Synthesis, characterization and biological investigation of platinum(ii) complexes with asparagusic acid derivatives as ligands

Article abstract of DOI:10.1039/C8DT02553C

After more than 50 years of platinum-based anticancer research only three compounds are in clinical use worldwide. The use of the well-known lead compound of this class of anticancer agents, cisplatin, is limited by its side effects and varying resistance mechanisms. Therefore, we report on platinum(ii) compounds with asparagusic acid derivatives as ligands which show interesting anticancer results on cisplatin resistant cell lines.

Full text of DOI:10.1039/C8DT02553C

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Synthesis, characterization and biological
investigation of platinum(II) complexes with
asparagusic acid derivatives as ligands†
Cite this: Dalton Trans., 2019, 48,
936
a,b
a
b
b
Jana Hildebrandt, Ralf Trautwein, Daniel Kritsch, Norman Häfner,
a
b
b
a
Helmar Görls, Matthias Dürst, Ingo B. Runnebaum* and Wolfgang Weigand
*
After more than 50 years of platinum-based anticancer research only three compounds are in clinical use
worldwide. The use of the well-known lead compound of this class of anticancer agents, cisplatin, is
limited by its side effects and varying resistance mechanisms. Therefore, we report on platinum(II) com-
pounds with asparagusic acid derivatives as ligands which show interesting anticancer results on cisplatin
resistant cell lines.
Received 22nd June 2018,
Accepted 5th December 2018
DOI: 10.1039/c8dt02553c
rsc.li/dalton
with aqua-complexes which are able to bind to the genomic
Introduction
Cisplatin and analogues
9
,15–17
DNA.
This interaction with the DNA results in a distor-
tion of the dsDNA structure and erroneous DNA replication
9
Since its first description as a molecule with anticancer activity and leads to apoptosis of the proliferating cells. Although this
in the 1960s, cisplatin has acted as one of the major drugs in previously described mechanism is well accepted as the mecha-
1
,2
chemotherapeutic treatment. The compound is mainly used nism of action, more and more publications additionally concen-
in the treatment of lung, head and neck, ovarian, bladder and trate on the understanding of the bioavailability of the drug after
2
–6
testicular cancer types.
several side effects e.g. hepato-, nephro-, neuro- and ototoxicity molecules will just lead to the inactivation of cisplatin.
as well as several resistance mechanisms inside the human compounds are designed to follow cisplatin’s mechanism of
The drug application is limited by i.v. application. Importantly, the potential interaction with other
18–20
Many
3
,7–10
body.
Although there is a great research community action and target the DNA, although the effectiveness of com-
working on improving platinum(II) cancer agents, only two pounds is likely reduced by resistance mechanisms i.e. those
additional molecules are approved worldwide, namely carbo- mediated by the DNA repair enzymes removing the platinum-
3
,7,10,11
9
platin and oxaliplatin.
Carboplatin, developed in 1989, adducts from the DNA. Additionally, more than 50 years of
is clinically used against advanced ovarian carcinomas, research did not identify a drug superior to cisplatin. Thus, new
3
,10
whereas oxaliplatin has been well-implemented against meta- strategies for drug design should be investigated.
static colorectal cancers since 2002.
Therefore,
All three complexes other researchers developed compounds for interaction with
contain a square-planar platinum(II) core and on one side, other, so-called non-classical targets, e.g. proteins and
1
0,12,13
1
1,13,14
6,7,14,21
amine-ligands.
The rational design of platinum(II) anti- enzymes.
These complexes do not follow the “basic rules”
cancer agents putting effective leaving groups on the other two for platinum-based anticancer compounds but some of them
6,7,22,23
coordination sides seems to be an important characteristic. In exhibit acceptable anticancer activity.
the case of cisplatin the molecule exhibits two chlorido
ligands, whereas carboplatin and oxaliplatin have O,O-biden-
tate ligands. Inside the cell, these ligands can be substituted
Asparagusic acid
Natural products are of high interest for medicinal appli-
cations. Sulfur-containing metabolites exemplify one group of
such compounds with biological activities influencing human
2
4
a
health. Next to metabolites, small sulfur-containing com-
pounds like glutathione also have important physiological
Institut für Anorganische und Analytische Chemie Friedrich-Schiller-Universität
Jena, Humboldstraße 8, 07743 Jena, Germanywolfgang.weigand@uni-jena.de;
Fax: +49 3641 948102; Tel: +49 3641 948160
2
5
roles. Asparagusic acid is a sulfur-containing five membered
heterocyclic ring (1,2-dithiolane-4-carboxylic acid) with a car-
boxylic acid function which is unique to asparagus from which
b
Klinik für Frauenheilkunde und Fortpflanzungsmedizin, Universitätsklinikum Jena
Friedrich-Schiller-Universität Jena, Am Klinikum 1, 07747 Jena, Germany
†
CCDC 1514265 for Pt1 and 1514266 for Pt7 (excluding structure factors). For
2
6–28
it was isolated first in 1948.
