Synthesis, antiproliferative and antibacterial activity of new amides of salinomycin

Article abstract of DOI:10.1016/j.bmcl.2014.02.042

A series of 11 novel amides of salinomycin were synthesized for the first time. All the obtained compounds were found to show potent antiproliferative activity against human cancer cell lines including the drug-resistant cancer cells. Four new salinomycin derivatives revealed good antibacterial activity against clinical isolates of methicillin-resistant Staphylococcus epidermidis (MRSE).

Full text of DOI:10.1016/j.bmcl.2014.02.042

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1724–1729
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, antiproliferative and antibacterial activity of new amides
of salinomycin
a
b
c
b
d
a
´
Michał Antoszczak , Ewa Maj , Joanna Stefanska , Joanna Wietrzyk , Jan Janczak , Bogumil Brzezinski ,
a,
⇑
´
Adam Huczynski
a Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland
b Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, Poland
c Medical University of Warsaw, Department of Pharmaceutical Microbiology, Oczki 3, 02-007 Warsaw, Poland
d Institute of Low Temperature and Structure Research, Polish Academy of Sciences, PO Box 1410, 50-950 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 11 novel amides of salinomycin were synthesized for the first time. All the obtained com-
pounds were found to show potent antiproliferative activity against human cancer cell lines including
the drug-resistant cancer cells. Four new salinomycin derivatives revealed good antibacterial activity
against clinical isolates of methicillin-resistant Staphylococcus epidermidis (MRSE).
Ó 2014 Elsevier Ltd. All rights reserved.
Received 15 January 2014
Revised 13 February 2014
Accepted 15 February 2014
Available online 25 February 2014
Keywords:
Amides
Polyether ionophores
Anticancer properties
Antibacterial activity
Natural compounds
In last decades natural substances have been in a sense redis-
covered as important ingredients in pharmaceutical industry
either in their chemically unchanged or synthetically modified
forms.1,2
carcinoma stem cells, prostate cancer stem cells, as well as lung
cancer cell lines.7 Additionally, it has been shown that the applica-
tion of SAL enhances the anticancer effect of radio- and chemo-
therapy.8 Moreover, the sodium salt of SAL is able to selectively
deplete the breast cancer stem cells with efficiency comparable
to that of SAL.9
The preliminary clinical study of salinomycin has been per-
formed by Cord Naujokat et al. on a small group of patients with
metastatic breast cancer or metastatic head and neck cancers.
Salinomycin (SAL) isolated from Streptomyces albus is an antibi-
otic belonging to natural polyether ionophores,3 exhibiting a large
spectrum of antimicrobial activity against Gram-positive bacteria,
including Staphylococcus aureus, mycobacteria, Plasmodium falcipa-
rum or Eimeria spp, parasites, and protozoa.4 For this reason, so-
dium salt of salinomycin (Bio-cox™, Sacox™) found commercial
application as a coccidiostatic and non-hormonal growth promot-
ing agent in livestock and poultry breeding.5 Screening of about
16.000 chemical compounds performed in 2009 showed that SAL
was the most effective against breast cancer stem cells, nearly
100-fold more active than the commonly used anticancer drug–
Paclitaxel (Taxol).6 Since this discovery, extensive research has been
carried out all over the world to elucidate the unusual properties of
SAL. Further studies proved that SAL shows antiproliferative
activity against various types of human tumour cells, for example
leukemic stem cells, including lymphocytic leukemia, colon
The patients treated with 200–300 lg/kg of SAL, every second
day for three weeks, have shown partial tumour regression and
only transient acute side effects, including tachycardia and mild
tremor, with neither severe nor long-term side effects that can
be observed to accompany the use of conventional chemothera-
peutic drugs. Thus, the preliminary results have permitted deter-
mination of
a drug dosage that yields clinically significant
benefits without excessive toxicity.10
The simplest method for preparing biologically effective com-
pounds is chemical modification of substances with proven high
biological activity. The synthesis, structure, as well as biological
activity of a series of O-acyl derivatives,11 amides12,13 and one
ester14 of SAL have been already described. The SAL derivatives
showed antimicrobial activity, among others against methicillin-
resistant hospital strains of Staphylococcus and anticancer activity
⇑
Corresponding author. Tel.: +48 618291287.
E-mail address: adhucz@amu.edu.pl (A. Huczyn´ ski).
http://dx.doi.org/10.1016/j.bmcl.2014.02.042
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

M. Antoszczak et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1724–1729
1725
in various cell phenotypes in the low micromolar range, providing
an excellent starting point for further drug discovery optimisation.
