Synthesis, structure and antimicrobial evaluation of a new gossypol triazole conjugates functionalized with aliphatic chains and benzyloxy groups

Article abstract of DOI:10.1016/j.bmcl.2016.07.033

Synthetic limitations in the copper-catalyzed azide alkyne cycloaddition (CuAAC) on gossypol's skeleton functionalized with alkyne (2) or azide (3) groups have been indicated. Modified approach to the synthesis of new gossypol–triazole conjugates yielded

Full text of DOI:10.1016/j.bmcl.2016.07.033

Bioorganic & Medicinal Chemistry Letters 26 (2016) 4322–4326
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, structure and antimicrobial evaluation of a new
gossypol triazole conjugates functionalized with aliphatic chains
and benzyloxy groups
Krystian Pyta a, , Marietta Blecha , Anna Janas , Katarzyna Klich , Paulina Pecyna , Marzena Gajecka b,c,
⇑
a
a
a
b
a
Piotr Przybylski
a
Faculty of Chemistry, A. Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland
Department of Genetics and Pharmaceutical Microbiology, Poznan University of Medical Sciences, Swiecickiego 4, 60-781 Poznan, Poland
Institute of Human Genetics, Polish Academy of Science, Strzeszynska 32, 60-479 Poznan, Poland
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthetic limitations in the copper-catalyzed azide alkyne cycloaddition (CuAAC) on gossypol’s skeleton
functionalized with alkyne (2) or azide (3) groups have been indicated. Modified approach to the synthe-
sis of new gossypol–triazole conjugates yielded new compounds (24–31) being potential fungicides.
Spectroscopic studies of triazole conjugates 24–31 have revealed their structures in solution, i.e., the
Received 18 February 2016
Revised 13 July 2016
Accepted 15 July 2016
Available online 17 July 2016
presence of enamine–enamine tautomeric forms and p–p stacking intramolecular interactions between
triazole arms. Biological evaluation of the new gossypol–triazole conjugates revealed the potency of 30
and 31 derivatives, having triazole–benzyloxy moieties, comparable with that of miconazole against
Fusarium oxysporum. The results of HPLC evaluation of ergosterol content in different fungi strains upon
treatment of gossypol and its derivatives enabled to propose a mechanism of antifungal activity of these
compounds.
Keywords:
Gossypol
1
,2,3-Triazoles
Antifungal
Mechanism of action
p
–
p
stacking
Ó 2016 Elsevier Ltd. All rights reserved.
Spectroscopy
Gossypol (Scheme 1), is a yellow pigment, present in various
structurally diverse triazole blocks to various biomolecules. The
use of 1,3-Dipolar Huisgen cycloaddition has enabled to synthesize
a number of new bioactive compounds and to modify agents of
parts of cotton plants acting as plant’s defense system against
pathogenic fungi and insects.1 This natural bisesquiterpene has
drawn the attention of many scientists because of its wide range
1
1
medical interest.
2
3
of biological activities including contraceptive, anticancer, antivi-
In this work we used the copper-catalyzed dipolar cycloaddi-
tion to modify gossypol molecule with triazole moieties because
triazole derivatives are well-known antifungal agents on their
4
5
ral or antimicrobial. Unfortunately, the use of gossypol in medi-
cal therapy is limited because of its side effects. A convenient way
6
1
2
to obtain less toxic compounds, with no compromise to antimicro-
own. Firstly, in our synthetic approach gossypol was subjected
to reactions with primary amines containing azide or alkyne func-
tions. These reactions in ethanol gave with very good yields (ꢀ85%)
symmetrically substituted Schiff base products 2 and 3 (Scheme 2).
Multiple attempts at direct conversion of compounds 2 and 3 with
respective alkyne or azide reagents into triazole derivatives have
failed. No expected products in the reaction mixture, even after
7
bial activity is to convert gossypol into its Schiff bases, hydra-
7
a,c,f,h
7a
zones
or oximes.
