Synthesis, biological evaluation and molecular docking studies of stellatin derivatives as cyclooxygenase (COX-1, COX-2) inhibitors and anti-inflammatory agents

Article abstract of DOI:10.1016/j.bmcl.2011.01.116

Stellatin (4), isolated from Dysophylla stellata is a cyclooxygenase (COX) inhibitor. The present study reports the synthesis and biological evaluation of new stellatin derivatives for COX-1, COX-2 inhibitory and anti-inflammatory activities. Eight deriva

Full text of DOI:10.1016/j.bmcl.2011.01.116

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1612–1616
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, biological evaluation and molecular docking studies of stellatin
derivatives as cyclooxygenase (COX-1, COX-2) inhibitors and
anti-inflammatory agents
Raju Gautam a, Sanjay M. Jachak a, , Vivek Kumar b, C. Gopi Mohan b
⇑
a Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, SAS Nagar, Mohali 160062, Punjab, India
b Centre for Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, SAS Nagar, Mohali 160062, Punjab, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Stellatin (4), isolated from Dysophylla stellata is a cyclooxygenase (COX) inhibitor. The present study
reports the synthesis and biological evaluation of new stellatin derivatives for COX-1, COX-2 inhibitory
and anti-inflammatory activities. Eight derivatives showed more pronounced COX-2 inhibition than stell-
atin and, 17 and 21 exhibited the highest COX-2 inhibition. They also exhibited the significant anti-
inflammatory activity in TPA-induced mouse ear edema assay and their anti-inflammatory effects were
more than that of stellatin and indomethacin at 0.5 mg/ear. The derivatives were further evaluated for
antioxidant activity wherein 16 and 17 showed potent free radical scavenging activity against DPPH
and ABTS radicals. Molecular docking study revealed the binding orientations of stellatin and its deriva-
tives into the active sites of COX-1 and COX-2 and thereby helps to design the potent inhibitors.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 2 September 2010
Revised 12 January 2011
Accepted 26 January 2011
Available online 2 February 2011
Keywords:
Stellatin
Chromones
Cyclooxygenase (COX)-1 and -2
Anti-inflammatory
Antioxidant
Molecular docking
Nonsteroidal anti-inflammatory drugs (NSAIDs) are of huge
therapeutic benefit in the treatment of rheumatoid arthritis and
various types of inflammatory conditions. The target for these
drugs is cyclooxygenase (COX), a rate limiting enzyme which con-
verts arachidonic acid into inflammatory prostaglandins. COX ex-
ists in two isoforms, COX-1 and COX-2. COX-1 is known as a
housekeeping enzyme and constitutively expressed in all tissues,
while COX-2 is constitutively expressed only in kidney, brain and
ovaries. COX-2 is increasingly expressed during inflammatory con-
Glc
HO
HO
O
O
O
O
O
O
O
O
1
OH O
OH O
3
4
O
O
O
O
O
O
O
OH
OH O
2
OH O
O
5
6
ditions by pro-inflammatory molecules such as IL-1, TNF-
a, LPS
and TPA.1–3
Figure 1. Natural anti-inflammatory chromones of plant origin.
Chromones constitute an important class of natural products
and are reported to exhibit anti-inflammatory,4–6 anti-arthritic,6
anti-cancer,7 immune-stimulation,7 anti-platelet,8 uricosuric,6
anti-allergic,6 anti-bacterial9 and antioxidant4 activities. As anti-
inflammatory agents, chromones exert their effects by inhibiting
various mechanisms suÀch as COX-1 and COX-2 enzymes,4 NO pro-
duction,7 PKC10 and O2 production in PMA- or f-MLF-stimulated
human neutrophils.10 The structures of some naturally occurring
As a part of our continuing program to discover COX-1 and
COX-2 inhibitory compounds from Indian medicinal plants,12–14
the n-hexane and EtOAc extracts of Dysophylla stellata (Labiatae)
were tested in a COX catalyzed prostaglandin biosynthesis assay
in vitro and a significant COX-1 and COX-2 inhibitory activity
was observed. The chromones 4–6 were isolated as the potent
COX inhibitory principles and 4 exhibited selectivity towards
COX-2 inhibition than COX-1.12 The HPLC analysis of D. stellata re-
vealed 4 as a major constituent15 and it was concluded that it could
be responsible for COX inhibitory activity of D. stellata. These find-
ings prompted us to synthesize the derivatives of 4 so as to study
the structure–activity relationship (SAR).
anti-inflammatory chromones, aloesin (1)4, norcimicifugin (2)11
,
petersinone 1 (3)7, stellatin (4)12, eugenin (5)12 and 5,7-dime-
thoxy-2-methylchromanone (6)12 are shown in Figure 1.