In addition, tests of SAL and its derivatives have clearly proven that
some of these compounds have a high antiproliferative effect
against normal and drug resistant cancer cells. These results indi-
cate that the biological effects of SAL derivatives are diverse on dif-
ferent bacterial or cancer cell lines and are strongly dependent on
chemical nature of O-acyl, amide or ester substituent.11–14
The main aim of this Letter is evaluation of anticancer and anti-
microbial activity of new derivatives of SAL. Therefore, a series of
new SAL amides was synthesized, characterized by X-ray and spec-
troscopic methods and tested against their antiproliferative and
antibacterial activity. Moreover, as the biological activity of the
new SAL derivatives is closely related to their ability to make com-
plexes with monovalent and divalent metals, it was tested using
the electrospray ionisation mass spectrometry (ESI MS).
In the present study, the antiproliferative effect of eleven SAL
amides (1–11) was tested in vitro using human promyelocytic leu-
kemia (HL-60) and its vincristine-resistant subline (HL-60/vinc),
human colon adenocarcinoma cell line (LoVo) and doxorubicin
resistant subline (LoVo/DX), and normal murine embryonic
fibroblast cell line (Balb 3T3). Multi-drug chemoresistance (MDR)
remains one of the most common reasons for failure of chemother-
apy. The membrane transporter protein belonging to the ABC
transporters family has been shown in vitro to effectively reduce
the intracellular concentration of several anticancer chemothera-
peutic agents such as doxorubicin. On the other hand, it is known
that cancer stem cells may act as master regulators during the pro-
cess of chemoresistance acquisition and are characterized by MDR
phenotype.15,16
43–88% (Scheme 1). The SAL dimers (9–11) were obtained in the
moderate yields of about 30% (Scheme 1). The purity and structures
of compounds 1–11 were determined on the basis of elemental
analysis, FT-IR and NMR methods. The 1H and 13C NMR signals were
assigned using one- and two-dimensional (COSY, HETCOR, HMBC
and NOESY) spectra. The exemplary NMR spectra are included in
the Supplementary material (Figs. S1–S4). The analytical signals
in the 1H and 13C NMR spectra and the position of the amide I band
in the FT-IR spectra of compounds 1–11, are collected in Table S1.
Detailed structural analysis of the biologically active com-
pounds is very important for better understanding of their antican-
cer and antimicrobial properties for structure–activity relationship
analysis (SAR), and related investigation. Therefore, one exemplary
compound of the studied series of derivatives that is p-fluor-
obenzylamide (6) was characterized by single crystal X-ray diffrac-
tion method. The single crystals of 6 were grown by crystallisation
in acetonitrile and their structure was determined using X-ray
crystallographic technique (Fig. 1). The crystallographic data and
structure refinement of compound 6 are summarized in Table S2
(Supplementary material).
The pseudo-cyclic conformation of 6 is stabilised by four N1–
Hꢀ ꢀ ꢀO10, O10–Hꢀ ꢀ ꢀO6, O9–Hꢀ ꢀ ꢀO7 and O8–Hꢀ ꢀ ꢀO7 weak intramo-
lecular hydrogen bonds showed in Figure 1, and the parameters
of this compound are collected in Table S3. The six-membered
rings of 6 exhibit the typical chair conformation. The intermolecu-
lar O8–Hꢀ ꢀ ꢀO1i hydrogen bond between the terminal hydroxyl
group (O8–H) of one molecule and the carbonyl atom of amide
group of the neighbouring molecule, together with the van der
Waals forces, stabilise the arrangement of 6 molecules in the crys-
tal (Fig. S5, Supplementary data). The bond lengths and angles
characterizing the geometry of the molecule are presented as Sup-
plementary material (Table S4). The absolute configuration of 6 is
unchanged and is the same as determined previously for salinomy-
cin, its amides and benzotriazole ester.12–14,18,19
The presence of the pseudo-cyclic structure of salinomycin
amides confirmed by X-ray is facilitates the formation of the
lipid-soluble pseudo-cyclic complexes of these compounds with
the metal cations. Since the biological activity of the polyether
antibiotics and its derivatives strongly depends on their ionopho-
retic properties, the ability of the new SAL derivatives to form com-
plexes with monovalent cations such as Li+, Na+, K+, Rb+, Cs+ and
divalent cations such as Mg2+, Ca2+, Sr2+, Ba2+ was studied by us
using ESI MS technique. The ESI MS spectra of the mixtures of
respective SAL amides with the monovalent and divalent metal
perchlorates (Fig. S6-S10) demonstrate that the amides (1–4, 6–
8) form exclusively 1:1 complexes with both types of metal
cations. Only the amide with the crown moiety (5) is able to form
different complexes with divalent cations (M) that is the (5+M)2+
and (5+MClO4)+ (Fig. S9). The last type of complexes has been pre-
viously observed for different monensin derivatives.12,13 Addition-
ally, dimers of SAL (9–11) are able to form complexes with
monovalent cations in 1:1 and 1:2 stoichiometry (Fig. S10).
