Design, synthesis and biological evaluation of photoaffinity probes of antiangiogenic homoisoflavonoids

Article abstract of DOI:10.1016/j.bmcl.2016.07.043

A naturally occurring homoisoflavonoid, cremastranone (1) inhibited angiogenesis in vitro and in vivo. We developed an analogue SH-11037 (2) which is more potent than cremastranone in human retinal microvascular endothelial cells (HRECs) and blocks neovascularization in animal models. Despite their efficacy, the mechanism of these compounds is not yet fully known. In the course of building on a strong foundation of SAR and creating a novel chemical tool for target identification of homoisoflavonoid-binding proteins, various types of photoaffinity probes were designed and synthesized in which benzophenone and biotin were attached to homoisoflavanonoids using PEG linkers on either the C-3′ or C-7 position. Notably, the photoaffinity probes linking on the phenol group of the C-3′ position retain excellent activity of inhibiting retinal endothelial cell proliferation with up to 72?nM of GI₅₀.

Full text of DOI:10.1016/j.bmcl.2016.07.043

Bioorganic & Medicinal Chemistry Letters 26 (2016) 4277–4281
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and biological evaluation of photoaffinity probes of
antiangiogenic homoisoflavonoids
Bit Lee a, Wei Sun a, Hyungjun Lee a, Halesha Basavarajappa b,c, Rania S. Sulaiman b,d,e, Kamakshi Sishtla b,
Xiang Fei a, Timothy W. Corson b,c,d, Seung-Yong Seo a,
⇑
a College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, South Korea
b Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
c Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
d Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
e Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A naturally occurring homoisoflavonoid, cremastranone (1) inhibited angiogenesis in vitro and in vivo.
We developed an analogue SH-11037 (2) which is more potent than cremastranone in human retinal
microvascular endothelial cells (HRECs) and blocks neovascularization in animal models. Despite their
efficacy, the mechanism of these compounds is not yet fully known. In the course of building on a strong
foundation of SAR and creating a novel chemical tool for target identification of homoisoflavonoid-bind-
ing proteins, various types of photoaffinity probes were designed and synthesized in which benzophe-
none and biotin were attached to homoisoflavanonoids using PEG linkers on either the C-30 or C-7
position. Notably, the photoaffinity probes linking on the phenol group of the C-30 position retain excel-
Received 9 June 2016
Revised 16 July 2016
Accepted 20 July 2016
Available online 21 July 2016
This paper is dedicated to Professor
Young-Ger Suh on the occasion of his 65th
birthday.
lent activity of inhibiting retinal endothelial cell proliferation with up to 72 nM of GI50
.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Homoisoflavonoids
Photoaffinity probes
Antiangiogenic agents
Human retinal microvascular endothelial
cells
Wet age-related macular degeneration
The identification of target proteins binding bioactive small
molecules is an essential task in drug development that can extend
the understanding of mechanisms and provide information for
designing new drug candidates.1–9 Among many approaches to
identify cellular targets of bioactive molecules, biochemical affinity
purification using synthetic affinity probes that mimic the struc-
ture of the bioactive compounds is a straightforward and powerful
method for identifying target molecules. Recently, photoaffinity
labeling has been considered a more efficient variant of this
method, as it can enrich for low-abundance or transiently-interact-
ing targets.10–14 So far, there have been a number of successful
examples that have determined the target molecules and identified
the binding site through the formation of a covalent bond between
the ligand and the specific protein.15–23 In general, photoaffinity
probes contain three functional groups: a bioactive scaffold, a pho-
toreactive group and a reporter tag.24 A biotin tag is widely
employed as a reporter tag because it binds streptavidin or avidin
with extremely high affinity.
Cremastranone (1), a naturally occurring homoisoflavanone is
reported to have antiangiogenic activity with some selectivity for
blocking proliferation of human retinal endothelial cells over other
ocular cell types.25–28 It inhibits ocular angiogenesis, without sub-
stantial toxicity, in mouse models of laser-induced choroidal neo-
vascularization (L-CNV) and oxygen-induced retinopathy (OIR).
These animal models recapitulate features of the blinding eye dis-
eases wet age-related macular degeneration and retinopathy of
prematurity, respectively. Cremastranone impinges on multiple
signaling pathways. It induces expression of p21WAF1 (CDKN1A),
which inhibits the cyclin-dependent kinase Cdc2 (CDK1).29 It also
blocks prostaglandin synthesis and decreases activation of the
mitogen activated protein kinases.30,31 Finally, it blocks nuclear
translocation of NF-
jB
and production of inflammatory
cytokines.25,31,32 Seeking more potent and selective compounds
than cremastranone, we identified SH-11037 which is observed
to have novel antiangiogenic activity against human retinal
⇑
Corresponding author. Tel.: +82 32 820 4949; fax: +82 32 820 4829.