In the 1960s a new cycloaddition reaction between alkyne and
+
azide in the presence of Cu cation leading to 1,2,3-triazoles was
8
discovered. The Meldal variant of cycloaddition with the use of
+
Cu -catalyst with a classical antioxidant system as, e.g., sodium
+
ascorbate, called the copper(I)-catalyzed azide–alkyne cycloaddi-
long reaction time (48 h) or increased amount of the Cu -catalyst
9
+
tion (CuAAC), is one of the most convenient and efficient exam-
(2:1 mixture of Cu with 2 or 3), could be explained by fact that
ples of ‘click chemistry’. This synthetic strategy of organic
chemistry was fully described by Kolb, Finn and Sharpless in a
landmark review published in 2001.10 Applications of ‘click
chemistry’ are wide-ranging as they allow attachment of many
both amines and acidic phenolic groups [especially at C(1) and C
0
(1 )] within the structures of 2 and 3 took part in coordination of
+
Cu -catalyst in the transition state of dipolar cycloaddition reac-
tion. Therefore, we changed our strategy and prepared the triazole
blocks separately (Scheme 2). First, we converted phthalimide N-
alkyl bromides (compounds 4 and 5) into respective phthalimide
N-alkyl azides (derivatives 6 and 7). These derivatives were further
⇑
Corresponding author. Tel.: +48 61 8291693; fax: +48 61 829 1505.
E-mail address: k.pyta@amu.edu.pl (K. Pyta).
http://dx.doi.org/10.1016/j.bmcl.2016.07.033
960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
0

K. Pyta et al. / Bioorg. Med. Chem. Lett. 26 (2016) 4322–4326
4323
modified into new triazole products 8–15 via dipolar cycloaddition
using various alkynes in the presence of CuOAc as a catalyst
Gossypol
(
Scheme 2). Removal of phthalimide protection group in the
O
O
O
H
11 1OH
H
time-consuming reaction with hydrazine (72 h) yielded various
new amine–triazole intermediates 16–23 with a moderate or good
yields (60–75%). Further condensation of the obtained intermedi-
ates, containing triazoles and different length alkyl chains or ben-
zyloxy groups, with gossypol molecule has given new Schiff base
products 24–31 at good yields (ꢀ80%). All synthesized products
O
7
H
OH
H
O 6
O
aldehyde-aldehyde
(2–31) were characterized in detail by ESI MS, HR-MALDI-TOF
and 1D and 2D NMR methods (Supplementary data). In view of
earlier reports describing the presence of different tautomeric
forms within gossypol as well as within gossypol derivatives it
was necessary to determine the structures of newly obtained
H
O
O
H
H
O
1
1
1OH
O
11
O 7
7
1
2
H
2
H
O
6
O
6
1
chemical entities 2, 3 and 24–31. In all H NMR spectra of 24–31
H
derivatives, the characteristic doublets at about 9.5 ppm appeared
ketol-ketol
lactol-lactol
1
13
(Fig. 1S). H– C HMBC correlation (Fig. 2S) revealed that these sig-
nals should be assigned to H(11) protons. Thus, taking into regard
the fact that H(11) signal is a doublet, it was clear that all synthe-
sized derivatives 2, 3 and 24–31 were present as symmetric enam-
Gossypol Schiff bases
R
N
R
ine–enamine tautomers. Furthermore, C(7) carbon atom signals
N
13
H
O
11
recorded in the
C NMR spectra were in the range 173.0–
H
11 1OH
1OH
O
7
7
1
73.6 ppm (Supplementary data), characteristic of quinone like
2
2
1
3
H
H
ketone carbonyl groups as previously reported. Structures of
compounds 2, 3 and 24–31 in solution are stabilized by the pres-
ence of collective intramolecular H-bond systems, as indicated by
the chemical shifts observed for O(1)H, O(6)H and NH protons in
O
6
O
6
imine-imine
enamine-enamine
Scheme 1. Structure and tautomeric forms of gossypol and its Schiff bases.