In contrast to unmodified salinomycin (SAL), which forms com-
plexes of 1:1 stoichiometry only with monovalent cations, espe-
cially Na+ and K+, salinomycin amides are able to form complexes
with both monovalent and divalent metal cations and of different
stoichiometries.
Taking into account this phenomenon, we decided to study the
antiproliferative activity of salinomycin derivatives on drug resis-
tant cells, expressing various transporters (e.g., p-glycoprotein)
and their parent cell lines to observe not only the antiproliferative
activity against cancer cells, but also the possibility to break the
barrier of chemoresistance.
Antimicrobial activity of compounds 1–11 was also tested
in vitro on Gram-positive and Gram-negative bacteria and fungi,
as well as against a series of clinical isolates of Staphylococcus. To
investigate the effect of different substitutions of the carboxylic
group of SAL on its bioactivity, eight new amide derivatives (1–
8) and three dimers (9–11) of SAL were synthesized using the
procedure developed previously by our group.12 To facilitate the
structural activity relationship analysis (SAR) we chose salinomy-
cin amides with different substituents such as: unsaturated alkyl
chain (propargylamine, 1), alkyl chains containing oxygen atoms
(2-(2-aminoethoxy)ethanol, 3) biogenic amines like cysteamine,
(2), putrescine (4), histamine (7), dopamine (8), containing fluori-
nated aromatic ring (4-fluorobenzylamine, 6) and crown ether
(2-aminomethyl-15-crown-5, 5). It is generally believed that di-
mers of biologically active compounds, such as antibiotics, can
show enhanced biological activity relative to that of the single li-
gand. Thus, the symmetrical dimeric SAL ligands, in which two
SAL molecules are linked by different spacer units (1,4-butanedi-
amine 9; p-phenylenediamine 10; 4,40-diaminobiphenyl, 11) were
also prepared to check the effects of linker length and its flexibility
on the biological activity of SAL.
Salinomycin sodium salt was isolated from veterinary
premix–SACOXÒ. Amide derivatives of salinomycin (1–11) were
obtained in the reaction between salinomycin acid (SAL) and
amines with addition of DCC (N,N0-dicyclohexylcarbodiimide) and
HOBt (1-hydroxybenzotriazole) following the procedures de-
scribed previously.12
All SAL amides can be easily isolated in pure form following the
purification by dry vacuum column chromatography.17 This
method was efficient and gave amides 1–8 in high yields of up to
The reason why SAL and its derivatives exhibit biological effects
is their ability to form lipid-soluble pseudo-cyclic complexes with
metal cations and transport them trough cell and mitochondrial
membranes. Derivatives of SAL with modified carboxylic groups
like amides can transport cations via an electrogenic mechanism.
The ESI MS measurement show the ability of SAL amides to form
complexes with monovalent and divalent cation, therefore the
biological activity of these compounds is confirmed also by their
ionophoretic properties.

1726
M. Antoszczak et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1724–1729
34
CH3
H3C
33
CH3
15
35
OH
O
39
H3C
O
9
17
24
21
11
O
O
20
31
40
H3C
38CH3
O
28
32
CH3
37
OH
O
CH3
OH
30 CH3
O
R
5
1
salinomycin acid (SAL)
R = OH
CH3
(a)
42
R = NH (alkyl or aryl)
2 (59%)
salinomycin amides (1-11)
SH
R=
1 (88%)
OH
HN
C CH
HN
O
NH2
4 (76%)
3 (71%)
HN
HN
O
HN
HN
O
O
5 (43%)
6 (82%)
O
O
F
HN
HN
OH
OH
N
7 (65%)
8 (68%)
N
H
NH
HN
9 (32%)
SAL
HN
HN
SAL
SAL
N
10 (38%)
H
NH
11 (33%)
Scheme 1. Reaction and conditions: (a) DCC, HOBt, R-NH2–appropriate amine, CH2Cl2/THF (3/1), 0 °C–1 h, then rt–24 h. Time for completion of the reaction at rt as indicated
by TLC. Yield of isolated and purified products in brackets. For the experimental procedure, see Ref. 12.