of α-lipoic acid which can act as a co-factor for e.g. pyruvate
The structure is close to that
crystallographic data in CIF or other electronic format see DOI: 10.1039/
C8DT02553C
936 | Dalton Trans., 2019, 48, 936–944
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multienzyme and is often compared regarding its activity and compounds Ramos-Lima et al. found that the replacement of
2
7,29,30
chemical behavior to this molecule.
disulfide moieties is essential for mechanisms in biology, bio- Moreover the PPh
chemistry, medicinal chemistry, organic synthesis, catalysis, those with PMe Ph-ligands because of their steric effects. In
This con- 2011 the synthesis and cytotoxic activity of 14 different
templation supplemented with the wide range of observed platinum(II) compounds with the PtP pharmacophore have
The reactivity of the amine ligands by phosphanes results in lower IC50 values.
3
containing complexes are more active than
7
3
2
2
9–38
coordination chemistry and materials science.
2 2
S
5
9
medicinal properties for this compound leads to high interest been published. Researchers observed high IC50 values on
in asparagusic acid and its analogues for medicinal chemists. the cell line A2780 in comparison to cisplatin for their phos-
The pharmacological properties of ingredients of asparagus phane platinum(II) complexes. Also the simple PtCl
2 3 2
(PPh )
are numerous and the research on that increased in the last which acts as a starting compound for many platinum(II) com-
2
4,25,27,28,39,40
59,67
few years.
Concentrating on asparagusic acid plexes exhibits very low cytotoxic activity.
Interestingly, the
itself, several useful characteristics have been observed: anti- resistance ratio for these PtP
2 2
S
complexes was much lower
cancer, antioxidant, antifungal, antibacterial, anti-dysenteric, than that for cisplatin, caused by lower IC50 values on resistant
anti-inflammatory, anti-abortifacient, anti-oxytocic, antiulcer cell lines compared to cisplatin itself. To point out, the IC50
and anticoagulant activities, and it should reduce the risk of value for cisplatin on A2780cis/r is 17.1 whereas the average
2
7,39
rheumatism and diabetes.
These observations are based resistant ratio of all eight analyzed compounds is 1.9 (range
5
9
on the knowledge that asparagusic acid acts as a growth- from 1.5 to 3.0). This may be a consequence of circumvent-
inhibitor on higher plants as well as it prevents plants from ing the resistance mechanisms proving the relevance of this
fungal-growth, which has been observed already in the group of compounds despite the fact that their IC50 values are
2
7,41
1
970s.
sic acid and its analogues or modified compounds is the cellu- this previous work has been PPh
3 2
lar uptake which is well-identified as a thiol-mediated tance factor. Therefore, we focus in our work on the (PPh )
Important for medicinal applications of asparagu- in general very high. The most promising phosphane ligand in
, because of the best resis-
Pt
3
mechanism. Asparagusic acid uptake is mediated by binding group with dichalcogenolato ligands. Due to the biological
to a cysteine molecule on the surface of the transferrin relevance of asparagusic acid, this kind of structure completes
4
2,43
receptor.
These facts and the ability to synthesize metal- our platinum-complexes to generate compounds with lower
complexes with dithiolato and diselenolato ligands (see below) IC50 values than cisplatin. It can be expected that they have the
form the basis for the design of our compounds discussed in same effects on the resistance factors, as previously described
this publication.
by Mügge et al. In addition, as described above, selenium con-
taining complexes result in low IC50 values in comparison to
sulfur containing ones. Thus, the aim of this study was to
Platinum(II) complexes with S/Se and P containing ligands
In 2010 Siemeling et al. reported on the oxidative addition of compare sulfur and selenium containing compounds as well
platinum(0) complexes to asparagusic acid along the sulfur– as the mixed ones. To the best of our knowledge, this has not
3
6
sulfur bond. We reported previously and later on this kind of been discussed before. To shed light on the biological activity of
reaction to build dithiolato platinum(II) compounds with phos- the above discussed complexes we designed seven platinum(II)
4
4–50
phane ligands.
synthesize platinum(II) complexes with sulfur and selenium dppma, whereas dppma is bis(diphenylphosphino)methyl-
based ligands some researchers focus on the anticancer amine or PPh ligands. These compounds were tested on
In general, cisplatin sensitive and resistant cell lines.
