Oxa/thiazole-tetrahydropyran triazole-linked hybrids with selective antiproliferative activity against human tumour cells

Article abstract of DOI:10.1039/c8nj02388c

Inspired by diverse marine bioactive compounds, the principle of molecular hybridization was applied to produce a series of new compounds combining diverse heterocyclic systems (oxa/thiazoles and tetrahydropyrans) via a triazole ring, attempting to increase the activity of individual building blocks. These new compounds exhibit a highly interesting antiproliferative activity against different human tumour cells and good selectivity when compared to normal cells. The formation of reactive oxygen species and the interaction with P-gp were also evaluated for the lead compounds.

Full text of DOI:10.1039/c8nj02388c

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Oxa/thiazole-tetrahydropyran triazole-linked
hybrids with selective antiproliferative activity
Cite this:DOI: 10.1039/c8nj02388c
against human tumour cells†
a
a
b
´
Marıa de los Angeles Fernandez, Irene Lagunes,
´
´
Guillermo Valdomir,
Juan I. Padron,bc Vıctor S. Martın,b Jose M. Padron *b and Danilo Davyt
a
*
´
´
´
´
´
Inspired by diverse marine bioactive compounds, the principle of molecular hybridization was applied to
produce a series of new compounds combining diverse heterocyclic systems (oxa/thiazoles and
tetrahydropyrans) via a triazole ring, attempting to increase the activity of individual building blocks.
These new compounds exhibit a highly interesting antiproliferative activity against different human
tumour cells and good selectivity when compared to normal cells. The formation of reactive oxygen
species and the interaction with P-gp were also evaluated for the lead compounds.
Received 14th May 2018,
Accepted 10th July 2018
DOI: 10.1039/c8nj02388c
rsc.li/njc
Introduction
In the literature of marine metabolites, there are a large
number of products that include heterocycles such as oxazoles
and thiazoles that exhibit powerful bioactivities.1 In particular,
oxa/thiazole marine metabolites with potent cytotoxic activity
are usually large molecules and have complex structures such
as enigmazole A (1)2 and phorboxazole A (2)3 (Fig. 1). However,
there are also small molecule metabolites containing these
heterocycles with relevant bioactivities such as the potent
anticancer compound streptochlorin (3)4 and the neuroactive
thiazoline pulicatin D (4).5 Moreover, there are reports of
several small compounds containing oxa/thiazoles with inter-
esting antiproliferative activities.6 Due to our interest in tetra-
hydropyran rings,7–9 the metabolites enigmazole A (1) and
phorboxazole A (2) draw our attention.
In the search for new bioactive products, the use of the
molecular hybridization concept was envisioned to produce
novel entities. Molecular hybridization is a powerful approach
for obtaining original lead structures valuable in the field
of drug discovery.10 This strategy has been used extensively
in the preparation of new antimalarial,11 antibacterial12 and
Fig. 1 (A) Structures of bioactive natural products containing oxazole and
tetrahydropyran rings. (B) Structures of small bioactive natural products
containing oxazole or thiazole rings.
a
´
´
´
Departamento de Quımica Organica, Facultad de Quımica, UdelaR, Av General
Flores 2124, 11800 Montevideo, Uruguay. E-mail: ddavyt@fq.edu.uy
b
c
´
´
Instituto Universitario de Bio-Organica ‘‘Antonio Gonzalez’’ (IUBO-AG), Centro de
´
Investigaciones Biomedicas de Canarias (CIBICAN), Universidad de La Laguna,
anticancer agents.13 Compounds obtained in this way show
improved activity, selectivity or reduced side effects. Remark-
ably, it has also been shown that it is possible to obtain active
hybrid drugs linking substructures or small fragments of
bioactive compounds.14,15
´
´
C/Astrofısico Francisco Sanchez 2, 38206 La Laguna, Spain.
E-mail: jmpadron@ull.es
´
´
Instituto de Productos Naturales y Agrobiologıa, CSIC, C/Astrofısico Francisco
´
Sanchez 3, 38206 La Laguna, Spain
† Electronic supplementary information (ESI) available: Experimental procedures
and compound characterization data. See DOI: 10.1039/c8nj02388c
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Scheme 1 Synthesis of an oxa/thiazole block.18
Fig. 2 Retrosynthetic analysis of hybrid compounds. * Relative stereo-
chemistry.
shown in Scheme 2. At this stage, we define the substituent R2 of
the final compounds. Then, allylic alcohols 7a–d were reacted with
methyl propiolate using 1,4-diazabicyclo[2.2.2]octane (DABCO) as
catalyst to produce the corresponding enol ethers,20 followed by
the in situ addition of TFA to promote the Prins cyclization in a
sequential reaction.