Figure 1. View of the molecular structure of 6 with the atoms labelling. Dashed lines represent the hydrogen bonds.

M. Antoszczak et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1724–1729
1727
Table 2
The new salinomycin amides (1–11) were evaluated for their
in vitro antiproliferative effect on four cancer and one normal cell
lines following the previously published procedures.13 Each com-
pound was tested on two human cancer cell lines displaying vari-
ous levels of drug resistance, such as human promyelocytic
leukemia (HL-60) and its vincristine-resistant subline (HL-60/vinc),
human colon adenocarcinoma cell line (LoVo), and doxorubicin
resistant subline (LoVo/DX). The antiproliferative effect was also
studied on normal murine embryonic fibroblast cell line (BALB/
3T3) for better description of cytotoxic activity of studied com-
pounds. The mean IC50 SD of the tested compounds are collected
in Table 1. To evaluate the activity of compounds 1–11 against the
cells with MDR (multidrug resistance) phenotype, two drug resis-
tant cancer cell lines that is HL-60/vinc and LoVo/DX were tested
and their indexes of resistance (IR) were calculated (Table 2). The
IR value indicates how many times more resistant is the subline
in comparison to its parental cell line.
The calculated values of the indexes of resistance (IR) and selectivity (SI) for
salinomycin (SAL) and its new amides (1–11)
Compound
HL-60
SI
HL-60/vinc
IR
LoVo
SI
LoVo/DX
SI IR
SI
SAL
1
2
3
4
5
6
7
8
22.07
6.47
5.53
2.22
9.47
1.35
20.27
7.79
2.05
7.28
10.07
—
5.45
4.05
1.97
10.99
1.74
6.22
1.16
2.98
7.46
2.48
4.95
7.99
—
16.88
5.40
0.65
1.08
1.60
1.30
11.20
1.06
1.47
1.85
2.49
—
26.08
9.60
0.60
2.76
2.78
3.69
19.57
0.99
1.34
5.13
7.20
—
0.65
0.56
1.07
0.39
0.58
0.35
0.57
1.07
1.10
0.36
0.35
0.38
3.29
0.50
1.28
1.52
1.16
6.80
1.04
0.83
1.47
1.26
9
10
11
—
Doxorubicin
Cisplatin
12.00
2.33
0.27
0.87
44.50
2.66
2.82
1.77
0.07
1.04
37.94
1.71
As shown in Table 1, SAL was active at low
lM ranges (1.0–
The IR (Index of Resistance) indicates how many times a resistant subline is
chemoresistant relative to its parental cell line. When IR is 0–2 the cells are sen-
sitive to tested compound; IR of the range 2–10 means that the cell shows moderate
sensitivity to a drug; IR above 10 indicates strong drug-resistance.
The SI (Selectivity Index) was calculated for each compounds using formula:
SI = IC50 for normal cell line (BALB 3T3)/IC50 for respective cancerous cell line. A
beneficial SI >1.0 indicates a drug with efficacy against tumour cells greater than
toxicity against normal cells.
4.7
lM) in the entire cancer cell lines tested, being the most active
against the LoVo/DX and HL-60 cell lines. This study shows that the
majority of the synthesized compounds exerted antiproliferative
activities at micromolar concentrations (IC50 from 2.0 to
36.7 lM) against the four human cancer cell lines and relatively
low toxicity to normal murine embryonic fibroblast cell line. Deriv-
atives 6 and 8 were active in the low micromolar concentration
range (IC50 2.3–6.9
IC50 values between 8.5 and 36.7
l
M), whereas compounds 2, 3, 5 and 7 showed
M for HL-60/vinc, LoVo and
compounds (1, 6, 8–11) showed moderate to high cytotoxic activ-
ity against LoVo/DX cancer cell line, which was higher than that of
the anticancer drugs such as doxorubicin and cisplatin (Table 1).
The selectivity index (SI), an important pharmaceutical param-
eter that facilitates the estimation of possible future clinical devel-
opment, was determined as the ratio of IC50 value for normal cell
line (BALB 3T3) to IC50 value for a respective cancerous cell line.