N
N
N
H
N
R
1
1
OH
1
O
7
N
3
R
HN
2
11 1OH
O
7
NH
2
HO
6
2
O
1
1
H
OH
tO
2
HO
6
E
HO 7
1
2
N
HO 6
H N
N
N
2
H
N
3
N
R
11
OH
E
tO
1
n
H
N
3
O
7
1
2
R
HN
11
1OH
HO
6
O
7
2
3
HO
6
2
2
2
2
2
2
3
3
4
n=2 R= ethyl
n=3 R= ethyl
5
6
7
8
9
0
1
n=2 R= n-propyl
n=3 R= n-propyl
n=2 R= n-butyl
n=3 R= n-butyl
n=2 R= benzyloxy
n=3 R= benzyloxy
R
R
O
O
11
1O H
R
O
2 4
N H
N
3
HO
HO
7
N
CuOAc/
ascorbic acid
N
N
n
N
N
2
N
N
n
2
H N
N
O
n
6
6
7
n=2
n=3
O
8
n=2 R= ethyl
16 n=2 R= ethyl
1
9
1
n=3 R= ethyl
17 n=3 R= ethyl
0
n=2 R= n-propyl
18 n=2 R= n-propyl
19 n=3 R= n-propyl
20 n=2 R= n-butyl
21 n=3 R= n-butyl
22 n=2 R= benzyloxy
23 n=3 R= benzyloxy
NaN
3
DMF
O
11 n=3 R= n-propyl
12 n=2 R= n-butyl
1
3 n=3 R= n-butyl
Br
n
14 n=2 R= benzyloxy
n=3 R= benzyloxy
N
15
O
4
5
n=2
n=3
Scheme 2. Synthetic approach to obtain novel Schiff bases of gossypol containing triazole ring.

4
324
K. Pyta et al. / Bioorg. Med. Chem. Lett. 26 (2016) 4322–4326
Figure 1. Energetically favorable structures of enamine tautomers of new gossypol derivatives, being in agreement with the spectroscopic data: (a) 29 (
D
H
f
° =
ꢁ
1
ꢁ1
ꢁ1
ꢁ
397.6 kJ mol and
x
C1–C2–C2
0
–C1
0
= 103°); (b) 31 (
D
H
f
° = ꢁ489.1 kJ mol and
x
C1–C2–C2
0
–C1
0
= 96°), (c) 30 (
D
H
f
° = ꢁ456.7 kJ mol and
x
C1–C2–C2
0
–C1
0
= 100°), calculated by
DFT method—DGauss using the B88-LYP GGA energy functional with the DZVP basis sets.
Table 1
Antifungal evaluation and logP values of 1 and 24, 26–31. MIC values are given in
lg/mL
Compound
Fungus strain
*
Aspergillus
brasiliensis
ATCC 16404
Aspergillus
fumigatus
ATCC 204305
Trichophyton
mentagrophytes
ATCC 9533
Rhizopus
stolonifer
ATCC
Fusarium
acuminatum
ATCC 46651
Fusarium oxysporum f. Fusarium oxysporum f. sp. logPcalc
sp. betae
lycopersici
56227b
1
2
2
2
2
2
2
3
3
256
256
—
256
256
256
256
128
—
256
256
—
256
256
256
256
256
—
128
256
—
256
256
256
256
256
—
128
128
—
128
128
128
128
64
128
256
—
256
256
256
256
128
—
32
64
64
64
64
64
64
16
16
16
32
64
64
64
64
64
64
16
16
16
6.68
7.30
7.84
8.35
8.67
8.89
9.09
8.25
8.60
5.72
4
5
6
7
8
9
0
1
—
—
Miconazole
—
—
—
—
*
logPcalc—values for 1 and 24–31 derivatives calculated by Molinspiration property engine v2013.0, http://www.molinspiration.com/.
0
0
5
.49–13.44 ppm’s range (Fig. 1S, Supplementary data). The DFT
calculated structures of selected gossypol derivatives revealed,
besides H-bond stabilization, the possibility of the stacking
decrease the value of
usually in the range 70–106°,
x
dihedral angle C(1)–C(2)–C(2 )–C(1 ) being
7
f,14
simultaneously increasing
value. The DFT calculated centroid–centroid distances between
f
DH °
p–p
interactions between the introduced triazole arms for 30 and 31
derivatives (Fig. 1). For the calculated structure of 29 its triazole
rings are too far away from each other to contribute to the effective
triazole and phenyl rings within 31 were of about 5 Å, whereas
within 30 this distance was about 3.7 Å, suggesting stronger
p–p
interactions in its structure (Fig. 1b). It is interesting to note that
1
p–p
stacking phenomenon (Fig. 1a). As concluded from our DFT
comparison of 30 and 31 H NMR spectra in the 4.1–5 ppm range
studies, a closer arrangement of triazoles within 29 would force
a significant twist of the bi-naphthalene moiety and would
(Fig. 1S) revealed significant differences in multiplicity of proton
signals assigned to methylene bridges, next to the ether linkage

K. Pyta et al. / Bioorg. Med. Chem. Lett. 26 (2016) 4322–4326
4325
between triazole and phenyl rings confirming in this way the
structures suggested by DFT calculations (Fig. 1c).