Inspired by this background, we decided to explore hybrids
that include oxa/thiazole scaffolds coupled with fragments
containing tetrahydropyran rings. Herein, we described the
design, preparation and preliminary biological evaluation of
a small and focused library of triazole-linked oxa/thiazole–
tetrahydropyran hybrids.
The resulting intermediates were treated without purifica-
tion with K2CO3 in dry MeOH to obtain the desired deprotected
4-hydroxytetrahydropyrans 8a–d (all cis compounds) as racemates
in three steps and in good yields. The relative configuration was
confirmed using the trifluoroacetic ester of 8a by means of coupling
constants and NOE analysis (see the ESI†). Then, the protection of
the free secondary alcohol using tert-butyldimethylsilyl trifluoro-
methanesulfonate (TBSOTf) was performed, followed by the
reduction of methyl esters 9a–d with LiAlH4, producing the primary
alcohols 10a–d in high yields. Reaction of 10a and 10b using
Parikh–Doering oxidation gave the desired aldehydes 11a–b. Unfor-
tunately, for 10c–d no reaction occurred under these conditions,
and a different approach for these two compounds was attempted.
Oxidations using diverse conditions such as P2O5 or IBX were
assayed but the reaction did not proceed. Fortunately, it was
achieved using (diacetoxyiodo)benzene (DAIB) as catalyst and
with a small excess of 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO), affording the desired aldehydes 11c–d. The alde-
hydes were converted in good yields into the corresponding
alkynes 12a–d using the Taber modification of the Bestmann–
Ohira reagent (13).21 With both building blocks in hand, we
produced the desired hybrid compounds using CuAAC (14a–p).
The products were obtained in moderate to excellent yields as
inseparable diastereomeric mixtures for compounds derived
from 6b, 6c and 6e, and as enantiomeric mixtures for compounds
derived from 6a and 6d (Table 1).
Some hybrid compounds containing these kinds of hetero-
cycles have been previously prepared in order to obtain bioactive
products. Nevertheless, these compounds used tetrahydropyrans
derived from carbohydrates, linked mostly with simple thiazoles,
which highly differ from the ones reported here.16 When con-
sidering the design of hybrid compounds, the first decision is
related to the selection of the best strategy to link both frag-
ments. Traditionally, we can consider three options, namely,
fusion, merging and linking through a spacer. In the particular
case of our hybrids, we decided to explore the latter. Thus, the
building blocks containing oxa/thiazoles produced from amino
acids and tetrahydropyrans prepared by Prins cyclization could
be linked via the copper(I) catalyzed version of the azide–alkyne
[3+2] cycloaddition (CuAAC) (Fig. 2).17 We have explored this
method18 earlier and considered that it would allow us to
combine the building blocks in a simple way. From the two
possible options, the azide moiety was located on the oxa/
thiazole block and the ethynyl moiety on the tetrahydropyran
block, based on the aforementioned information.
Results and discussion
Chemistry
The first step was the preparation of the building blocks.
Briefly, the oxa/thiazole blocks were synthesised as described
Antiproliferative activity
previously18 starting from commercially available amino acids The antiproliferative activity of compounds 14a–p and a subset
alanine, phenylalanine and isoleucine. The method allowed us of their precursors was evaluated against the human solid
to produce enantiomerically pure oxazoles 6a–c and thiazoles tumour cell lines A549 (non-small cell lung), HBL-100 (breast),
6d–e (Scheme 1).
HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and
The tetrahydropyran containing blocks were obtained using WiDr (colon). The results of growth inhibition after 48 h of
Hart’s strategy based on the Prins cyclization of enol ethers exposure are given as GI50 (Table 2). The standard anticancer
with trifluoroacetic acid (TFA) as a promoter (Scheme 2).19 drugs cisplatin (CDDP) and 5-FU (5-fluorouracil) were used as
Allylic alcohols 7a–c were prepared from the corresponding reference drugs. Overall, the hybrid compounds (14a–p)
aldehydes by a Barbier reaction. For the symmetrical alcohol showed interesting activities against all cell lines, whilst the
7d, a double Grignard addition on ethyl formate was utilized as oxa/thiazole precursors 5–6 were inactive (GI50 4 100 mM).