The bioactivity of each compound was evaluated by a combination
of its IC50 value and the corresponding SI. Higher values of SI indi-
cate greater anticancer specificity and SI greater than 3 was consid-
ered as highly selective. The results collected in Table 2 indicate
that SAL and its amides appeared to be less toxic against normal
embryonic fibroblasts than cisplatin and doxorubicin. SAL and its
derivative 6 have high SI from 5.45 to 26.08, indicating that these
compounds will rather selectively kill cancer cells than normal
ones (Table 2).
l
LoVo/DX cancer line. The most sensitive cell line was HL-60, be-
cause almost all SAL derivatives are active under low micromolar
concentrations. It is interesting to note that SAL and its most active
derivatives revealed antiproliferative activity against both chemo-
resistant cell lines similar or higher than that of typical anticancer
drugs as cisplatin and doxorubicin against BALB/3T3 fibroblasts
and were less toxic than these drugs.
The results obtained indicate that SAL and its derivatives 8 and
especially 6 exhibited the highest ability to inhibit the proliferation
of different cancer cell lines (Table 1) in comparison to those of the
other SAL derivatives obtained. It clearly shows that different
amide substituents attached to the SAL moiety might affect the
activity and also that the presence of aromatic ring with the polar
groups, such as F or OH, is preferable over the presence of aliphatic
groups. The data given in Table 1 show that all compounds tested
were active against cell lines expressing drug-resistant phenotype
(IR below 10), while for doxorubicin IR is over 44. Even six
The antimicrobial activity of SAL and its amides (1–11) was stud-
ied in vitro against the typical Gram-positive cocci, Gram-negative
Table 1
Antiproliferative activity of salinomycin (SAL) and its amides (1–11). Data are given as IC50 [lM]
Compound
Cancer cells
Normal cells
BALB 3T3
HL-60
HL-60/vinc
LoVo
1.5 0.4
LoVo/DX
SAL
1
2
3
4
5
6
7
8
1.2 0.5
5.7 2.2
3.1 0.6
17.8 2.1
3.7 0.8
23.2 3.7
2.3 0.2
4.4 0.8
2.8 1.1
2.7 0.1
2.0 0.7
4.4 1.4
4.7 1.7
11.3 1.3
34.0 7.4
30.9 5.4
23.1 6.2
27.0 4.7
6.7 1.2
33.1 4.6
6.9 1.1
13.5 2.1
16.1 5.1
NA
1.0 0.1
3.9 1.0
28.5 5.0
14.3 5.2
12.6 5.8
8.5 4.8
2.3 0.5
34.8 3.8
4.3 0.7
3.9 1.3
2.8 0.6
3.1 0.8
25.8 9.0
37.1 6.4
17.1 1.0
39.4 2.1
35.1 4.7
31.3 5.2
45.8 20.9
34.5 6.6
5.7 2.2
19.8 2.9
20.2 1.9
NA
6.9 1.0
26.5 6.2
36.7 2.4
21.9 3.5
24.1 2.2
4.1 0.1
32.5 5.3
3.9 0.2
10.7 3.0
8.1 2.6
8.4 2.8
9
10
11
Doxorubicin
Cisplatin
0.04 0.02
4.00 3.3
1.8 0.3
10.6 2.2
0.17 0.06
5.2 1.1
6.5 1.8
8.9 0.8
0.5 0.3
9.2 2.3
The IC50 value is defined as the concentration of a compound that corresponds to a 50% growth inhibition. Human promyelocytic leukemia (HL-60) and its vincristine-
resistant subline (HL-60/vinc); human colon adenocarcinoma cell line (LoVo) and doxorubicin resistant subline (LoVo/DX); normal murine embryonic fibroblast cell line
(BALB 3T3). Data are expressed as the mean SD; NA–not active in concentrations used (up to 100 lg/ml).

1728
M. Antoszczak et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1724–1729
rods and yeast-like organisms (Table 3), and against a series of clin-
ical isolates of methicillin-resistant Staphylococcus epidermidis
(MRSE) according to the procedure published by us previously.12
Hospital strains of methicillin-resistant Staphylococcus were iso-
lated from different biological materials of patients of the Warsaw
Medical University Hospital. MRSE is a species of antibiotic-resis-
tant bacterium commonly found both on the skin and in the noses
of healthy people.