Because it is already well-known how to compounds with four different asparagusic acid derivatives and
3
5
1–61
activity of these groups of metal complexes.
most researchers found high IC50 values for sulfur-containing
platinum(II) complexes in comparison to cisplatin, but results
proving higher cytotoxic activity were identified for the sel-
Results and discussion
Synthesis and characterization
5
2,55,57,62
enium-containing species.
Fuks et al. reported in 2010
on a comparison study between platinum(II) complexes with
sulfur or selenium containing ligands showing that the sel- For Pt2, Pt4 and Pt6, the first step is the preparation of
enium compound was the most promising on HeLa cervical (dppma)PtCl starting from (COD)PtCl which was prepared by
carcinoma cells. Next to sulfur phosphor donor ligands also adding COD (1,5-cyclooctadiene) to K PtCl as described in the
General synthesis of Pt1–Pt7 is described in
Therefore, several phosphane containing platinum(II) com- Scheme 1. For the dithiolate compounds Pt1 and Pt2
2
2
5
5
2
4
5
9,63
76,77
form strong and inert bonds with the platinum(II) ion.
literature.
6
4–74
plexes are known in the literature.
Several publications (Scheme 1a), the first step is the deprotonation of both SH
examine the cytotoxic activity of these kinds of compounds, groups at the dihydroasparagusic acid with K CO . In a next
2
3
1
and most of them have a higher IC50 value compared to cispla- step the corresponding PtCl
tin.
2
L
2
(L = PPh
3
or dppma, for more
2
6
7,69,70,74
Nevertheless, some publications show lower IC50 information see Scheme 1) component is added to the solu-
values for their compounds compared to that of cisplatin on tion of the deprotonated diasparagusic acid in CHCl /EtOH,
3
resistant-cell lines pointing to a different mechanism of followed by stirring at room temperature for 16 hours. After
6
5,66,70,75
−1
action overcoming the resistance mechanisms.
4
the addition of an aqueous solution of KHSO (c = 2 mol L ),
Concentrating on the structure–activity-relationships of these the crude product is purified by column chromatography (see
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asparagusic acid derivative. For the dppma containing com-
pounds Pt2 and Pt6 their molecular peaks are observed as well
as characteristic isotopic patterns. Compound Pt4 has been
characterized only by NMR spectroscopic methods.
Platinum(II) complexes Pt1 and Pt7 (Fig. 1) are characterized
by means of single crystal X-ray structure determination.
Molecular structures of the ligands L2 and L3 were discussed
7
8
previously. For compound Pt7 are at least two independent
molecules in the unit cell but just one is shown and discussed
because bond lengths and angles are very similar. All of them
Scheme 1 Synthesis and overview of the platinum(II) complexes Pt1–
Pt7 with their corresponding asparagusic acid derivatives as ligands L1–
36
L7. Pt1 was first published by Siemeling et al. Reagents and conditions:
a (for Pt1/Pt2): (i) 1 equiv. dihydroasparagusic acid, 4 equiv. K CO
0 ml EtOH, r.t.; (ii) 1 equiv. PtCl , 10 ml CHCl , r.t., 16 h; (iii) KHSO
for Pt1–Pt7): (i) 1.05 equiv. corresponding ligand, 3.15 equiv. NaBH
0 ml EtOH, r.t., 10 min; (ii) 0.5 M HCl, r.t., 5 min; (iii) K CO , 1 equiv.
PtCl , 10 ml CHCl , r.t., 16 h; (iv) KHSO
3
6,44,59
2
3
,
are in the same range like those reported earlier.
; b structures platinum(II) atoms reside in a slightly distorted
In both
1
2
L
2
3
4
(
4
,
square-planar coordination sphere similar to those reported
1
2
3
44,59
previously.
ligands the P1–Pt–P2 angle is, in both cases, larger than 90°
99.96°(5) for Pt1 and 97.38°(5) for Pt7), contrary to angles
reported for the platinum(II) compounds by Mügge et al.,
Because of the steric demand of the PPh3
2
L
2
3
4
.