The chemical modifications of 4 were carried out at 5-OH to
introduce the different functionality. The 5-O-alkylation was
⇑
Corresponding author. Tel.: +91 172 2214683; fax: +91 172 2214692.
E-mail address: sanjayjachak@niper.ac.in (S.M. Jachak).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.01.116

R. Gautam et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1612–1616
1613
R
H3CO
H3CO
O
CH3
OH O
22, R = Cl
23
24
, R = Br
, R = I
e
H3CO
H3CO
O
CH3
HO
HO
O
CH3
CH3
H3CO
HO
O
CH3
CH3
H3CO
H3CO
O
CH3
a
d
+
OR O
OH O
17
OH O
16
OH O
4
7
, R = CH3
a
a
b, c
8, R = CH3CH2
9
, R = CH3CH2CH2
H3CO
RO
O
H3CO
O
O
CH3
RO
RO
O
10, R = CH3CH2CH2CH2
11, R = CH2=CH-CH2
H3CO
R
12
, R = (CH3)2C=CH-CH2
OH O
O
OH O
13, R = C6H5-CH2
O
20
, R = CH2=CH-CH2
18
, R = CH2=CH-CH2
14, R = CH3
15, R = C6H5
21, R = (CH3)2C=CH-CH2
19, R = (CH3)2C=CH-CH2
Scheme 1. Reagent and conditions: (a) K2CO3/(CH3)2CO, RX, reflux, 12–24 h, 35–85%; (b) (CH3CO)2O/CH3COONa, reflux, 2 h, 75%; (c) K2CO3/(CH3)2CO, PhCOBr, reflux, 24 h,
64%; (d) AlCl3/C7H8, reflux, 12 h, 30–70%; (e) NCS (22), NBS (23), NIS (24)/ACN, rt, 4–24 h, 20–75%.
carried out with alkylating agents using anhydrous K2CO3 in ace-
tone16 to furnish compounds 7–13 (Scheme 1) in good yields
(65–85%), except 10 (35%). The reaction of 4 with (CH3CO)2O and
anhydrous CH3COONa afforded 14 in a fairly good yield (75%)17
while 15 was synthesized in the similar way as O-alkyl derivatives.
To introduce the free OH, demethylation was performed with
anhydrous AlCl3 in toluene.18 The reaction of 4 with AlCl3 for 2 h
resulted in the formation of 16 in a high yield (80%), but, when
the reaction time was extended to 12 h, 16 (70%) and 17 (20%) both
were formed. Ethers 18–21 were synthesized from 16 and 17
respectively, using K2CO3 and alkyl bromides in high yields
(80–90%). The reaction of 16 with alkyl bromide resulted in the
regioselective monoalkylation at 6-position (18–19). Similarly,
the regioselective dialkylation at 6-and 7-positions was observed
in 20, 21. The reaction of 4 with NCS/NBS/NIS in acetonitrile gave
22–24 wherein regioselective halogenation was observed at 8-po-
sition. Of the synthetic derivatives, 8–13, 15, 18 and 20–24 were
found as new compounds when they were searched on Scifinder
and Reaxys databases (The spectral, MS and elemental data of
new compounds are submitted as Supplementary data).
nyl group at 5-position (as in 12) did not alter the COX-1 inhibition
whereas it showed improved COX-2 inhibition. The conversion of
OH into an ester (14 and 15) also decreased the COX-1 and COX-
2 inhibitory activity. The conversion of methoxyl groups of 4 into
the hydroxyl groups improved both COX-1 and COX-2 inhibitory
activity (16 and 17) with more pronounced effect towards COX-2
inhibition. Eugenin (5), an isolated chromone with one methoxyl
group less than stellatin, showed better COX-1 inhibition than
stellatin without having much effect on COX-2. The replacement
of free OH groups at 6- and 7-position by an allyl or isoprenyl
groups (18–21) improved the COX-1 and COX-2 inhibitory activity
(except 18, in case of COX-1). The halogenated derivatives (22–24)
did not show ‘noticeable’ effect on COX inhibition as their inhibi-
tion was even less than that of stellatin.