E-mail address: syseo@gachon.ac.kr (S.-Y. Seo).
http://dx.doi.org/10.1016/j.bmcl.2016.07.043
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.

4278
B. Lee et al. / Bioorg. Med. Chem. Lett. 26 (2016) 4277–4281
microvascular endothelial cells (HRECs) and blocks neovasculariza-
tion in the OIR and L-CNV models.27,33 Although the studies of
mechanisms and medicinal chemistry could contribute to many
therapeutic facets of the antiangiogenic homoisoflavonoids, their
exact mechanisms of action and cellular targets remain unknown,
so the search for direct interacting proteins is valuable.34,35 Herein
we report design and synthesis of homoisoflavonoid–biotin conju-
gates for inhibiting proliferation of endothelial cells and identify-
significant loss of activity by elongating a tethered biotin moiety
with hydrophilic groups. Unfortunately, the introduction of a
tether to the site of the NHBoc group in SH-11037 (2) was proven
to be problematic due to the low reactivity of the amino group and
instability of the ester group in the course of Boc-deprotection or
linking with a carbamate.
The synthesis of intermediate 10 is outlined in Scheme 1.24,36
Similar to the procedures reported previously, the synthesis of
biotinylated benzophenone was commenced with two different
alkylations of 4,40-dihydroxybenzophenone, which was treated
with propargylic bromide and K2CO3, followed by DIAD-mediated
Mitsunobu reaction using 3-(Boc-amino)-1-propanol to afford the
resulting bis-ether 7. The azide 8 which was obtained from treat-
ment of commercially available p-nitrophenyl ester of biotin
(Biotin-ONp) with N3-PEG3-CH2CH2NH2 was coupled with bis-ether
7 by Cu-catalyzed Huisgen 1,3-dipolar cycloaddition,37 followed by
the treatment of the resulting 1,2,3-triazole 9 with TFA to afford
benzophenone-linked biotin intermediate 10 in good yield. In
future target identification studies, 10 can also be utilized as a neg-
ative control compound which lacks the homoisoflavanone moiety.
To prepare the first photoaffinity probe 3, the bioactive and
racemic 3-benzyl-4-chromanone ( )-11 was chosen as a starting
material (Scheme 2).25–27 The phenolic OH on the C-30 position
was alkylated with tert-butyl bromoacetate under basic conditions,
followed by the acidic treatment of the ester 12 to afford the car-
boxylic acid 13. Finally, the carboxylic acid 13 was coupled with
the intermediate 10 by HBTU-mediated amidation to provide the
desired photoaffinity probe 3 in moderate yield.
For the photoaffinity probes modified at the para-position of the
phenylalanyl group of 2, Boc-Tyr(Bn)-OH was introduced into com-
pound 11 at the C-30 position by using EDCI (Scheme 3). The deben-
zylation of the ester 14 afforded the resulting compound 15, which
has a free OH group. The alkylation of 15 with benzyl bromoacetate
and subsequent hydrogenolysis under H2 and Pd/C generated the
carboxylic acid 16. In the end, the carboxylic acid 16 was coupled
with the intermediate 10 by HBTU-mediated amidation to afford
the desired photoaffinity probe 4a in good yield.
ing targets, adapting
a
synthetic strategy we previously
employed to generate homoisoflavanones.