(
the Experimental section). Another option for the preparation which show P–Pt angles typically for the dppe ligand of ∼85°.
of Pt1/Pt2 as well as for all other Pt(II) compounds (Pt3–Pt7) is The S1/Se1–Pt–S2/Se2 angles are close to 90°. The two Pt–P
to start with the asparagusic acid derivatives L1–L4. The first bond lengths are slightly longer (∼2.28 Å) than those which
5
9
step is reduction to a dianionic species using NaBH
by removal of unreacted NaBH with an aqueous solution of P2–Pt–S2, P1–Pt–Se1, are P2–Pt–Se2 are between 81° and 90°.
HCl and addition of K CO to adjust the pH value. Next steps The bond lengths of the corresponding X/Y to platinum(II) are
4
followed were published previously (∼2.25 Å). The angles P1–Pt–S1,
4
2
3
are similar to those described above: addition of PtCl
PPh , dppma), stirring overnight and work up steps (see the Se1–Pt 2.4427(5)). The carboxylic function of Pt1 forms inter-
Experimental section).
molecular hydrogen bonds with another unit (Fig. 1) leading
2 2
L (L = longer for Pt7 than for Pt1 (for example S1–Pt 2.3375(13) and
3
The compounds are characterized by NMR spectroscopy, to a dimeric structure in the crystal.
mass spectrometry and elemental analysis (see the
3
1
1
Biological activity
Experimental section). The
P{ H}NMR spectrum of Pt1
1
95
shows one singlet at 26.3 ppm with the corresponding
satellites as well as for Pt6 at 34.0 ppm with
Pt- The IC50 values of all platinum(II) complexes were determined
Pt- as well as with the MTT-assay (see the Experimental section for further
1
95
7
7
2
Se-satellites ( J
= 34.6 Hz). The unsymmetrically substi- conditions) on two different ovarian carcinoma cell lines
Se–P
tuted S/Se platinum(II) compounds Pt3 and Pt4 show a typical SKOV3 and A2780 (par – parental) as well as on their cisplatin-
3
1
1
AB spin system in the P{ H} NMR spectra. Mass spectra show resistant analogues (SKOV3cis and A2780cis; see the
7
9
the molecular peak as well as the characteristic isotopic Experimental section for preparation details). Cisplatin acts
pattern for compounds Pt1, Pt3, Pt5 and Pt7 with the PPh
as a reference and IC50 values were determined under the
3
ligand. All of them show the fragment m/z = 720 in the Micro- same conditions for platinum(II) compounds. Determined IC50
ESI pos. spectrum, which can be detected as a loss of the values (Table 1) for cisplatin confirmed significantly higher
Fig. 1 Left: Molecular structures of Pt1 in the crystal. Middle: Dimeric unit of Pt1 in the crystal, displaying intermolecular hydrogen bonding. Ellipsoids
are drawn at 50% probability level, hydrogen atoms have been omitted for clarity. Selected bond lengths (Å) and angels (°): P1–Pt 2.2847(13), P2–Pt
2.2925(12), S1–Pt 2.3375(13), S2–Pt 2.3472(13), C1–S1 1.818(6), C3–S2 1.822(5), P1–Pt–P2 99.96(5), P1–Pt–S1 88.75(5), S1–Pt–S2 90.09(4), P2–Pt–S2
81.09(5), C1–S1–Pt 107.60(19), C3–S2–Pt 103.09(19). Right: Molecular structures of Pt7 in the crystal. Only one of the two individual molecules
present in the asymmetric unit is shown. Ellipsoids are drawn at 50% probability level, and hydrogen atoms have been omitted for clarity. Selected
bond lengths (Å) and angels (°): P1–Pt 2.2351(14), P2–Pt 2.2866(13), Se1–Pt 2.4427(5), Se2–Pt 2.4733(6), C1–Se1 1.962(5), C3–Se2 1.971(6), P1–Pt–P2
9
7.38(5), P1–Pt–Se1 88.32(3), Se1–Pt–Se2 90.23(2), P2–Pt–Se2 84.12(4), C1–Se1–Pt 107.02(16), C3–Se2–Pt 101.09(19).
938 | Dalton Trans., 2019, 48, 936–944
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Table 1 IC50 values for Pt1–Pt7 on ovarian carcinoma cell lines SKOV3, to SKOV3 and A2780 (see Table 1). This results in improved
A2780 and their cisplatin-resistant analogues SKOV3cis and A2780Cis.