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Scheme 2 Synthesis of racemic tetrahydropyran blocks.
Table 1 Synthesis of hybrid compounds
Oxa/thiazole block
Tetrahydropyran block
R1
R2
X
Hybrid (yield %)
6a
6b
6c
6d
6e
6a
6b
6c
6e
6a
6b
6c
6e
6b
6c
6e
12a
12a
12a
12a
12a
12b
12b
12b
12b
12c
12c
12c
12c
12d
12d
12d
H
Bn
(S)-sec-Bu
H
Bn
H
Bn
(S)-sec-Bu
Bn
H
Bn
(S)-sec-Bu
Bn
Bn
(S)-sec-Bu
Bn
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
i-Pr
i-Pr
i-Pr
O
O
O
S
14a (52)
14b (78)
14c (81)
14d (55)
14e (82)
14f (32)
14g (66)
14h (97)
14i (86)
14j (49)
14k (73)
14l (85)
14m (82)
14n (58)
14o (43)
14p (93)
S
O
O
O
S
O
O
O
S
i-Pr
CH2Bn
CH2Bn
CH2Bn
CH2Bn
Allyl
Allyl
Allyl
O
O
S
*Relative stereochemistry.
In contrast, the tetrahydropyran precursors (9a–12a) we tested all the human tumour cell lines tested. This reinforces our
gave dual results. previous findings that the presence of the TBS group might
On the one hand, intermediates 9a–10a induced antiprolifera- contribute to the activity of these products, at least when con-
tive effects in all cell lines and in the range of 18–40 mM. On the sidering its influence on the lipophilicity of the end products.22
other hand, compounds 11a–12a were inactive.
Hybrid compound 14n displayed the most potent activity
Noteworthily, compound 15 (see the ESI†), which is the (3.1–6.6 mM) against all cell lines and was selected initially as
deprotected analog of 14b and was prepared in previous attempts the lead compound to infer some structure–activity relation-
to produce the desired hybrid compounds, lacks activity against ships. Taking the data as a whole (Fig. 3), we can observe that
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Table 2 Calculated lipophilicity (C log P) and antiproliferative activity (GI50) against human cells of hybrid compounds 14a–p and selected intermediates.
Values are given in mM and represent mean values of at least three independent experiments Æ standard deviation
Compound
C log P
A549
HBL-100
HeLa
SW1573
T-47D
WiDr
BJ-hTert
5a
5b
5c
5d
5e
6a
6b
6c
0.96
2.68
2.68
1.34
3.08
À0.14
1.60
1.59
0.25
1.98
3.98
3.92
3.93
4.33
2.73
4.91
4.90
3.11
5.30
2.01
3.89
4.64
4.76
3.03
4.91
4.80
5.77
3.54
3.43
4.40
0.68
4100
4100
4100
4100
4100
4100
4100
4100
4100
4100
32 Æ 6.0
23 Æ 0.6
4100