The reports on SAR of flavonoids (2-phenylchromones) sug-
gested that 4-oxo functional group of the C-ring is essential for
COX inhibitory activity; the C2–C3 double bond enhances the
activity and reduction of this double bond results in decreased
or loss of inhibitory activity.19,20 The similar trend was also ob-
served in the case of the studied chromones and inhibition was
seemed to depend on number and position of hydroxyl residues.
The presence of 5-OH is essential for COX inhibitory activity,
however, isoprenyl group seems to be ideal replacement. The
presence of 6-OH further increased the COX-1 and COX-2 inhib-
itory activity. Therefore, the SAR study helped us to establish a
basic pharmacophore (Fig. 2) responsible for the activity. A chro-
mone with C2–C3 double bond, a carbonyl group at 4-position of
A-ring and a 5-OH on B-ring are essential features for the COX
inhibitory activity.
The synthesized chromones (7–24) were evaluated for in vitro
COX-1 and COX-2 inhibitory activity in a COX catalyzed prosta-
glandin biosynthesis assay as described by us previously.12,13 Ini-
tially, the compounds were tested at 30 lM and their effects on
COX-1 and COX-2 inhibition are shown in Table 1. The study was
further extended to examine the concentration-activity responses
at different concentrations to determine the IC50 values for COX-
1 and COX-2. Five compounds (16, 17 and 19–21) showed better
COX-1 inhibitory activity than stellatin with IC50 values in the
range of 14–22
exhibited more COX-2 inhibitory activity than that of stellatin
(IC50s, 8–18 M). Compound 17 (5,6,7-trihydroxy-2-methylchro-
mone) exhibited the highest COX-2 inhibition (IC50 8.87 M) fol-
lowed by 21 (IC50 10.35 M). The COX-2 inhibitory effect of 17
was >2-fold as compared to stellatin (IC50 19.7 M). The results
of the present study suggests that chromones acts as non-selective
inhibitors of COX enzymes and showed anti-inflammatory effects.
In case of ether derivatives, the introduction of a chain length
up to four carbons (7–11) and a benzyl group (13) resulted in a de-
creased COX-1 and COX-2 inhibitory activity; however, an isopre-
l
M; whereas seven compounds (12 and 16–21)
Ten compounds (11, 12 and 16–23) were evaluated further for
anti-inflammatory in a TPA-induced mouse ear edema assay as de-
scribed earlier by us.12,13 All the compounds showed significant
anti-inflammatory activity. Compound 17 exhibited the highest
anti-inflammatory activity with 90.7% reduction in the ear edema
followed by 21 (85.1% reduction). The anti-inflammatory effects
of 17 and 21 were more than that of stellatin (69.4%) and indo-
methacin (81.4%) at the same dose levels. Compounds 12, 16, 19
and 20 showed anti-inflammatory activity comparable to indo-
methacin (Table 1) and their anti-inflammatory effects were in or-
der: 20 > 16 > 19 > 12.