Resistant factors (RF) were calculated for each substance
resistant factors (RF). Cisplatin shows RF 3.6 (SKOV3) and 4.7
7
8
(
A2780) whereas the investigated compounds resulted in a RF
near to 1, Table 1. Previously reported results of sulfur contain-
ing platinum(II) compounds showed for A2780 and its resist-
ant-analogue that these molecules exhibit a higher IC50 value
SKOV3par
[μM]
SKOV3cis
[μM]
A2780par
[μM]
A2780cis
[μM]
Substance
Pt1
RF(Pt1)
Pt2
RF(Pt2)
Pt3
RF(Pt3)
Pt4
RF(Pt4)
Pt5
RF(Pt5)
Pt6
RF(Pt6)
Pt7
RF(Pt7)
CDDP
RF (CDDP)
5.5 (±1.3)
4.3
22.0 (±0.2)
0.6
17.8 (±5.2)
1.1
n.m.
23.5 (±1.8)
12.2 (±2.3)
18.7 (±3.7)
n.m.
9.8 (±1.6)
1.2
11.7 (±1.6)
1.4
9.7 (±2.7)
1.6
n.m.
11.8 (±0.9)
5
9
on the resistant cell line than on the sensitive one. This is
16.1 (±1.7) also observable for Pt1 and Pt2 (Table 1). IC50 values for most
of our compounds are in the same range than those already
16.0 (±1.9)
5
9
reported. Nevertheless, herein we used different incubation
times (48 h to 72 h) pointing to a higher cytotoxic activity of
our complexes. The best results are detected for selenium-con-
taining compounds Pt6 and Pt7, both of them show lower IC50
values on resistant cell lines than cisplatin and Pt7 shows
lower IC50 values for the resistant cell lines than for the sensi-
tive ones. This means that complex Pt7 exhibits an increased
cytotoxic activity for resistant tumour cells in comparison to
the parental, sensitive carcinoma cells. To conclude, we can
confirm from the previously published results that these kinds
of compounds show good RF, that Se/Se-containing platinum(II)
n.m.
—
—
13.7 (±6.6)
1.2
9.8 (±1.8)
1.2
6.3 (±0.9)
0.7
3.8 (±2.8)
3.6
15.9 (±2.1)
12.2 (±6.4)
4.3 (±1.4)
13.5 (±4.4)
5.4 (±2.4)
3.1
5.0 (±3.5)
1.1
7.8 (±0.9)
0.8
1.3 (±±.2)
4.7
17.0 (±4.5)
5.4 (±1.9)
5.9 (±1.6)
6.1 (±2.1)
values for the cisplatin-resistant analogues of both cell lines. complexes show a higher activity than sulfur containing ones
Parental SKOV3 and A2780 show higher cytotoxic activity of cis- and we can add the fact that especially Pt7 is a promising
5
5,59
platin in comparison to Pt1–Pt7. Interestingly, whereas IC50 candidate to target resistant cell lines.
values for cisplatin increase in SKOV3cis and A2780cis cells,
An overview of all IC50 values, the mean IC50 for the com-
IC50 is not increasing for most of the platinum(II) complexes pounds and their properties are given in Fig. 2. This overview
with asparagusic acid derivatives. Contrarily, in some cases depicts some SARs of the compounds. As mentioned before
IC50 values decrease in a significant way. Similar results have Pt7, with a Se–Se ligand, is the most active compound and has
been shown under the same conditions for our latest pub- a mean IC50 value of 6.09 μM which is comparable to that of
lished platinum(II) complexes with sulfur- and oxygen-contain- cisplatin (mean IC50 value 6.18 μM). Interestingly, also the
8
0
ing ligands. Compound Pt2 shows for SKOV3 an IC50 value second most active compound Pt6 contains a Se/Se ligand.
of 22.0 (±0.2) μM but SKOV3cis exhibits a significantly lower Moreover, the hydrophobicity of the residue R may play an
IC50 value of 12.2 (±2.3) μM. Also compound Pt7 has an important role. Pt7 is more active than Pt5 despite the identi-
increased influence on SKOV3cis and A2780cis in comparison cal structure except the residues (–COO–Et vs. –H and –COOH).
Fig. 2 IC50 values for the platinum(II) complexes ordered by rising mean IC50 (calculated with all four IC50 values per substance) and the character-
istics of the compounds. The strength of the SARs for the different characteristics is depicted on the right.