On the basis of our SAR investigations in which the A and B-ring
modifications of homoisoflavonoids with trimethoxy and Boc-
phenylalanyl groups, respectively, had the most beneficial effects
on its activities and selectivities, trifunctional photoaffinity probes
were designed. We synthesized three kinds of photoaffinity probes
(3–5) by linking a trimethoxy derivative of cremastranone and
peptidylated active analog SH-11037 (2) to benzophenone and bio-
tin (Fig. 1) plus a control compound which lacks the homoisofla-
vanone moiety, for the future goal of detecting proteins that
interact with the homoisoflavonoid-labeled photoaffinity probes
in cell lysates. In particular, we modified the homoisoflavanone
scaffold at both C-7 and C-30 position with a benzophenone pho-
toreactive group for crosslinking and a biotin reporter group
through polyethylene glycol (PEG) as a linker. Thus, it was initially
considered to prepare a photoaffinity reagent linking on the phe-
nolic OH group of the C-30 position. It has been noted that the
selected substituents such as N-Boc phenylalanyl moiety, which
is added to the C-30 position of homoisoflavanone, are essential
for the improved antiangiogenic effect. However, because it is
uncertain where
a linker might impinge on function, we
anticipated that SH-11037 (2) could also be modified at the
para-position of the phenylalanyl group as well as C-7 without a
HO
O
O
5
3'
4'
MeO
HO
OH
6
A
B
We next investigated the synthesis of an amide-containing pho-
toaffinity probe, which might have increased stability compared to
the ester probe 4a. This amide compound 4b was synthesized from
homoisoflavanone 1727 having an amino group on the C30 position
to which Boc-Tyr(Bn)-OH was added by EDCI-mediated amidation
(Scheme 4). The resulting amide 18 was treated with H2 and Pd/C
to generate phenol 19. With phenol 19 in hand, the alkylation with
7
OMe
Cremastranone (1)
MeO
O
HNBoc
MeO
MeO
O
O
O
OMe
SH-11037 (2)
Design of photoaffinityprobes
MeO
MeO
O
O
NHBoc
O
3'
MeO
MeO
MeO
MeO
O
Bp
Bt
a-b
O
O
OMe
3
4
HO
OH
O
O
O
Bp
Bt
6
7
HNBoc
+
X
O
O
HN
c
H
O
Biotin-ONp
O
NH
N3
N
H
(X = O or NH)
O
O
OMe
O
3
S
8
H
MeO
HNBoc
O
d
MeO
O
O
O
HN
H
S
O
O
Bt
Bp
Bt
7
O
OMe
NH
N
N
N
H
5
O
O
3
2
N
H
O
R
biotin
9
(R = NHBoc)
10 (R = NH3+ CF3CO2
O
e
O
HN
-
H
)
Bp
O
O
NH
N
N
3
2 S
N
H
N
benzophenone
H
Scheme 1. Synthesis of benzophenone-linked biotin compound (10). Reagents and
conditions: (a) K2CO3, propargylic bromide, acetone, 82%; (b) DIAD, Boc-amino-
propanol, PPh3, THF, 70%; (c) 11-azido-3,6,9-trioxaundecan-1-amine, iPr2NEt, CH2-
Cl2, 49%; (d) CuSO4ꢀ5H2O, sodium ascorbate, t-BuOH/H2O, 40%; (e) TFA, CH2Cl2, 72%.
Figure 1. Structures of cremastranone (1), homoisoflavanone analogue SH-11037
(2) and photoaffinity probes (3–5). Bp: benzophenone, Bt: biotin.

B. Lee et al. / Bioorg. Med. Chem. Lett. 26 (2016) 4277–4281
4279
MeO
O
O
MeO
O
O
MeO
O
O
MeO
MeO
OH
MeO
MeO
O
CO2t-Bu
MeO
MeO
O
CO2H
a
b
OMe
OMe
OMe
11
12
13
O
MeO
O
O
O
O
O
HN
H
MeO
MeO
O
c
O
N
O
O
NH
N
N
N
H
H
2 S
3
N
H
OMe
3
Scheme 2. Synthesis of photoaffinity probe (3). Reagents and conditions: (a) t-butyl bromoacetate, K2CO3, acetone, reflux, 95%; (b) TFA, CH2Cl2, 70%; (c) 10, HBTU, iPr2NEt,
DMF, 30%.
Boc
O
OBn
MeO
MeO
O
MeO
O
O
NH
MeO
MeO
OH
MeO
MeO
a
b
O
O
O
OMe
OMe
11
15
14
Boc
O
OH
c-d
Boc
O
O
CO2H
NH
NH
MeO
O
O
NH
MeO
MeO
MeO
MeO
e
O
O
O
O
OMe
OMe
16
O
Boc
O
O
O
MeO
O
O
HN
H
MeO
MeO
O
N
O
O
NH
H
N
N
N
H
3
2 S
O
H
N
O
OMe
4a
Scheme 3. Synthesis of photoaffinity probe (4a). Reagents and conditions: (a) Boc-Tyr(Bn)-OH, EDCI, DMAP, rt, 94%; (b) H2, Pd/C, EtOAc, 88%; (c) K2CO3, benzyl bromoacetate,
acetone, reflux; (d) H2, Pd/C, EtOAc, 97% for 2 steps; (e) 10, HBTU, iPr2NEt, DMF, 67%.
