A solid- and solution-phase-based library of 2β-methyl substituted penicillin derivatives and their effects on growth inhibition of tumor cell lines

Article abstract of DOI:10.1039/c4md00430b

We described the design, synthesis and antiproliferative properties of a series of twenty 2β-methyl substituted penicillin derivatives. This analysis includes evaluation against HeLa and MCF-7 human tumor cell lines and LM3 and B16-F0 murine tumor cell lines. The epithelial cell line derived from the normal mammary gland of mice (NMuMG) and the mouse embryo fibroblast cell line (3T3) were used as controls (non-cancer cells). This journal is

Full text of DOI:10.1039/c4md00430b

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A solid- and solution-phase-based library of
2β-methyl substituted penicillin derivatives
and their effects on growth inhibition of
tumor cell lines†
Cite this: DOI: 10.1039/
c4md00430b
a
a
a
Dora B. Boggián, Patricia G. Cornier, Ernesto G. Mata, Viviana C. Blank,b
*
b
b
*
Mariano G. Cárdenas and Leonor P. Roguin
Received 25th September 2014,
Accepted 15th December 2014
We described the design, synthesis and antiproliferative properties of a series of twenty 2β-methyl
substituted penicillin derivatives. This analysis includes evaluation against HeLa and MCF-7 human tumor
cell lines and LM3 and B16-F0 murine tumor cell lines. The epithelial cell line derived from the normal
mammary gland of mice (NMuMG) and the mouse embryo fibroblast cell line (3T3) were used as controls
(non-cancer cells).
DOI: 10.1039/c4md00430b
www.rsc.org/medchemcomm
Introduction
antiproliferative chemotherapy. In this sense, N-thiolated,12
1,4-diaryl13 1,3,4-triaryl,14 and polyaromatic15 2-azetidinones
The β-lactam ring is an active agent whose efficiency has been
proven in a large number of clinically significant therapeutic
areas.1 Apart from being the key structural element of the
most broadly prescribed antibiotics, such as penicillins,
cephalosporins, carbapenems and monobactams (Fig. 1),2
β-lactams have offered a new panorama with the development
of some derivatives as potent cholesterol absorption inhibi-
tors, including commercial ezetimibe (Fig. 1).3 The β-lactam
skeleton is also found in prostate specific antigen, thrombin,4
human cytomegalovirus protein,5 human leukocyte elastase,6
cysteine protease,7 and human fatty acid amide hydrolase8
inhibitors. This class of compounds has also been considered as
peptidomimetic species for mimicking certain properties of pro-
teins.9 Their non-antibacterial uses and the constant need for
new antibiotics to attack the problem of bacterial resistance to
traditional drugs have maintained and even increased the inter-
est in the chemistry of β-lactams. Last but not least, β-lactams
are key synthons for the preparation of various heterocyclic com-
pounds of biological importance.10 For example, substituted
hydroxy-β-lactams have been used in the semisynthesis of pacli-
taxel (Taxol) and related compounds from baccatin III.11
have been reported as active against cancer cells. Apart from
being considered as prodrugs for the ADEPT strategy,16 ceph-
alosporin derivatives have also shown anticancer activity.17
Penicillins are a major class of β-lactams and the oldest used as
antibacterial agents. We have recently reported antiproliferative
studies on a series of triazolyl aminoacylIJpeptidyl) penicillins.18
These hybrid compounds, prepared by azide–alkyne cyclo-
addition as the key reaction step, were evaluated against
cancer cell lines, and several of them show high selectivity
and cytotoxic activity.
As part of our efforts to discover new potential anti-cancer
drugs, we have synthesized a solid and solution-phase-based
Interestingly, we and others have recently demonstrated
that β-lactam derivatives can also be useful in the field of
a Instituto de Química Rosario (CONICET – UNR), Facultad de Ciencias
Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531,
2000 Rosario, Argentina. E-mail: mata@iquir-conicet.gov.ar
b Instituto de Química y Fisicoquímica Biológicas (UBA – CONICET),
Facultad de Farmacia y Bioquímica. Universidad de Buenos Aires, Junín 956,
C1113AAD Buenos Aires, Argentina
† Electronic supplementary information (ESI) available: Experimental procedures,
characterisation data, description of cell lines, culture conditions and cell
proliferation assay. See DOI: 10.1039/c4md00430b
Fig. 1 The β-lactam ring is present in several commercially available drugs.