The activities of new gossypol derivatives 24–31 were tested
against selected fungi (Table 1) and some bacteria strains
acuminatum. In the latter case (F. acuminatum) gossypol was as
active as compound 30. The most interesting results were obtained
for Fusarium spp. strains isolated from plants (cabbage and toma-
toes). Although MIC determined for gossypol in this case was equal
(
Table 1S). The MIC values for the tested compounds determined
against bacteria strains revealed that only parent compound 1–
gossypol showed MIC value of 16 g/mL almost for all tested
to 32
surprisingly compounds 30 and 31 were the most active
(MICs = 16 g/mL). Furthermore, the level of activity of the deriva-
lg/mL which is lower than the values determined for 24–29,
l
l
Gram-positive strains (Table 1S). From among the studied deriva-
tives, only compound 24, having the shortest alkyl chains at tria-
zole arms, showed low antibacterial activity against
Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus
tives containing triazole–benzyloxy moieties (30 and 31) was com-
parable with that of miconazole. Taking all these tests into account,
new derivatives of gossypol having triazole–benzyloxy moieties
(compounds 30 and 31) are more promising potential antifungal
agents for agriculture than those having introduced triazole rings,
functionalized by simple alkyl chains of different lengths (com-
pounds 24–29).
pneumoniae strains (MIC = 256
explained by the lowest lipophilicity of all studied compounds
Table 1). Antifungal tests of 24–31 were performed on well-
known plant pathogens which evoke serious problems in agricul-
lg/mL) which probably could be
(
In view of the obtained antifungal data we propose the mecha-
nism of action of gossypol and its active derivatives. It is known
from the literature that the transformation of steroids in human
organism, e.g., the conversion of cortisone into cortisol via inhibi-
tion of 11-beta-hydroxysteroid dehydrogenase of type 1/
1
5
ture (Table 1). Microbiological tests against Aspergillus brasiliensis
showed that compounds 24–29 as well as gossypol were poorly
active. Introduction of triazole–benzyloxy moiety to gossypol
skeleton improved antifungal activity of compound 30, in contrast
to its antibacterial potency. Aspergillus fumigatus and Trichophyton
mentagrophytes responsible for transmission of skin diseases from
species to species were found to be insensitive to nearly all com-
1
6
HSD11B1/by gossypol evokes hypokalemia. On the other hand,
sterols metabolism processes in fungi are often the target of many
antifungal agents, especially those having azole moieties in the
1
7
pounds of this group with MIC values equal 256
l
g/mL (for 24–
structure as, e.g., fluconazole. Taking this information into regard
we anticipated that mechanism of antifungal activity of 1 and its
triazole-containing derivatives may be concerned with biosynthe-
sis inhibition of ergosterol, whose presence is crucial to control the
permeability and fluidity of fungi plasma membranes/a similar
3
0) or 256 and 128 g/mL (for 1), respectively. Compound 30
l
showed
MIC = 64
a
l
moderate activity against Rhizopus stolonifer
g/mL), even higher than that of gossypol and its deriva-
(
tives 24–29. The synthesized compounds 24–31 showed the high-
est activity against Fusarium spp. strains, with the exception of F.
1
8
function as cholesterol in animals/. The limited production of
+
NADPH, O
2
NADP ,H
2
O
a
CH OH
2
HO
HO
NADPH, O
2
Lanosterol
b
+
NADP , H
2
O
+
NADP , H
2
O
NADPH, O
HO
2
c
CHO
HO
HO
Ergosterol
Scheme 3. Key steps of ergosterol biosynthesis in fungi catalyzed by lanosterol 14-
a-demethylase (ERG11)—steps a, b, c.