Boc
OBn
MeO
MeO
O
MeO
O
O
NH
H
MeO
MeO
NH2
MeO
MeO
N
a
b
O
O
O
OMe
Boc
OMe
17
19
18
OH
Boc
O
CO2H
3
NH
NH
MeO
O
O
NH
H
H
MeO
MeO
N
MeO
MeO
N
c-d
e
O
O
O
O
OMe
OMe
20
O
Boc
O
O
MeO
O
O
H
3
HN
H
MeO
MeO
N
O
N
O
O
NH
N
N
N
H
H
2 S
3
O
N
H
O
OMe
4b
Scheme 4. Synthesis of photoaffinity probe (4b). Reagents and conditions: (a) Boc-Tyr(Bn)-OH, EDCI, DMAP, rt, 72%; (b) H2, Pd/C, EtOAc, 99%; (c) K2CO3, benzyl
4-bromobutanoate, acetone, reflux; (d) H2, Pd/C, EtOAc, 73% for 2 steps; (e) 10, HBTU, iPr2NEt, DMF, 86%.
benzyl 4-bromobutyrate followed by debenzylation provided the
carboxylic acid 20. Finally, the carboxylic acid 20 was coupled with
the intermediate 10 by HBTU-mediated amidation to afford the
desired photoaffinity probe 4b in good yield.
The linking site of the final photoaffinity probe was different
from that of the previous probes. Thus benzophenone-linked biotin
could be attached at the C-7 position of 2 using our synthetic
approach to cremastranone (Scheme 5). According to the proce-
dures reported previously,27 the known acetophenone 21 as a
starting material was converted to 7-hydroxy-5,6-dimethoxy-4-
chromanone 22 via 2 steps in good yield. The C-7 alkylation of
the compound 22 with benzyl 4-bromobutyrate provided the
compound 23. Subsequently, the aldol condensation of 23 with
isovanillin under acidic conditions gave the unstable
3-benzylidene-4-chromanone 24. EDCI-mediated esterification of
24 with Boc-Phe-OH and the catalytic hydrogenation reaction
using H2, Pd/C resulted in the removal of the benzyl group and
the saturation of the double bond to give the desired homoisofla-
vanone 25 having butyric acid at the C-7 position. The acid 25
was coupled with the intermediate 10 by HBTU-mediated amida-
tion to afford the final photoaffinity probe 5 in moderate yield.
It is obviously important that the synthesized probes retain
potency in biological assays. Therefore, we tested the anti-prolifer-
ative activity of the probes as well as intermediates on human reti-
nal microvascular endothelial cells (HRECs) and human umbilical
vein endothelial cells (HUVECs). We also measured the endothelial

4280
B. Lee et al. / Bioorg. Med. Chem. Lett. 26 (2016) 4277–4281
MeO
O
MeO
O
O
MeO
O
O
MeO
BnO
MeO
HO
MeO
O
a-b
c
d
OH
BnO2C
21
22
23
25
Boc
O
MeO
O
MeO
O
O
NH
MeO
O
OH
OMe
MeO
e-f
g
O
BnO2C
O
HO2C
O
OMe
24
Boc
MeO
O
NH
MeO
3O
O
S
H
H
N
N
H
H
N
N
N
3
O
HN
O
O
O
O
OMe
NH
O
O
O
5
O
Scheme 5. Synthesis of photoaffinity probe (5). Reagents and conditions: (a) (CH3O)2CHN(CH3)2, toluene, 80 °C, then c-HCl, 50 °C, 97%; (b) H2, Pd/C, MeOH, 99%; (c) K2CO3,
benzyl 4-bromobutanoate, acetone, reflux, 80%; (d) isovanillin, p-TsOH, benzene, reflux, 54%; (e) Boc-Phe-OH, EDCI, DMAP, rt; (f) H2, Pd/C, EtOAc, 70% for 2 steps; (g) 10,
HBTU, iPr2NEt, DMF, 36%.
