (Scheme 5). The first approach in-
volves the Suzuki–Miyaura coupling between 21 and io-
dide 15, which is readily prepared by Takai olefination29
of aldehyde 14 (Scheme 4). A subsequent Suzuki–Miya-
ura coupling of 22 with boronate 18 gave after deprotec-
tion the o-[9,12]-benzo LX analog 9. The 15-deoxy
analog 10 was prepared similarly via the coupling of
22 with the corresponding boronate 20. Interestingly,
we have also shown that it is possible to construct these
benzo-LX analogs in one-pot, in somewhat lower yields,
by using iterative Pd-mediated couplings between 21
and the required alkenyl fragments (15, 19) without
intermittent isolation steps.
For a side-by-side comparison of the anti-inflammatory
action of the LX analogs, a dose of 15 lg kgÀ1 or
ꢀ300 ng/mouse was used since it was most efficacious
in previous studies. As shown in Table 2, the o-[9,12]-
benzo analog 9, and m-[9,12]-benzo analog 11 were most
effective, both exhibiting a statistically significant ꢀ32%
inhibition of PMN infiltration (n = 5–10, P < 0.005 and
P < 0.05, respectively, compared to control). The o-
[9,14]-benzo analog 13 was the least effective, decreasing
PMN infiltration by ꢀ22% compared to control (one-
tailed t-test), while mice treated with the o-[9,10]-benzo
analog 12 failed to inhibit PMN numbers in a statisti-
cally significant manner. Interestingly, the 15-deoxy o-
[9,12]-benzo analog 10 did show some activity in this
model (ꢀ24%), despite lacking the 15-OH group.
An alternative and potentially more versatile strategy
for the synthesis of 23 (Scheme 5) involves the consecu-
tive Heck-type coupling of 21 with alkenes 25 and 28,
which were prepared via the titanium-mediated methyl-
enation30 of aldehydes 14 and 27. Interestingly, the first
Heck coupling of o-bromophenyl boronic acid 21 with
25 proceeded selectively at the boronic acid position,31
affording the corresponding bromide 22, which was sub-
jected to a second Heck-type coupling under the Jeffery
conditions32 to give 23. A novel one-pot iterative cou-
pling of 21 with 25 and 28 was also shown to afford
23, without isolation of 22.
These results indicate that the new benzo-LXA4 analogs
are: (a) readily prepared via short and efficient synthetic
pathways, (b) are resistant to enzymatic catalysis rela-
tively to LXA4, and (c) exhibit potent LX-like anti-
inflammatory actions in vivo. While the analogs of this
series share a common benzo-fused backbone and
5S,6R-vicinal hydroxyl groups, there are subtle differ-
Table 1. Metabolic conversion of benzo-LXA4 analogs by recombi-
nant eicosanoid oxido-reductase (EOR)
Compound
EOR conversion EOR relative
conversion
rate (%)
rate (lM/min)
The m-[9,12]-benzo LX analog 11 was prepared simi-
larly by starting with m-bromophenyl boronic acid 29
(Scheme 6). The extended benzo-LX analog 12 was pre-
pared as shown in Scheme 7 from 2-bromo styryl boro-
nic acid 33, which was synthesized from 2-bromo-phenyl
acetylene 32 using the hydroboration procedure re-
ported by Matteson.33 Suzuki–Miyaura coupling of 33
with bromide 19, prepared via the stereospecific bromin-
ation34 of boronate 18 (Scheme 4), gave bromide 34
which was converted to the corresponding pinacol bor-
onate 35 under a Pd-catalyzed reaction with bis-pinaco-
lato diboron.35 Coupling of 35 with iodide 15 (Scheme
4) formed, after desilylation, the o-[9,10]-benzo-LX ana-
log 12 (Scheme 7). Finally, as shown in Scheme 8, the
1 (LXA4)
2-Me (ATLa)
9 (o-[9,12]-Benzo)
2.42
0.21
0.19
100
9
8
10 (o-[9,12]-Benzo, 15 deoxy) 0.04
2
11 (m-[9,12]-Benzo)
12 (o-[9,10]-Benzo)
13 (o-[9,14]-Benzo)
0.45
0.14
0.09
19
6
4
Each compound was incubated with 50 ng of recombinant EOR at
37 °C (0.1 M Tris–HCl, pH 9.0, 1 mM NAD+, 100 lL total volume)
for 25 min and the rate of NADH formation was monitored. Initial
reaction velocities were calculated using linear regression analysis of
the linear phase of conversion. Rate values represent means SEM,
n = 3.

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N. A. Petasis et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1382–1387
Table 2. Anti-inflammatory action of benzo-LXA4 analogs
In the rank order comparison of these analogs, with
ATLa (3), the most potent were analogs 9 and 11 reduc-
ing PMN infiltration in a statistically significant manner
by ꢀ32%, versus 40% for 3. Earlier results showed that
indomethacin, a commonly prescribed NSAID, reduces
PMN infiltration by ꢀ35–40% in this model of peritoni-
tis,36 providing validation of the clinical significance of
the degree of activity observed with these new analogs
and point to a novel mechanism of action for reducing
inflammation which goes beyond the simple inhibition
of the production of prostanoids. Our results (Table 2)
demonstrate that both the o- and m-benzo LX analogs
blocked PMN infiltration to a similar degree. Since these
two analogs differ mainly in the angular orientation be-
tween the C1–C8 and C13–C20 fragments, this suggests
that LX-receptor interactions exhibit conformational
flexibility. In contrast to the other analogs tested, com-
pound 12 was found to be the least active, suggesting
a possible importance of the overall size of the tetraene
unit, or more specifically the need for a cis-orienting
group (Z-alkene or benzo-ring) at a more appropriate
location of the LX structure.