l
l
l
l

1614
R. Gautam et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1612–1616
Table 1
COX-1, COX-2 inhibitory and anti-inflammatory activities of the synthesized chromones
Compound
COX inhibition at 30
l
Ma
(IC50
COX-1
,
l
M)
Anti-inflammatory activityb
COX-1
COX-2
COX-2
Dose (mg/ear)
Increase in ear thickness (mm)
% reduction in ear edema
Control
4
5
7
8
9
10
11
12
13
14
15
16
17
18
19
—
—
—
—
—
0.270 0.008
—
71.50 0.32
85.59 0.10
70.35 0.09
54.85 1.33
40.16 0.13
28.45 2.09
56.18 0.32
70.09 0.77
63.41 1.66
59.02 0.12
45.84 2.33
78.10 0.87
87.45 1.08
68.33 1.05
80.67 0.34
74.09 0.63
82.33 1.12
66.85 0.66
63.76 0.90
57.21 2.33
59.01 1.76
98.23 0.33
13.01 0.63
80.15 0.06
78.50 0.29
47.42 1.12
49.75 0.76
48.35 0.87
52.45 0.33
73.87 1.33
82.54 0.19
48.13 0.09
46.22 0.56
68.14 0.10
84.99 0.33
94.12 0.66
81.53 0.45
83.23 2.08
89.54 0.88
91.67 0.34
50.32 1.89
67.03 1.33
37.70 0.76
20.32 2.08
50.99 0.34
95.57 0.48
22.3
17.8
—
—
—
19.7
20.1
—
—
—
0.5
0.5
—
—
—
0.082 0.009*
69.44 3.50
73.20 1.78
—
—
—
—
66.66 4.69
77.16 2.16
—
—
—
78.40 2.44
90.74 2.28
71.30 2.53
77.77 1.30
80.24 3.09
85.18 2.61
61.11 3.33
70.37 2.26
—
0.071 0.004*
—
—
—
—
—
—
—
38.28
22.87
—
—
—
19.75
14.38
26.04
18.67
21.57
17.17
27.18
29.32
—
21.25
17.64
—
—
—
15.35
8.87
18.01
15.49
13.54
10.35
43.41
25.42
—
0.5
0.5
—
—
—
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
—
0.090 0.012*
0.061 0.005*
—
—
—
0.058 0.006*
0.025 0.006**
0.077 0.004*
0.060 0.004*
0.053 0.008**
0.040 0.007**
0.105 0.010*
0.080 0.007*
—
20
21
22
23
24
Curcuminc
Indomethacinc
Celecoxibc
35.09
0.18
—
79.20
—
0.15
—
0.5
—
—
—
0.050 0.005**
—
81.48 2.15
—
a
b
c
Values are expressed as mean S.E.M of three determinations (n = 3).
Six animals per group and data is expressed as mean S.E.M of six determinations (n = 6).
Positive controls used.
*
p < 0.05 versus control (Dunnett’s t-test).
p < 0.01 versus control (Dunnett’s t-test).
**
4
perform molecular docking studies to understand the ligand-pro-
tein interactions, and COX-1/COX-2 selectivity in detail. The dock-
ing studies were carried out as per the method described
previously by us.14 The crystal structures of COX-1 (1EQG)22 and
COX-2 (1PXX)23 complexed with ibuprofen and diclofenac respec-
tively were used for docking. FlexX, an automated docking pro-
gram, was used to dock these compounds into the active sites of
COX-1 and COX-2 enzyme and the most stable conformation based
on the best FlexX scoring function was selected. All the calculations
were performed using SYBYL7.124 software installed on SGI worksta-
tion. The active site of the enzyme was defined to include residues
within 6.5 Å radius around bound inhibitor. The energy minimiza-
tion was carried out using Tripos force field and the partial charges
were calculated using the same method. The complexes were min-
R
= X
Decreased activity
R4
1
O
A
2
3
R3
R2
8
R
= R = OH
C
= C and 4-oxo
3
2
7
2
3
B
Enhanced activity
(Isoprenyl ideal
replacement)
essential structural
requirements
6
4
O
R1
1
R
= OH
(Isoprenyl ideal substituent)
Figure 2. Structure–activity relationship of chromones.
It has been reported that in inflammatory disorders, excessive
imized in
0.05 kcal/mol was reached. The distance dependent dielectric func-
tion ( = 4r) was used. The FlexX successfully docked 4 and its
derivatives into the active sites of COX-1 and COX-2 enzyme and
the total scores of their complexes are given as a Supplementary
data (in Table).