Table 1
Growth inhibitory activity (GI50, lM) of photoaffinity probes and their intermediates on the proliferation of microvascular (HREC), macrovascular (HUVEC) and other ocular (92-1,
Y79 and ARPE19) cells
Compd
HREC
HUVEC
92-1
Y79
ARPE19
1a
0.22 (0.12–0.39)b
0.055 (0.032–0.094)
0.072 (0.00035–0.15)
0.21 (0.041–1.1)
42 (4.1–444)
44 (11–171)
2 (0.81–5.1)
0.51 (0.26–1.0)
0.047 (0.0062–0.36)
>100
0.38 (0.24–0.59)
0.75 (0.37–1.5)
>100
0.44 (0.15–1.3)
>100
>100
12 (2.7–55)
>100
48 (17–132)
>100
>100
>100
>100
>100
>100
>100
>100
9.8 (2.1–45)
12 (5.7–25)
>100
>100
>100
>100
>100
>100
>100
NDc
ND
>100
>100
>100
>100
ND
ND
>100
ND
2a
3
4a
4b
5
11a
14a
16
18a
20
0.012 (0.0018–0.084)
>100
22 (3.0–168)
>100
>100
0.39 (0.12–1.3)
>100
0.0079 (0.0018–0.035)
>100
a
b
c
The GI50 values reported in Ref. 27.
95% confidence interval shown in parentheses.
ND, not determined.
cell specificity of these compounds by measuring their effects on
the proliferation of non-endothelial ocular cell lines, Y79
(retinoblastoma cell line), 92-1 (uveal melanoma cell line) and
ARPE19 (retinal pigment epithelium cell line). The results are sum-
marized in Table 1. Among newly synthesized probes, 3 exhibited
excellent inhibitory activity with GI50 value of 72 nM against
HRECs in spite of the incorporation of the benzophenone photore-
active group and biotin reporter group. Probe 4a (GI50 = 210 nM)
also retained potency comparable to cremastranone (1) and
SH-11037 (2), but lost some specificity. In contrast, amide probe
4b and C-7 linking probe 5 had somewhat reduced activity on
HREC cell proliferation. Therefore, the probes 3 and 4a would be
very promising tools for target identification of antiangiogenic
homoisoflavonoid-binding proteins.
In conclusion, we have designed and synthesized novel
photoaffinity probes of antiangiogenic homoisoflavonoids with
photoreactive benzophenone and biotin. In order to search for
the photoaffinity probes which retain potency, the attachment of
benzophenone and biotin was on C30 and C-7 position of homoiso-
flavonoids. Among them, the probes 3 and 4a exhibited potent
anti-proliferative and endothelial-cell specific activity when com-
pared with the activity of the natural product cremastranone and
improved analogue SH-11037.
Korea (NRF) funded by the Ministry of Education (NRF-
2013R1A1A2007151) and the Korea Health Technology R&D Pro-
ject through the Korea Health Industry Development Institute
(KHIDI), funded by the Ministry of Health & Welfare (HI14C1135)
to S-YS; grants to TWC from the International Retinal Research
Foundation, Carl Marshall and Mildred Almen Reeves Foundation,
Ralph W. and Grace M. Showalter Research Trust, Retina Research
Foundation, NIH NEI (R01EY025641) and NIH NCATS
(KL2TR001106); and by an unrestricted grant from Research to
Prevent Blindness, Inc.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.07.
043. These data include MOL files and InChiKeys of the most
important compounds described in this article.
References and notes
1. Cong, F.; Cheung, A. K.; Huang, S. M. Annu. Rev. Pharmacol. Toxicol. 2012, 52, 57.
2. Futamura, Y.; Muroi, M.; Osada, H. Mol. Biosyst. 2013, 9, 897.
3. Heal, W. P.; Dang, T. H. T.; Tate, E. W. Chem. Soc. Rev. 2011, 40, 246.
4. Lomenick, B.; Olsen, R. W.; Huang, J. ACS Chem. Biol. 2011, 6, 34.
5. Park, J.; Koh, M.; Park, S. B. Mol. Biosyst. 2013, 9, 544.
6. Rix, U.; Superti-Furga, G. Nat. Chem. Biol. 2009, 5, 616.
7. Schenone, M.; Dancik, V.; Wagner, B. K.; Clemons, P. A. Nat. Chem. Biol. 2013, 9,
232.
Acknowledgments
8. Titov, D. V.; Liu, J. O. Bioorg. Med. Chem. 2012, 20, 1902.
9. Ziegler, S.; Pries, V.; Hedberg, C.; Waldmann, H. Angew. Chem., Int. Ed. 2013, 52,
2744.