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library of 2β-methyl substituted penicillins and evaluated
their in vitro antiproliferative activity against four cancer
cell lines and two non-cancer cells, and some conclusions
on the preliminary structure–activity relationship have
been drawn.
were treated with excess of heterocyclic thiols (HS-Het)
and catalytic amounts of p-toluenesulfonic acid (p-TsOH), in
refluxing toluene.22 Under these conditions and in the absence
of an external nucleophile, the initially formed disulfide inter-
mediates (3e–k) underwent an internal rearrangement, assisted
by p-TsOH, to yield the 2β-IJheterocyclyl)thiomethyl penams
(8ae–bk). After cleavage, esterification and purification by col-
umn chromatography, the 2β-IJheterocyclyl)thiomethyl penicil-
lins (9ae–bk) were isolated, in good overall yields for the entire
synthetic sequence (see Table 1). When 9af was treated with
tributylphosphine (Bu3P) in methanol,23 the dehalogenated
product 9df was obtained. On the other hand, sulfide 9bj was
treated with excess of m-CPBA to give the corresponding sul-
fone 10bj in good yield.
Benzyl ester derivatives were synthesized by a solution-
phase strategy (Scheme 2). The corresponding sulfoxide (11a)
was treated with heterocyclic thiols (HS-Het) and p-TsOH,
under the conditions described above. The benzyl 6,6-dibromo-
2β-IJheterocyclyl)thiomethyl penicillanates (12) were reduced by
Bu3P to give the dehalogenated derivatives (13de–dk). Other-
wise, by treating 13de with excess of m-CPBA, sulfone 14de
was obtained. Finally, compound 15a was synthesized from
11a according to a literature procedure.22
Results and discussion
Chemistry
We have developed
a convenient solid-phase synthetic
sequence for the preparation of 2β-methyl substituted penam
derivatives using the commercially available and cost-effective
Merrifield resin.19 The synthesis started with the immobiliza-
tion of 6,6-dihalo- and 6α-halopenicillanic acids on the resin
using standard methodology. Oxidation of the resin-bound penam
sulfide (1, Scheme 1) under 1.5 equiv. of m-chloroperbenzoic acid
(m-CPBA) leads to the sulfoxides (2). The key step for the gen-
eration of the 2β-methyl substituted penicillins is the thermal
rearrangement of the corresponding sulfoxides.20 For the gener-
ation of the 2β-chloromethyl penam derivatives, 6,6-dihalo- and
6α-halopenicillanate sulfoxides tethered to the Merrifield resin (2)
were treated with 1.5 equiv. of 2-mercaptobenzothiazole (2-MBT)
and heated in refluxing benzene, to give the unsymmetrical
monobactam disulfides (3). Then, the penam system is re-
established by addition of sulfuryl chloride in dicloromethane at
−40 °C, affording the immobilized 2β-chloromethyl penicillanates
(4a–c).21 Final products were obtained by treatment with alu-
minum chloride21 followed by esterification with diazomethane,
to give the methyl 6,6-dihalo- and 6α-halo-2β-chloromethyl
penicillanates (5b–c) in good overall isolated yield (see Table 1).
Alternatively, sulfone 7a was obtained by oxidation of sulfide 4a
with an excess of m-CPBA, followed by cleavage and methyla-
tion, according to the procedure described above.