a stepwise manner till the gradient convergence
free radical generation takes place and several NSAIDs and pheno-
lic compounds with anti-inflammatory activity are reported to act
as radical scavengers.21 Therefore, antioxidant property of the syn-
thesized chromones was evaluated using DPPH and ABTS radical
scavenging in vitro assays.12–14 The compounds were tested at
e
30 lM and it was observed that except 16 and 17, all other com-
The compound 17 was found to dock into the active site of COX-
1 with interaction energy of À14.66 kcal/mol. It formed three
hydrogen bonds with Tyr385, Met522 and Ser530 into the active
site of COX-1 and bonding distance between 5-OH of 17 and OH
of Tyr385 2.62 Å (HÁ Á ÁO); 4-C@O of 17 and OH of Ser530 2.58 Å
(HÁ Á ÁO); 7-OH of 17 and C@O of Met522 1.88 Å (HÁ Á ÁO) were ob-
served. The ring A and B of 17 were surrounded by the active site
amino acid residues Ser121, Leu123, Val349, Tyr385, Met522 and
Ser530 (Fig. 3a). The compound 17 could dock successfully into
the COX-2 active site as well. The binding energy of interaction ob-
tained for 17 (À17.74 kcal/mol) was found to be highest. The great-
er interaction energy of 17 and COX-2 enzyme complex
rationalizes the tighter binding of 17 into the COX-2 active site
and this binding may be attributed to its three hydrogen bonding
interactions with Met522 and Ser530. The bonding distance be-
pounds were weakly active and unable to scavenge >10% DPPH
radical. No improvement in the radical scavenging property was
observed even when their concentration was increased up to
100
strongly scavenged the DPPH radical and the scavenging effect of
17 was about 2-times more than that of trolox (IC50, 15.72 M)
and better than curcumin (IC50, 12.12 M). The same trend of the
antioxidant activity was also observed in the ABTS assay. Com-
pound 16 (IC50, 14.36 M) and 17 (IC50, 10.60 M) showed strong
ABTS radical scavenging activity and their effects were comparable
(16) or better (17) than those of trolox (IC50, 16.23 M) and curcu-
min (IC50, 13.08 M).
lM. Compound 16 (IC50, 13.15 lM) and 17 (IC50, 7.96 lM)
l
l
l
l
l
l
The COX-1, COX-2 inhibitory and significant anti-inflammatory
activity of 4 and its derivatives (11, 12 and 16–23) prompted us to

R. Gautam et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1612–1616
1615
Val 349
Asn375
Ser 530
Val 349
Tyr 385
Ser 530
Ser 121
Tyr 385
Ser 121
Leu123
Leu123
Met 522
Met 522
(a)
(b)
Figure 3. Binding of compound 17 at the active site of COX-1 (a) and COX-2 (b).
Tyr 385
Ser 530
Tyr 385
Ser 121
Thr 206
Gly 435
Val 291
Leu123
Met 522
His 388
(a)
(b)
Figure 4. Binding of stellatin (4) at the active site of COX-1 (a) and COX-2 (b).
tween 7-OH of 17 with O of Met522 1.99 Å (H...O); 5-OH of 17 and
OH of Ser530 1.88 Å (HÁ Á ÁO) and 4-C@O of 17 and OH of Ser530
1.98 Å (HÁ Á ÁO) of COX-2 were observed. The 6-OH, 5-OH, 4-C@O
and 2-Me of 17 were surrounded by the active site amino acid res-
idues Gly526, Ser530, Ser530 and Leu352, respectively (Fig. 3b).
The compound 4 was docked into the active site of COX-1 and
the interaction energy of À10.69 kcal/mol was obtained. Only
one hydrogen bonding interaction between the 5-OH of 4 and
C@O of Tyr385 (HÁ Á ÁO, 2.13 Å) of COX-1 was observed (Fig. 4a).
Compound 4 was also found to dock into the active site of COX-2
with interaction energy of À12.88 kcal/mol. Two hydrogen bond-
ing interactions of 4 were observed with the bonding distances
as follow: 4-C@O of 4 and OH of Ser530 (OÁ Á ÁH, 1.88 Å); 4-C@O
of 4 and OH of Try385 of COX-2 (OÁ Á ÁH, 2.13 Å). The 2-Me and 7-
OMe of 4 was surrounded by active site amino acid residues
Leu123, Met522 and Tyr385 (Fig. 4b).
The interaction with amino acid Ser530 is important for enzyme
inhibitory activity and is well exemplified by the binding interac-
tion of aspirin with COX-1/COX-2.25 Tyr385 is responsible for the
abstraction of 13-pro-S-hydrogen from arachidonic acid.26 In case
of complex of 4 with COX-1, the hydrogen bonding interaction
with Ser530 was found to be absent, which could be a probable
reason for the observed selectivity of 4 towards COX-2 inhibition.
Further, the scoring function of 4 and 17 complexes with COX-2
suggests them as the preferred ligand for COX-2 than COX-1 and
provides rationale for selectivity of enzyme inhibitory activity.