Compound
Inhibition of PMN
infiltration (%)
3 (ATLa)
40.53
32.21
23.86
31.97
17.33
22.34
9 (o-[9,12]-Benzo)
10 (o-[9,12]-Benzo, 15 deoxy)
11 (m-[9,12]-Benzo)
12 (o-[9,10]-Benzo)
13 (o-[9,14]-Benzo)
Compounds were injected by intravenous bolus injection (15 lg kgÀ1
/
100 lL of sterile saline) via the tail vein of 6- to 8-week-old male FVB
mice followed by peritoneal injection of zymosan A (1 mg/1 mL).
Peritoneal lavages were collected (2 h) and total leukocytes, PMNs,
and monocytes were enumerated. Inhibition of PMN infiltration was
determined by comparison to inflammation (peritonitis) initiated by
zymosan A plus vehicle (100 lL of sterile saline). Values represent
means SEM, n = 5–10.
ences among the analogs studied. Examining the impact
of these structural differences in both anti-inflammatory
and enzymatic catalysis provided some insights into
structure–function relationships.
Earlier generations of LXA4 analogs were shown to re-
sist inactivation by EOR, mainly through the use of an
(R)-OH group at C15.10 In view of this, the benzo LX
analogs presented here were synthesized having the (R)
configuration at this position. In addition, a benzo-fused
ring was inserted at various positions of the labile tetrae-
ne backbone of LXA4 because of the inherent chemical
instability of the conjugated E,E,Z,E tetraene. This
modification not only enabled a simplified, highly con-
vergent and stereoselective synthesis, but also provided
overall conformational rigidity. All of the benzo LX
analogs reported here demonstrated significant resis-
tance to enzymatic dehydrogenation at C15 (Table 1),
a feature found to enhance bioactivity.3,4 Comparison
among these new LX analogs showed that the 15-deoxy
analog 10 was not converted by 15-EOR to an apprecia-
ble extent, confirming that EOR acts primarily at the
C15 (x-6) OH group and not at the vicinal 5- and 6-
hydroxyls of these compounds. While analog 10 was
essentially inert to enzymatic catalysis, the other four
analogs were inefficiently converted but were not more
resistant than ATL-Me. Analog 13 (used as a racemic
mixture at C15) was also resistant to 15-EOR, even
though half of it had the 15S configuration. Presumably,
by placing a benzene ring at the site of the 13E C@C
bond in 13, which is adjacent to the C15 OH, the com-
pound no longer has the preferred allylic alcohol struc-
ture,4 and it is also more hindered. Otherwise, these
results suggest that the presence of the benzene ring fur-
ther away from the C15 OH does not confer any addi-
tional resistance to EOR inactivation.
In the present study, a new class of benzo-LX analogs
was designed that are resistant to enzymatic catalysis
and demonstrated diverse and potent LX-like anti-
inflammatory actions. It should be noted that although
a related series of benzo-LXA4 analogs were previously
reported,37 those earlier analogs had the 5,6-diol unit
with the unnatural 5S,6S- and 5R,6S-configurations,
rather than the biologically relevant 5S,6R configuration
of LXA4 and ATL. Moreover, the previous analogs
lacked stereospecificity at the x-proximal hydroxyl
group (i.e., C15), unlike the most active analogs pre-
sented here. Also, the 6S-isomer of natural LXA4, de-
noted 6SLXA4, is essentially devoid of bioactivity.1
Given the high stereochemical fidelity exhibited by the
lipoxins both in terms of their metabolic inactivation
by oxido-reductases as well as their receptor-binding ac-
tions that are sensitive to hydroxyl group stereochemis-
try, even relatively small changes in the structures of
these molecules can have a dramatic effect on their bio-
activities in vivo.
Overall, the new series of LX analogs reported herein
have potent anti-inflammatory activities in vivo reduc-
ing the infiltration of neutrophils to an inflamed site
in vivo, and unlike the native LXA4, ATL, and earlier
generations of LX analogs, they are also characterized
by an increased chemical stability, while they can be
readily synthesized via stereocontrolled, highly conver-
gent, and efficient synthetic routes. The combined char-
acteristics of these new LX-like molecules,38,39 therefore,
make them appealing candidates for pharmacological
applications and for the development of new anti-
inflammatory therapeutics.
The LXA4 analog ATLa (3) has been established as the
benchmark of LX analogs, demonstrating potent anti-
inflammatory actions as well as resistance to inactiva-
tion.4,13 While other currently available non-steroidal
anti-inflammatory drugs (NSAIDs) exhibit similar
anti-inflammatory properties, LXs and their analogs
are far more potent, requiring two to three orders of
magnitude lower concentration for a similar action.17
Acknowledgments
Support by NIH Grants P50-DE-016191 and R01-
HL079312 is gratefully acknowledged.

N. A. Petasis et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1382–1387
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