4100
4100
4100
4100
4100
4100
4100
4100
4100
4100
33 Æ 8.3
21 Æ 2.3
4100
4100
4100
4100
4100
4100
4100
4100
4100
4100
4100
32 Æ 6.7
19 Æ 1.7
4100
4100
4100
4100
4100
4100
4100
4100
4100
4100
4100
24 Æ 6.7
18 Æ 0.3
4100
4100
4100
4100
4100
4100
4100
4100
4100
4100
4100
35 Æ 4.5
28 Æ 5.3
4100
4100
4100
4100
4100
4100
4100
4100
4100
4100
4100
40 Æ 8.9
20 Æ 1.8
4100
6d
6e
9a
10a
11a
12a
14a
14b
14c
14d
14e
14f
14g
14h
14i
14j
14k
14l
14m
14n
14o
14p
15
4100
4100
4100
4100
4100
4100
17 Æ 1.5
21 Æ 5.9
12 Æ 3.7
16 Æ 0.9
24 Æ 2.4
45 Æ 3.2
10 Æ 1.8
5.9 Æ 0.4
17 Æ 3.7
12 Æ 0.9
17 Æ 4.2
9.2 Æ 3.3
10 Æ 3.1
4.6 Æ 0.7
8.0 Æ 3.2
11 Æ 2.7
4100
19 Æ 1.2
5.2 Æ 0.6
6.0 Æ 2.1
18 Æ 0.1
20 Æ 2.3
38 Æ 2.2
13 Æ 1.8
4.4 Æ 1.2
16 Æ 5.5
14 Æ 1.7
88 Æ 5.1
13 Æ 1.6
4100
18 Æ 0.4
36 Æ 7.1
27 Æ 3.4
17 Æ 1.7
37 Æ 8.3
32 Æ 2.2
7.7 Æ 2.6
5.5 Æ 0.63
5.8 Æ 1.6
11 Æ 1.0
8.7 Æ 1.5
5.8 Æ 0.6
25 Æ 15
4.3 Æ 1.0
4.2 Æ 0.5
7.3 Æ 2.6
4100
16 Æ 2.6
4.2 Æ 0.4
4.6 Æ 1.5
15 Æ 1.8
11 Æ 2.3
36 Æ 4.0
7.5 Æ 2.8
7.0 Æ 1.5
7.5 Æ 2.1
10 Æ 1.5
22 Æ 5.7
9.0 Æ 1.6
6.2 Æ 0.8
4.5 Æ 0.2
6.4 Æ 0.6
7.7 Æ 1.3
4100
20 Æ 1.7
12 Æ 1.2
14 Æ 1.1
16 Æ 3.7
23 Æ 1.9
43 Æ 5.9
10 Æ 0.6
8.5 Æ 0.4
13 Æ 4.0
17 Æ 0.4
41 Æ 16
13 Æ 2.1
4100
18 Æ 1.0
9.1 Æ 4.5
16 Æ 1.0
16 Æ 1.9
28 Æ 6.0
35 Æ 2.4
7.2 Æ 3.5
7.6 Æ 1.2
12 Æ 2.4
14 Æ 1.5
29 Æ 6.7
15 Æ 4.6
4100
4100
53 Æ 1.9
4100
6.6 Æ 1.9
4.5 Æ 0.2
13 Æ 3.3
4100
5.5 Æ 0.5
10 Æ 1.1
13 Æ 1.0
4100
3.1 Æ 0.4
6.9 Æ 2.1
9.8 Æ 2.5
4100
41 Æ 7.0
53 Æ 7.6
52 Æ 5.8
CDDP
5-FU
0.04
À0.89
21 Æ 0.6
1.9 Æ 0.2
5.5 Æ 2.3
2.0 Æ 0.3
15 Æ 4.7
3.0 Æ 0.4
4.3 Æ 1.6
15 Æ 2.3
47 Æ 18
26 Æ 5.3
49 Æ 6.7
14 Æ 2.4
5.5 Æ 0.5
n.t.
oxazole derivatives are in general more active than their corres- experiment to HeLa cells, which were exposed to compounds
ponding thiazole analogs. When considering the substituent 14b and 14l at a low and a high dose (1 and 10 mM), and an
R1, it appears that glycine derivatives (R1 = H) produced less incubation time of 48 h. The results of relative ROS production
active compounds (14a, 14d, 14f, 14j). In contrast, for Bn (0.9 at 1 mM, 1.2 at 10 mM) reveal that no relevant increase of
(14b, 14e, 14g, 14i, 14k, 14m, 14n, 14p) or (S)-sec-butyl (14c, 14h, ROS production was observed.
14l, 14o) analogs there is no clear selectivity. Finally, the allyl group
at R2 gave the best activity values.