Figure 2. Amount of ergosterol [mg/1 g of dry mass of fungi], produced upon treatment of 1 or 30 and determined via HPLC method from the area of the retention peaks at Rt/
ergosterol/ = 8.26 min. [mobile phase: 5:95 H O/CH OH, flow 1 mL/min, kmax = 282 nm] after different incubation times of the following fungi strains: (a) R. stolonifer, (b) F.
2 3
acuminatum.

4
326
K. Pyta et al. / Bioorg. Med. Chem. Lett. 26 (2016) 4322–4326
ergosterol in plants and fungi is often concerned with inhibition of
Med. Chem. 1995, 38, 2427; (c) Pacheco, L. B.; Castro-Garza, J.; Perez-Eguia, E.;
Zepeda-Herrera, H.; Chico-Mijares, K.; Carranza-Rosales, M. P.; Said-Fernandez,
S.; Gonzalez-Garza, M. T. Pharm. Sci. 1996, 2, 333; (d) Yang, J.; Chen, G.; Li, L. L.;
Pan, W.; Zhang, F.; Yang, J.; Wu, S.; Tien, P. Bioorg. Med. Chem. Lett. 2013, 23,
2619.
(a) Mace, M. E.; Stipanovic, R. D.; Bell, A. A. Nat. Toxins 1993, 1, 294; (b)
Abraham, K. J.; Pierce, M. L.; Essenberg, M. Phytochemistry 1999, 52, 829.
(a) Kovaci, P. Curr. Med. Chem. 2003, 10, 2711; (b) Salem, C. B.; Slim, R.; Elouni,
B.; Hmouda, H.; Bouraoui, K. Drug Safety 2007, 30, 727.
19
ERG11 by antifungal agents (Scheme 3). To check this hypothesis
we applied a HPLC method for analytical determination of ergos-
terol amount in derivatized fungi material (Fig. 2—standard
strains), which was further applied to study the influence of 1
and 30 on the concentration level of this important steroidal
metabolite (Fig. 2, Scheme 3). Analysis of data concerned R. stoloni-
fer and F. acuminatum strains without added compounds at differ-
ent time of incubation, indicated the relatively constant level at
5
6
7
.
.
.
(a) Li, L.; Li, Z.; Wang, K.; Liu, Y.; Li, Y.; Wang, Q. Bioorg. Med. Chem. 2016, 24,
474; (b) Li, L.; Li, Z.; Wang, K.; Zhao, S.; Feng, J.; Li, J.; Yang, P.; Liu, Y.; Wang, L.;
Li, Y.; Shang, H.; Wang, Q. J. Agric. Food Chem. 2014, 62, 11080; (c) Przybylski, P.;
Pyta, K.; Remlein-Starosta, D.; Schroeder, G.; Brzezinski, B.; Bartl, F. Bioorg. Med.
Chem. Lett. 2009, 19, 1996; (d) Tukfatullina, I. I.; Tilyabaev, K. Z.;
Mamadrakhimov, A.; Salakhutdinov, B. A.; Kamaev, F. G.; Yuldashev, A. M.;
Dowd, M. K.; Talipov, S. A.; Ibragimov, B. T.; Aripov, T. F. Chem. Nat. Compd.
2008, 44, 440; (e) Fish, R. G.; Groundwater, P. W.; Gwynfor, M. J. J. Tetrahedron:
Asymmetry 1995, 6, 873; (f) Przybylski, P.; Pyta, K.; Stefanska, J.; Ratajczak-
Sitarz, M.; Katrusiak, A.; Huczynski, A.; Brzezinski, B. Eur. J. Med. Chem. 2009,
ꢀ
2 mg/1 g or at ꢀ3 mg/1 g of this steroid per analyzed dry fungi
mass, respectively (Fig. 2).