The antimicrobial properties of salinomycin and its derivatives
against typical bacteria strains are expressed by the minimum
inhibitory concentration (MIC) (Table 3). Antibacterial activity
evaluation largely depends on various substituents in the amide
group of salinomycin derivatives. It is worth noticing that the com-
pounds which expressed the higher anticancer activity, were not
the ones showing the strongest activity against bacteria. Attempts
were made to correlate antibacterial activity of these compounds
with changing substituents at amide moiety.
properties of obtained compounds were studied by ESI MS show-
ing that amides of SAL are able to form complexes with monova-
lent and divalent cations, while unmodified SAL is able to form
complexes only with monovalent cations. The activity tests of com-
pounds 1–11 clearly show that some of them, especially the
amides with dopamine (8) and 4-fluorobenzyl substituent (6), indi-
cate relatively high antiproliferative effect (e.g., against multidrug-
resistant and their parental cancer cell lines). These compounds are
less toxic for normal murine fibroblasts cells than the currently
used anticancer drugs such as cisplatin and doxorubicin. We have
provided evidence that the four new amides containing saturated
alkyl chain with additional heteroatom such as sulfur (2), oxygen
(3) and nitrogen (4) or SAL dimer linked by 4,40-diaminobiphenyl
spacer (11) show antibacterial activity against human pathogenic
bacteria, including drug resistant strains of Staphylococcus epide-
rmidis. It is interesting to note that the most antiproliferative active
SAL derivatives are not the ones showing the strongest antibacte-
rial activity and vice versa.
These results indicate that the antiproliferative and antibacte-
rial effects of salinomycin amides strictly depend on chemical
nature of amide substituent (1–11). The SAL derivatives displayed
antiproliferative activity in various cell types in the low micromo-
lar range, providing an excellent starting point for further drug
discovery optimisation. These results are important for the devel-
opment of molecules with dual potential anticancer and antibacte-
rial activity.
Among the compounds tested, only SAL and four amide deriva-
tives (2–4 and 11) showed activity against Gram-positive bacteria.
Compounds (1, 5–10) were practically inactive towards all micro-
organisms tested (MIC P256 lg/ml). The amides containing alkyl
chains with sulfur, oxygen or nitrogen atoms (2–4) or dimer of
SAL with the 4,40-diaminobiphenyl linker (11) show a considerably
stronger activity against Gram-positive bacteria than the other sal-
inomycin amides. Salinomycin and its amides are inactive against
the strains of Candida and Gram-negative bacteria.
Amides 2–4 and 11 exhibit good potency in inhibiting the
growth of MRSE, with MICs in the range of 16–64
were slightly less active than unmodified SAL (MIC = 8–16
l
g/ml, which
g/ml).
Acknowledgments
l
To summarize, a simple and efficient one-pot methodology for
the synthesis of eleven new amides of salinomycin (1–11) is de-
scribed. The simplicity of this method, high yields, easy work-up
and purification of the products by flash chromatography and crys-
tallization are its key advantages. The molecular structure of one
amide (6) has been characterised by X-ray method proving the
pseudo-cyclic structure of this compound. The ionophoretic
Financial support by grant of the Polish National Science Centre
(NCN)–No. 2011/03/D/ST5/05884 is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.02.
042. These data include MOL files and InChiKeys of the most
important compounds described in this article.
Table 3
Antibacterial activity of salinomycin (SAL) and its amides (2–4, 11) against standard
bacteria and methycyllin-resistant hospital strains of Staphylococcus epidermidis
(MRSE). Data are given as MIC [
l
g/ml]
References and notes
Reference strains
SAL
2
3
4
11
Ciprofloxacin
1. (a) Kinghorn, A. D.; Chin, Y.-W.; Swanson, S. M. Curr. Opin. Drug Discov. Devel.
2009, 12, 189; (b) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2007, 70, 461; (c)
Butler, M. S. J. Nat. Prod. 2004, 67, 2141.
2. (a) Rong-Guang, S. Curr. Mol. Pharmacol. 2008, 1, 50; (b) Clardy, J.; Walsh, C.
Nature 2004, 432, 829; (c) Ravelo, A. G.; Estevez-Braun, A.; Chavez-Orellana, H.;
Perez-Sacau, E.; Mesa-Siverio, D. Curr. Top. Med. Chem. 2004, 4, 241; (d)
Kingston, D. G. I.; Newman, D. J. Natural Products as Anticancer Agents. In Wiley
Encyclopedia of Chemical Biology 2008.
Standard bacteria
S. aureus
NCTC 4163
S. aureus
ATCC 25923
S. aureus
ATCC 6538
S. aureus
ATCC 29213
S. epidermidis
ATCC 12228
S. epidermidis
ATCC 35984
2
2
2
4
2
2
16
16
16
32
32
32
32
32
32
64
64
64
32
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