Interaction with P-glycoprotein
In order to look for selectivity, we tested the six most potent To determine whether or not P-glycoprotein (P-gp) could affect the
compounds of the series (14b, 14h, 14l, 14n–p) against the activity of 14b and 14l, we determined the GI50 values after 48 h of
(non-tumour) human fibroblast cell line BJ-hTert. The results exposure to the abovementioned compounds in wild type and
(Table 2) show that compounds 14b and 14l were inactive and P-gp overexpressing SW1573 cells, and in the absence or presence
therefore appear as promising leads for further investigation. of the P-gp transport inhibitor verapamil (at a fixed concentration
In fact, our compounds display a better selectivity profile than of 10 mM). The standard microtubule interacting drugs, known
the standard drugs CDDP and 5-FU. The remaining analogs substrates of P-gp, paclitaxel and vinblastine were used for
exhibited GI50 values against BJ-hTert cells in the range of comparison purposes. Table 3 shows the GI50 values obtained
41–53 mM, which still represent selectivity toward tumour cells. after 48 h of drug exposure. For better comparison of the data, we
defined the resistance factor (Rf) for a given compound as the ratio
Oxidative stress measurement in HeLa cells
of GI50 values against the P-gp overexpressing and the wild-type
In order to determine whether the antiproliferative activity of cell lines, respectively. In the absence of verapamil, we observed
the hybrid compounds was related to the production of reactive that 14b and 14l were not affected by P-gp overexpression (Rf = 2
oxygen species (ROS), we run the ROS-Glot H2O2 assay. This and 1, respectively). In contrast, vinblastine was the most affected
luminescence test allows the detection of H2O2 directly, mini- (Rf = 2388). Co-treatment with verapamil produced a decrease in Rf
mizing the false hit rate. In addition, ROS in cells are converted for both antimitotic drugs. However, for 14b and 14l, the Rf value
to H2O2 (the longest-lived ROS). Therefore, an increase in H2O2 remained constant. These results indicate that the activity of 14b
can reflect a general increase in the ROS level. We applied this and 14l is not affected by the overexpression of P-gp.
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Fig. 3 GI50 range plot of tested compounds. X = O, yellow bars. X = S, orange bars.
Table 3 Anti-proliferative activity (GI50) of 14b and 14l and tubulin-interacting drugs in SW1573 and SW1573/P-gp cell lines. Values are given in nM and
represent the mean values of at least three independent experiments Æ standard deviation
À Verapamil
SW1573
+ Verapamil
SW1573
SW1573/P-gp
Rfa
SW1573/P-gp
Rf
14b
14l
Paclitaxel
Vinblastine
12 041 Æ 938
27 206 Æ 3034
1.5 Æ 0.5
28 074 Æ 1238
21 805 Æ 9678
196 Æ 53
2
1
128
11 912 Æ 3608
21 464 Æ 3665
1.6 Æ 0.2
29 340 Æ 9860
31 616 Æ 14 164
4.2 Æ 0.9
2
1
3
1
0.9 Æ 0.3
2051 Æ 682
2388
0.8 Æ 0.2
1.0 Æ 0.5
a
Rf represents the ratio between GI50 SW1573/P-gp and SW1573.
Conclusions
Acknowledgements
A small library of oxa/thiazole-tetrahydropyran triazole-linked This research was supported by CSIC Grupos No. 654 and No.
´
hybrid compounds has been synthesized. The building blocks 983, PEDECIBA Quımica and the Spanish MINECO. Co-financed
were connected by a molecular hybridization process using by the European Regional Development Fund (ERDF) (CTQ2014-
CuAAC. The results on the antiproliferative activity of the hybrid 56362-C2-1-P). G. V. would like to thank ANII (Agencia Nacional de
´
´
compounds showed that the molecular hybridization process Investigacion e Innovacion) for the award of a doctoral fellowship.
allows obtaining active compounds from inactive building blocks.
Further mechanistic studies demonstrated good selectivity for
compounds 14b and 14l against non-tumour cells and that
the abovementioned derivatives were not substrates for P-gp
Notes and references
extrusion. In summary, we have exemplified that CuAAC represents
a plausible strategy to bind blocks of heterocyclic structures to
expand the chemical space of bioactive compounds. Future work
will shed light on the role of the stereochemistry of the
tetrahydropyran block in the antiproliferative activity.
1 (a) D. Davyt and G. Serra, Mar. Drugs, 2010, 8, 2755;
(b) Z. Jin, Nat. Prod. Rep., 2013, 30, 869.
2 N. Oku, K. Takada, R. W. Fuller, J. A. Wilson, M. L. Peach,
L. K. Pannell, J. B. McMahon and K. R. Gustafson, J. Am.
Chem. Soc., 2010, 132, 10278.
3 P. Searle and T. F. Molinsky, J. Am. Chem. Soc., 1995,
117, 8126.