Analytical tests for R. stolonifer exhibited a significantly
decreased content level of ergosterol, in the presence of both refer-
ence compound 1 and derivative 30 in three independently per-
formed experiments. However, for tests with compound 30 the
concentration of produced ergosterol was lower (ꢀ1 mg/1 g) than
in tests with 1, which is in line with the earlier determined MIC
R. stolonifer values, lower for 30 than that of 1 (Table 1). In turn,
the tests of ergosterol concentration in F. acuminatum upon addi-
tion of 1 and 30 demonstrated in both cases comparably decreased
content of this metabolite with the time. Nevertheless, irrespective
of the analyzed fungi strain, the content of ergosterol found in ana-
lyzed material after 96 h of incubation was significantly reduced,
indicating the mechanism of antifungal activity of this group of
gossypol derivatives. Unfortunately, at this stage of our studies
we were unable to point out in detail the enzyme inhibited by
gossypol derivatives.
4
4, 4393; (g) Dodou, K.; Anderson, R. J.; Lough, W. J.; Small, D. A. P.; Shelley, M.
D.; Groundwater, P. W. Bioorg. Med. Chem. 2005, 13, 4228; (h) Kenar, J. J. Am. Oil
Chem. Soc. 2006, 83, 269.
Huisgen, R. Proc. Chem. Soc. 1961, 357. October.
Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
0. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004.
11. (a) Kumar, P.; Sharma, P. K.; Hansen, J.; Jedinak, L.; Reslow-Jacobsen, C.;
Hornum, M.; Nielsen, P. Bioorg. Med. Chem. 2016, 24, 742; (b) Hu, Q.; Kong, J.; Li,
Y.; Zhang, X. Talanta 2016, 147, 516; (c) Mohamed, Z. H.; El-Koussi, N. A.;
Mahfouz, N. M.; Youssef, A. F.; Abdel Jaleel, G. A.; Shouman, S. A. Eur. J. Med.
Chem. 2015, 97, 75; (d) Pyta, K.; Klich, K.; Domagalska, J.; Przybylski, P. Eur. J.
Med. Chem. 2014, 84, 651; (e) Tamura, K.; Kumagai, N.; Shibasaki, M. J. Org.
Chem. 2014, 79, 3272.
2. (a) He, J.-B.; He, H.-F.; Zhao, L.-L.; Zhang, L.; You, G.-Y.; Feng, L.-L.; Wan, J.; He,
H.-W. Bioorg. Med. Chem. 2015, 23, 1395; (b) Zhang, Z.; Jiang, W.; Jian, Q.; Song,
W.; Zheng, Z.; Wang, D.; Liu, X. Food Chem. 2015, 168, 396; (c) Wang, Z.-J.; Gao,
Y.; Hou, Y.-L.; Zhang, C.; Yu, S.-J.; Bian, Q.; Li, Z.-M.; Zhao, W.-G. Eur. J. Med.
Chem. 2014, 86, 87.
8
9
1
.
.
1
Acknowledgement
13. (a) Salas, C.; Armstrong, V.; Lopez, C.; Tapia, R. A. Magn. Res. Chem. 2008, 46,
91; (b) Rozwadowski, Z. J. Mol. Struct. 2005, 753, 127; (c) Gunatilaka, A. A. L.;
1
Fernando, H. C.; Kikuchi, T.; Tezuka, Y. Magn. Res. Chem. 1989, 27, 803.
4. (a) Przybylski, P.; Pyta, K.; Ratajczak-Sitarz, M.; Katrusiak, A.; Brzezinski, B. Pol.
J. Chem. 2009, 83, 747; (b) Przybylski, P.; Pyta, K.; Ratajczak-Sitarz, M.;
Katrusiak, A.; Brzezinski, B. Struct. Chem. 2008, 19, 983; (c) Przybylski, P.; Pyta,
K.; Wicher, B.; Gdaniec, M.; Brzezinski, B. J. Mol. Struct. 2008, 889, 332; (d)
Dowd, M. K.; Stevens, E. D. J. Chem. Crystallogr. 2007, 37, 765; (e) Dowd, M. K.;
Stevens, E. D. J. Incl. Phenom. 2005, 51, 65; (f) Dowd, M. K.; Stevens, E. D. J. Chem.
Crystallogr. 2004, 34, 559; (g) Dowd, M. K.; Stevens, E. D. Acta Crystallogr., C
Financial assistance of the Polish Ministry of Science—Grant No.
366/IP3/2013/72 is gratefully acknowledged by K.P., M.B., A.J., K.