This work was supported by a grant from the Basic Science
Research Program through the National Research Foundation of

B. Lee et al. / Bioorg. Med. Chem. Lett. 26 (2016) 4277–4281
24. Trippier, P. C. ChemMedChem 2013, 8, 190.
4281
10. Dorman, G.; Prestwich, G. D. Trends Biotechnol. 2000, 18, 64.
11. Hatanaka, Y.; Sadakane, Y. Curr. Top Med. Chem. 2002, 2, 271.
12. Lapinsky, D. J. Bioorg. Med. Chem. 2012, 20, 6237.
13. Li, G.; Liu, Y.; Yu, X.; Li, X. Bioconjugate Chem. 2014, 25, 1172.
14. Smith, E.; Collins, I. Future Med. Chem. 2015, 7, 159.
25. Basavarajappa, H. D.; Lee, B.; Fei, X.; Lim, D.; Callaghan, B.; Mund, J. A.; Case, J.;
Rajashekhar, G.; Seo, S.-Y.; Corson, T. W. PLoS One 2014, 9, e95694.
26. Lee, B.; Basavarajappa, H. D.; Sulaiman, R. S.; Fei, X.; Seo, S.-Y.; Corson, T. W.
Org. Biomol. Chem. 2014, 12, 7673.
15. Corson, T. W.; Cavga, H.; Aberle, N.; Crews, C. M. ChemBioChem 2011, 12, 1767.
16. Kotoku, N.; Nakata, C.; Kawachi, T.; Sato, T.; Guo, X. H.; Ito, A.; Sumii, Y.; Arai,
M.; Kobayashi, M. Bioorg. Med. Chem. 2014, 22, 2102.
27. Basavarajappa, H. D.; Lee, B.; Lee, H.; Sulaiman, R. S.; An, H.; Magana, C.;
Shadmand, M.; Vayl, A.; Rajashekhar, G.; Kim, E. Y.; Suh, Y. G.; Lee, K.; Seo, S.-Y.;
Corson, T. W. J. Med. Chem. 2015, 58, 5015.
17. Lee, K.; Ban, H. S.; Naik, R.; Hong, Y. S.; Son, S.; Kim, B. K.; Xia, Y.; Song, K. B.;
Lee, H. S.; Won, M. Angew. Chem., Int. Ed. 2013, 52, 10286.
18. Mizuhara, T.; Oishi, S.; Ohno, H.; Shimura, K.; Matsuoka, M.; Fujii, N. Bioorg.
Med. Chem. 2013, 21, 2079.
19. Naik, R.; Won, M.; Ban, H. S.; Bhattarai, D.; Xu, X.; Eo, Y.; Hong, Y. S.; Singh, S.;
Choi, Y.; Ahn, H. C.; Lee, K. J. Med. Chem. 2014, 57, 9522.
28. Shim, J. S.; Kim, J. H.; Lee, J.; Kim, S. N.; Kwon, H. J. Planta Med. 2004, 70, 171.
29. Kim, J. H.; Kim, K. H.; Yu, Y. S.; Kim, Y. M.; Kim, K. W.; Kwon, H. J. Biochem.
Biophys. Res. Commun. 2007, 362, 848.
30. du Toit, K.; Drewes, S. E.; Bodenstein, J. Nat. Prod. Res. 2010, 24, 457.
31. Hur, S.; Lee, Y. S.; Yoo, H.; Yang, J. H.; Kim, T. Y. J. Dermatol. Sci. 2010, 59, 163.
32. Lee, Y. S.; Hur, S.; Kim, T. Y. Allergy 2014, 69, 453.
20. Park, J.; Oh, S.; Park, S. B. Angew. Chem., Int. Ed. 2012, 51, 5447.
21. Shi, H.; Zhang, C. J.; Chen, G. Y.; Yao, S. Q. J. Am. Chem. Soc. 2012, 134, 3001.
22. Suzuki, T.; Okamura, T.; Tomohiro, T.; Iwabuchi, Y.; Kanoh, N. Bioconjugate
Chem. 2015, 26, 389.
23. Zhang, L.; Zhang, Y.; Dong, J.; Liu, J.; Zhang, L.; Sun, H. Bioorg. Med. Chem. Lett.
2012, 22, 1036.
33. Sulaiman, R. S.; Merrigan, S.; Quigley, J.; Qi, X.; Lee, B.; Boulton, M. E.; Kennedy,
B.; Seo, S.-Y.; Corson, T. W. Sci. Rep. 2016, 6, 25509.
34. La Clair, J. J. Nat. Prod. Rep. 2010, 27, 969.
35. Sulaiman, R. S.; Basavarajappa, H. D.; Corson, T. W. Exp. Eye Res. 2014, 129, 161.
36. Tae, H. S.; Hines, J.; Schneekloth, A. R.; Crews, C. M. Org. Lett. 2010, 12, 4308.
37. McKay, C. S.; Finn, M. G. Chem. Biol. 2014, 21, 1075.