4 C. In-Kwon, H. J. Shin, H.-S. Lee and H. J. Kwon, J. Microbiol.
Biotechnol., 2007, 17, 1338.
Conflicts of interest
The authors confirm that this article has no conflict of interest.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018
New J. Chem.

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Paper
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5 Z. Lin, R. R. Antemano, R. W. Hughen, Ma. D. B. Tianero, 13 N. Kerru, P. Singh, N. Koorbanally, R. Raj and V. Kumar,
O. Peraud, M. G. Haygood, G. P. Concepcion, B. M. Olivera,
A. Light and E. W. Schmidt, J. Nat. Prod., 2010, 73, 1922.
6 (a) X.-H. Liu, P.-C. Lv, J.-Y. Xue, B.-A. Song and H.-L.
Zhu, Eur. J. Med. Chem., 2009, 44, 3930; (b) D. Sellanes,
Eur. J. Med. Chem., 2017, 142, 179.
14 For reviews on Natural Hybrid Compounds: (a) G. Metha and
V. Singh, Chem. Soc. Rev., 2002, 31, 324; (b) L. F. Tietze, H. P. Bell
and S. Chandrasekhar, Angew. Chem., Int. Ed., 2003, 42, 3996.
˜
´
F. Campot, I. Nu´nez, G. Lin, P. Esposito, S. Dematteis, 15 (a) K. Kobayashi, Y. Fujii, Y. Hirayama, S. Kobayashi and
˜
´
J. Saldana, L. Domınguez, E. Manta and G. Serra, Tetra-
hedron, 2010, 66, 5384; (c) C. Wu, Z.-W. Liang, Y.-Y. Xu,
W.-M. He and J.-N. Xiang, Chin. Chem. Lett., 2013, 24, 1064;
(d) H. Zhou, J.-Q. Cheng, Z.-S. Wang, F.-H. Chen and
X.-H. Liu, Curr. Top. Med. Chem., 2016, 16, 3582.
I. Hayakawa, Org. Lett., 2012, 14, 1290; (b) D. Havrylyuk,
B. Zimenkovsky and R. Lesyk, Mini-Rev. Org. Chem., 2015,
12, 66; (c) D. Havrylyuk, O. Roman and R. Lesyk, Eur. J. Med.
¨
Chem., 2016, 113, 145; (d) T. Frolich, B. Ndreshkjana,
J. K. Muenzner, C. Reiter, E. Hofmeister, S. Mederer,
M. Fatfat, C. El-Baba, H. Gali-Muhtasib, R. Schneider-
Stock and S. B. Tsogoeva, ChemMedChem, 2017, 12, 226;
(e) A. Bisi, C. Cappadone, A. Rampa, G. Farruggia, A. Sargenti,
F. Belluti, R. M. C. Di Martino, E. Malucelli, A. Meluzzi,
S. Iotti and S. Gobbi, Eur. J. Med. Chem., 2017, 127, 577.
´
´
7 (a) P. O. Miranda, M. A. Ramırez, V. S. Martın and
J. I. Padron, Org. Lett., 2006, 8, 1633; (b) P. O. Miranda,
R. M. Carballo, V. S. Martın and J. I. Padron, Org. Lett.,
2009, 11, 357; (c) S. J. Perez, P. O. Miranda, D. A. Cruz,
´
´
´
´
´
´
´
I. Fernandez, V. S. Martın and J. I. Padron, Synthesis, 2015,
´
´
1791; (d) S. J. Perez, M. Purino, P. O. Miranda, V. S. Martın, 16 (a) T. Li, L. Guo, Y. Zhang, J. Wang, Z. Li, L. Lin, Z. Zhang, L. Li,
´
´
I. Fernandez and J. I. Padron, Chemistry, 2015, 21, 15211;
J. Lin, W. Zhao, J. Li and P. G. Wang, Carbohydr. Res., 2011,
346, 1083; (b) J. Li, Z. Li, T. Li, L. Lin, Y. Zhang, L. Guo, Y. Xu,
W. Zhao and P. Wang, Biochemistry, 2012, 77, 194; (c) L.-T. Li,
L.-F. Zhou, Y.-J. Li, J. Huang, R.-H. Liu, B. Wang and P. Wang,
Bioorg. Med. Chem. Lett., 2012, 22, 642; (d) J.-P. G. Seerden,
G. Leusink-Ionescu, R. Leguijt, C. Saccavini, E. Gelens, B. Dros,
T. Woudenberg-Vrenken, G. Molema, J. A. A. M. Kamps and
R. M. Kellogg, Bioorg. Med. Chem. Lett., 2014, 24, 1352.
´
´
(e) J. Scoccia, S. J. Perez, V. Sinka, D. A. Cruz, J. M. Lopez-
Soria, I. Fernandez, V. S. Martın, P. O. Miranda and J. I.