K. and P.P.
1
0
Supplementary data
2
003, 59, o397; (h) Przybylski, P.; Ratajczak-Sitarz, M.; Katrusiak, A.; Schilf, W.;
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.07.
Wojciechowski, G.; Brzezinski, B. J. Mol. Struct. 2003, 655, 293; (i) Gdaniec, M.;
Ibragimov, B. T.; Dabaev, B. N. J. Incl. Phenom. 1990, 8, 423; (j) Gdaniec, M.;
Ibragimov, B. T.; Dabaev, B. N. Acta Crystallogr.,
Honkeldieva, M. T.; Talipov, S. A.; Kunafiev, R.; Ibragimov, B. T. Acta
Crystallogr. 2015, E71, 1421.
C 1990, 46, 810; (k)
0
33.
References and notes
15. (a) Fravel, D.; Olivain, C.; Alabouvette, C. New Phytol. 2003, 157, 493; (b)
Saravanakumar, K.; Yu, C.; Dou, K.; Wang, M.; Li, Y.; Chen, J. Biol. Control 2016,
94, 37.
1
.
(a) Baksha, R.; Mavlanov, G. T.; Nasirova, G. B.; Djataev, S. A. J. Biol. Sci. 2006, 6,
1
126; (b) Wang, X.; Howell, C. P.; Chen, F.; Yin, J.; Jiang, Y. Adv. Food Nutr. Res.
16. (a) Lepesheva, G. I.; Hargrove, T. Y.; Anderson, S.; Kleshchenko, Y.; Furtak, V.;
Wawrzak, Z.; Villalta, F.; Waterman, M. R. J. Biol. Chem. 2010, 285, 25582; (b)
Lepesheva, G. I.; Park, H.-W.; Hargrove, T. Y.; Vanhollebeke, B.; Wawrzak, Z.;
Harp, J. M.; Sundaramoorthy, M.; Nes, W. D.; Pays, E.; Chaudhuri, M.; Villalta,
F.; Waterman, M. R. J. Biol. Chem. 2010, 285, 1773.
17. (a) Nett, J. E.; Andes, D. R. Infect. Dis. Clin. N. Am. 2016, 30, 51; (b) Omeara, T. R.;
Veri, A. O.; Ketela, T.; Jiang, B.; Roemer, T.; Cowen, L. E. Nat. Commun. 2015, 6,
6741.
2
009, 58, 21; (c) Przybylski, P.; Huczynski, A.; Pyta, K.; Brzezinski, B.; Bartl, F.
Curr. Org. Chem. 2009, 13, 124; (d) Tian, X.; Ruan, J.; Huang, J.; Fang, X.; Mao, Y.;
Wang, L.; Chen, X.; Yang, C. Sci. China Life Sci. 2016, 59, 122.
Dodou, K. Exp. Opin. Invest. New Drug 2005, 14, 1419.
2
3
.
.
(a) Hu, Y.-F.; Chang, C.-J. G.; Brueggemeier, R. W.; Lin, Y. C. Cancer Lett. 1994, 87,
1
7; (b) Coyle, T.; Levante, S.; Shetler, M.; Winfield, J. J. Neuro-Oncol. 1994, 19,
2
5; (c) Ye, W.; Chang, H.-L.; Wang, L.-S.; Huang, Y.-W.; Shu, S.; Dowd, M. K.;
Wan, P. J.; Sugimoto, Y.; Lin, Y. C. Anticancer Res. 2007, 27, 107.
18. Bui, T. T.; Suga, K.; Umakoshi, H. Langmuir 2016, 32, 6176.
19. Liu, J.-Y.; Shi, C.; Wang, Y.; Li, W.-J.; Zhao, Y.; Xiang, M.-J. Res. Microbiol. 2016,
166, 153.
4
.
(a) Lin, T.-S.; Schinazi, R. F.; Zhu, J.; Birks, E.; Carbone, R.; Si, Y.; Wu, K.; Huang,
L.; Prusoff, W. H. Biochem. Pharmacol. 1993, 46, 251; (b) Royer, R. E.; Deck, L. M.;
Vander, Jagt T. J.; Martinez, F. J.; Mills, R. G.; Young, S. A.; Vander, Jagt D. L. J.