In vitro antiproliferative studies
The in vitro antiproliferative activity of a library of twenty
2β-methyl substituted penicillin derivatives was initially
evaluated at 20 μM concentration against epithelial cells
derived from the normal mammary gland of mice (NMuMG)
and fibroblast cells from mouse embryo (3T3) (Fig. 2). Based
on results obtained for these non-neoplastic cells, only
those compounds without toxicity towards non-cancer cells
(i.e., those that inhibited less than 50% cell proliferation in
either NMuMG cells or 3T3 cells at 20 μM) were selected for
In the case of the preparation of 2β-IJheterocyclyl)-
thiomethyl penam derivatives, immobilized sulfoxides (2)
Scheme 1
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Table 1 Library of 2β-methyl substituted penicillins
Entry
Compound
Y
X
Z
R
n
Yielda (%)
1
2
3
4
5b
5c
7a
Cl
Br
Br
Br
H
H
Br
Br
Cl
Cl
Cl
Me
Me
Me
Me
0
0
2
0
54
48
37
52
9ae
5
6
9af
Br
Br
Br
Br
Me
Me
0
0
70
43
9ag
7
8
9ah
9ai
Br
Br
Br
Br
Me
Me
0
0
60
52
9
9be
9bf
Cl
Cl
H
H
Me
Me
0
0
40
46
10
11
12
9bh
9bj
Cl
Cl
H
H
Me
Me
0
0
50
44
13
14
9bk
9df
Cl
H
H
H
Me
Me
0
0
48
32b
15
10bj
Cl
H
Me
2
34c
16
17
13de
13df
H
H
H
H
Bn
Bn
0
0
46d
17d
18
19
13dk
14de
15a
H
H
Br
H
H
Br
Bn
Bn
Bn
0
2
0
19d
11e
32d
20
Cl
a
Obtained by solid-phase synthesis, unless otherwise stated. Yield after AlCl3 cleavage and esterification with CH2N2, and calculated on the
basis of the manufacturer's loading of the Merrifield resin. b Yield from 9bf (solution-phase synthesis). c Yield from 9bj (solution-phase synthesis).
d
Yield from compound 11a (solution-phase synthesis). e Yield from 13de (solution-phase synthesis).
Scheme 2
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Fig. 2 Effect of synthetic penicillin derivatives on the proliferation of non-neoplastic cell lines. 2 × 104 cells per well (NMuMG and 3T3) were
incubated in the presence or absence of 20 μM of different compounds for 72 h at 37 °C. Cell proliferation was determined by colorimetric
determination of hexosaminidase levels.24 Results are expressed as the percentage of growth obtained in the absence of compounds (control) and
represented as mean S.E.M. of three different experiments. The antiproliferative activity of compounds 14de, 10bj and 15a was not evaluated in
3T3 cells.
further studies. Thus, compounds 14de, 10bj, 15a, 9ag, 9ah,
9ae and 7a were not tested in tumor cells. The anti-
proliferative effect of the remaining selected compounds was
then determined in two human tumor cell lines (cervix HeLa
adenocarcinoma; breast MCF-7 cancer) and two murine cell
lines (LM3 mammary adenocarcinoma; B16-F0 melanoma)
(Fig. 3). As shown in Fig. 3, the compounds that caused a
reduction of ≥50% in the growth of tumor cell lines at 20 μM
concentration were: 13de, 13df, 9df, 9bj, 9af, 9bk, 9be and
9bf (HeLa cells); 9df and 9af (MCF-7 cells); 9bj, 9af and 9be
(B16-F0); 9df, 13dk, 9bj, 9af, 9bk and 9be (LM3). IC50 values,
defined as compound concentrations that produce 50%
growth inhibition, were determined from dose–response curves
only for these derivatives and are summarized in Table 2. Con-
sequently, IC50 values corresponding to compounds that
inhibited less than 50% tumor cell proliferation at 20 μM were
Fig. 3 Effect of some synthetic penicillin derivatives on the proliferation of different human and murine cell lines. 1 × 104 cells per well (B16-F0) or
2 × 104 cells per well (HeLa, MCF-7, LM3) were incubated in the presence or absence of 20 μM of different compounds for 72 h at 37 °C. Cell
proliferation was determined by colorimetric determination of hexosaminidase levels.24 Results are expressed as the percentage of growth
obtained in the absence of compounds (control) and represented as mean S.E.M. of three different experiments.
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not evaluated. In order to establish the selectivity of the tested
compounds, we decided to compare the IC50 values obtained
in tumor cells with those obtained in NMuMG cells, the non-
cancer cell line more susceptible to the cytotoxic effect of peni-
cillin derivatives. Therefore, we defined the relative potency
(RP) of each compound in a particular tumor cell line as the
ratio of the IC50 obtained in NMuMG to the IC50 value
obtained in tumor cells. The higher this value, the greater the
antitumor potency and selectivity is exhibited by a compound
(Table 2). Based on RP values obtained, the most potent and
selective penicillin derivatives (RP ~4–7) were compound 13de
followed by compounds 13df, 9df and 9af. Within this group,
compounds 13de and 13df are selective for HeLa cells,
although 13de showed a higher potency than 13df. Further-
more, compounds 9df and 9af, showing a similar RP to com-
group at position 3 of the tetrazole ring showed an increase
in cytotoxicity against normal cells; 9ag inhibits 90% of cell
growth in NMuMG and about 50% in 3T3 cell lines, while 9ai
inhibits those cell lines by approximately 20% and 35%,
respectively.