Padron, Org. Lett., 2017, 19, 4834.
8 (a) P. O. Miranda, L. G. Leon, V. S. Martın, J. I. Padron and
J. M. Padron, Bioorg. Med. Chem. Lett., 2006, 16, 3135;
(b) L. G. Leon, P. O. Miranda, V. S. Martın, J. I. Padron
and J. M. Padron, Bioorg. Med. Chem. Lett., 2007, 17, 3087.
´
´
´
´
´
´
´
´
´
´
´
´
´
9 (a) M. A. Purino, M. A. Ramırez, A. H. Daranas, V. S. Martın 17 (a) V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless,
´
´
and J. I. Padron, Org. Lett., 2012, 14, 5904; (b) T. Martın,
Angew. Chem., Int. Ed., 2002, 41, 2596; (b) M. Meldal and
C. W. Tornoe, Chem. Rev., 2008, 108, 2952.
´
´
´
J. I. Padron and V. S. Martın, Synlett, 2014, 12; (c) S. J. Perez,
´
´
´
´
M. A. Purino, D. A. Cruz, J. M. Lopez-Soria, R. M. Carballo, 18 G. Valdomir, J. I. Padron, J. M. Padron, V. S. Martın and
´
´
´
´
M. A. Ramırez, I. Fernandez, V. S. Martın and J. I. Padron,
D. Davyt, Synthesis, 2014, 46, 2451.
´
´
Chem. – Eur. J., 2016, 22, 15529; (d) S. J. Alvarez-Mendez, 19 D. J. Hart and C. E. Bennett, Org. Lett., 2003, 5, 1499.
´
´
J. R. Saad, C. E. Tonn, V. S. Martın and C. Garcıa, Arabian 20 (a) C. S. Barry, J. D. Elsworth, P. T. Sedan, N. Bushby,
J. Chem., 2016, DOI: 10.1016/j.arabjc.2016.01.008.
J. R. Harding, R. W. Alder and C. L. Willis, Org. Lett.,
2006, 8, 3319; (b) P. T. Seden, J. P. H. Charmant and
C. L. Willis, Org. Lett., 2008, 10, 1637; (c) D. Tejedor,
10 (a) Design of Hybrid Molecules for Drug Development, ed.
M. Decker, Elsevier, 2017; (b) S. B. Tsogoeva, Mini-Rev.
Med. Chem., 2010, 10, 773; (c) M. O. Pedrosa, R. M. Duarte
da Cruz, J. O. Viana, R. O. Moura, H. M. Ishiki, J. M. Barbosa
´
´
´
´
S. J. Alvarez-Mendez, J. M. Lopez-Soria, V. S. Martın and
´
F. Garcıa-Tellado, Eur. J. Org. Chem., 2014, 198.
Filho, M. F. Diniz, M. T. Scotti, L. Scotti and F. J. Bezerra 21 D. F. Taber, S. Bai and P.-F. Guo, Tetrahedron Lett., 2008,
Mendonça Junior, Curr. Top. Med. Chem., 2017, 17, 1044. 49, 6904.
11 D. Agarwal, R. D. Gupta and S. K. Awasthi, Antimicrob. Agents 22 (a) O. J. Donadel, T. Martın, V. S. Martın, J. Villar and
´
´
´
J. M. Padron, Bioorg. Med. Chem. Lett., 2005, 15, 3536;
Chemother., 2017, 61, e00249.
´ ´ ´
(b) J. M. Padron, O. J. Donadel, L. G. Leon, T. Martın and
12 Y.-Q. Hu, S. Zhang, Z. Xu, Z.-S. Lv, M.-L. Liu and L.-S. Feng,
Eur. J. Med. Chem., 2017, 141, 335.
´
V. S. Martın, Lett. Drug Des. Discovery, 2006, 3, 29.
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