While it was noted that both COX-1 and COX-2 share almost sim-
ilar active site residues and difference lies in its active site volume
(COX2 has larger active site volume- 417 Å3; while COX-1 has
smaller active site volume-366 Å3) respectively, determined using
Q-SiteFinder program.27 It further shows that inhibitors of COX-1
can equally inhibit COX-2, thus assuming equipotency, while the
larger sized molecule seems to be more selective towards COX-2
due to its increased active site volume. It is also important to note
that the mode of binding of compound 17 in COX-1 and COX-2 is
slightly different due to its difference in the active site volumes
(Fig. 3), and the selectivity issue was further supported by our
experimental analysis showing better inhibitory activity of
8.87 lM with COX-2 (Table 1).
In conclusion, eighteen stellatin derivatives including thirteen
new compounds were synthesized and seven compounds (12 and
16–21) showed more pronounced COX-2 inhibition than naturally
occurring chromone, stellatin. The SAR study revealed that a chro-
mone skeleton with C2–C3 double bond, C@O at 4-position and OH
at 5-position are essential features for COX inhibition. Two com-
pounds (17 and 21) exhibited greater anti-inflammatory activity
than indomethacin and two compounds (16 and 17) showed the
potent radical scavenging activity as an antioxidant agent. Molec-

1616
R. Gautam et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1612–1616
12. Gautam, R.; Srivastava, A.; Jachak, S. M.; Saklani, A. Fitoterapia 2010, 81, 45.
13. Gautam, R.; Karkhile, K. V.; Bhutani, K. K.; Jachak, S. M. Planta Med. 2010, 76,
1564.
14. Selvam, C.; Jachak, S. M.; Thilagavathi, R.; Chakraborti, A. K. Bioorg. Med. Chem.
Lett. 2005, 15, 1793.
ular docking study further helped in supporting the observed COX-
2 selectivity. The findings of the study inferred that the dual func-
tioning of 17 as a COX inhibitor and antioxidant agent render it as a
lead molecule for further development of new anti-inflammatory
agents.
15. Gautam, R.; Srivastava, A.; Jachak, S. M. Nat. Prod. Commun. 2010, 5, 555.
16. General procedure for the synthesis of O-alkylated chromones (7–13 and 18–
21): To a stirred solution of 4/16/17 (0.42 mmol) in dry acetone (5–8 mL),
K2CO3 (0.84 mmol) and an appropriate alkylating agent (0.84 mmol) were
added and the resulting mixture was refluxed at 70 °C for 12–24 h. The
reaction was stopped by quenching with water and the aqueous portion was
extracted with EtOAc (3 Â 25 mL). The organic layer was separated, washed
with brine solution and dried over anhydrous sodium sulphate. The solvent
was removed under vacuum and the crude product was purified by Si gel CC
using hexane–EtOAc as an eluent.
17. Joshi, B. S.; Ravindranath, K. R. J. Chem. Soc., Perkin Trans. I 1977, 4, 433.
18. Raychaudhary, S.; Seshadri, T. R. Ind. J. Chem. 1973, 11, 1228.
19. Takano-Ishikawa, Y.; Goto, M.; Yamaki, K. Phytomedicine 2006, 13, 310.
20. Gautam, R.; Jachak, S. M. Med. Res. Rev. 2009, 29, 767.
21. Maffei Facino, R. M.; Cairini, M.; Saibene, L. Arch. Pharm. Med. Chem. 1996, 329,
457.
22. Selinsky, B. S.; Gupta, K.; Sharkey, C. T.; Loll, P. J. Biochemistry 2001, 40, 5172.
23. Rowlinson, S. W.; Kiefer, J. R.; Prusakiewicz, J. J.; Pawlitz, J. L.; Kozak, K. R.;
Kalgutkar, A. S.; Stallings, W. C.; Kurumbail, R. G.; Marnett, L. J. J. Biol. Chem.
2003, 278, 45763.
24. SYBYL 7.1 Molecular Modelling Software; Tripos Associates Inc.: 1699 S. Hanley,
St. Louis MI 63144, USA.
25. Kalgutkar, A. S.; Crews, B. C.; Rowlinson, S. W.; Garner, C.; Seibert, K.; Marnett,
L. J. Science 1998, 280, 1268.
26. Thuresson, E. D.; Lakkides, K. M.; Rieke, C. J.; Sun, Y.; Wingerd, B. A.; Micielli, R.;
Mulichak, A. M.; Malkowski, M. G.; Garavito, R. M.; Smith, W. L. J Biol. Chem.
2001, 276, 10347.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.01.116.
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