Regarding position 6 of a penam nucleus, the presence of
the halides appears to have no influence on the cytotoxic
activity. Thus, dibromo derivative 9af did not show any signif-
icant difference in activity compared to its dehalogenated
analogue 9df. No significant differences were observed in
cytotoxicity between the two carboxylic acid protective groups
of 2β-methyl penicillins, benzyl and methyl esters. This is
exemplified by similar activity values obtained for compound
13dc and its analogue 9dc.
pound 13df, also exerted a slight antiproliferative effect in Conclusions
other tumor cell lines. In addition, compound 13dk was mod-
In conclusion, a series of 2β-methyl substituted penicillin
erately effective in LM3 cells. It should be considered that
since compounds 13de, 13df and 13dk could not be tested at
concentrations higher than 80 μM due to their lower solubility
in the culture medium, the RP values reported correspond to
the minimal difference between the efficacy in NMuMG and
tumor cells.
Compounds 9bj, 9bk, 9be and 9bf showed a slight and
similar antitumor potency (RP ~2). However, although 9bj
and 9be were effective in HeLa, B16-F0 and LM3 cells, 9bk
was selective for HeLa and LM3 cells, and 9bf only for HeLa.
Compounds 5c, 9ai, 9bh and 5b, which were tested for
being not cytotoxic in non-cancer cells (Fig. 2), showed no
antiproliferative effect in the tumor cell lines herein studied.
derivatives were synthesized and the in vitro cytotoxic activi-
ties against four human tumor cell lines and two normal
cells were evaluated. Some of the tested compounds showed
satisfactory antitumor activity, especially compounds 13de,
13df, 9df and 9af which displayed higher values and good rel-
ative potencies. We have explored the structure–activity rela-
tionships and some general conclusions have been drawn.
2β-ij(Benzothiazol-2-yl)thio]methyl and 2β-ij(4,5-diphenyl-oxazol-
2-yl)thio]methyl have shown to be the most promising penam
derivatives of this series.
Our work demonstrates the possibility of obtaining new
antitumor leaders by simple chemical transformations from
a given molecular framework. The use of 2β-methyl substituted
penicillin derivatives may help to discover new related com-
pounds with potent and selective cell growth inhibitory activity
which could be further tested as potential therapeutic agents
for cancer treatment.
Structure–activity relationships
Analysis of the data obtained in this study allowed us to draw
some significant conclusions about the structure–activity
relationships of this type of molecule, regarding their anti-
proliferative activity.
Acknowledgements
As shown in Table 2, derivatives having 2-mercapto-
benzothiazole (9be, 9bj and 13de), 2-mercapto-4,5-dihydro-
thiazole (9bk and 13dk) and 2-IJmethylthio)-4,5-diphenyloxa-
zole (9af, 9bf, 9df, 13df) at the 2β-methyl position of the
penam nucleus showed the highest antiproliferative activity
against cancer cells. Oxidation of the thiazolidine sulfur atom
is directly related to cytotoxicity in normal cells (NMuMG).
Thus sulfone derivatives 14de and 10bj affect the growth of
normal cells NMuMG (inhibit approximately 60% and 90%
growth rate, respectively) to a greater extent than sulfide
derivatives 13de and 9bj (25% and 35%, respectively).
We have also noted that the introduction of a chlorine
atom at the 2β-methyl position of the penam nucleus is detri-
mental to antitumor activity since those derivatives were
either cytotoxic against normal cells or innocuous to both
normal and tumor cells (5c, 15a, 7a and 5b). The presence of
the tetrazole heterocycle at the 2β-methyl position (9ag and 9ai)
is remarkably unfavorable for the antitumor activity of these
compounds. Furthermore, the incorporation of a phenyl
Support from CONICET, ANPCyT, UBA and UNR from Argentina
is gratefully acknowledged. P.G.C. thanks CONICET for the
fellowship.
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