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1
77
The most active compounds harbour either PPh
3 3 4 2
(Pt7) or dppma and H Se HMBC NMR spectra 85% H PO and Me Se was
(Pt6) as ligands pointing to a slightly higher activity of PPh3. used as an external standard, respectively. Mass spectra were
Nevertheless, the ligand seems not to be able to break the recorded with a Finnigan MAT SSQ 710 instrument. Elemental
superior role of the asparagusic acid structure (Se vs. S) as Pt1 analysis was performed with a Leco CHNS-932 apparatus.
(PPh3, S–S) is less active compared to Pt6 (1/2 dppma, Se–Se).
Silica gel 60 (0.015–0.040 mm) was used for column chromato-
graphy and TLC was performed using Merck TLC aluminium
sheets (Silica Gel 60 F254).
Conclusions
Preparation of the platinum(II) complexes
The investigated platinum(II) complexes containing dichalco-
Method A. One equivalent of dihydroasparagusic acid was
genolato ligands were all characterized using NMR spec- dissolved in ethanol (10 ml for 0.1 mmol) and a fourfold
troscopy, MS spectrometry and elemental analysis. Pt1 and Pt7 excess of an aqueous solution of K CO was added. After stir-
were characterized in addition to X-ray diffraction analysis ring for 5 minutes one equivalent of a [PtP Cl ] suspension in
showing a slightly distorted square-planar coordination sphere chloroform was added and stirred overnight. The resulting
for the platinum(II) atom. All of these compounds were tested yellow solution was acidified with an aqueous KHSO solution
with MTT-assays for their cytotoxic behaviour. Albeit the com- and extracted with CHCl three times. Before removal of the
pounds do not show a higher activity as Cisplatin against the solvent, the combined organic phases were washed with water
tested sensitive ovarian cancer cell lines, the data suggest that and dried with Na SO . Purification of the crude product by
2
3
2
2
4
3
2
4
some compounds are able to specifically target resistant cell column chromatography using dichloromethane/acetone (5 : 1)
lines under the tested conditions. For the cell line SKOV3cis gave the complexes after precipitation from chloroform/hexane
the compounds Pt2, Pt6 and Pt7 have a lower IC50 value than as slight yellow solids.
cisplatin; for A2780cis this is observable for the compounds
Pt6 and Pt7. To point out Pt7 shows a high cytotoxic activity on equivalents) were suspended in ethanol (10 ml for 0.1 mmol).
all four cancer cell lines and lower IC50 values for the two cis- After addition of 3.15 equivalents NaBH and stirring for
Method B. The cyclic 1,2-dichalcogenolane derivatives (1.05
4
platin-resistant cell lines. In SKOV3cis for example the IC50 is 10 minutes the resulting clear solution was acidified with
significantly lower than that for cisplatin (4.3 ± 1.4 μM in com- diluted hydrochloric acid and then treated with aqueous
parison to 13.5 ± 4.4 μM, respectively). Therefore, this com-
pound should be validated as a substitute for cisplatin in the genolate. To this solution a suspension of [PtCl
treatment of resistant tumours. High resistance factors (RF valent) in chloroform was added and stirred overnight. After
IC50 resistant/IC50 sensitive) for CDDP (3.6 and 4.7 for A2780 treatment with aqueous KHSO the mixture was extracted with
K
2
CO
3
to deprotonate the intermediately occurring dichalco-
2 2
L
] (one equi-
4
and SKOV3) reflect the resistance status for cisplatin, whereas chloroform three times and the combined organic phases were
the RF values for substances Pt1–Pt7 are lower. For Pt7 and washed with water and dried with Na SO , followed by removal
2
4
Pt2 it is, as described above, lower than 1. This indicates that of the solvent under reduced pressure. Subsequent column
the platinum(II) compounds with asparagusic acid derivatives chromatography with dichloromethane/acetone (5 : 1) as the
as ligands are not detoxified by the same resistance mecha- mobile phase and precipitation from chloroform/n-hexane
nisms as cisplatin in the resistant cell lines. Moreover, some gave the complexes as yellow powders.
platinum(II) compounds (i.e. Pt7) may specifically target cells
8
1
[
Pt(dppma)Cl
In a Schlenk flask 0.498 g (1.331 mmol) of [Pt(cod)Cl
solved in 70 mL of CHCl and 532 mg (1.331 mmol) dppma
2
]
with cisplatin resistance associated aberrations because of
lower IC50 values on resistant cell lines than on sensitive ones.
2
] was dis-
3
was added. The mixture was stirred overnight at room tempera-
ture and reduced to 5 mL, resulting in the formation of a
white precipitate. This was filtered off, washed with a small
amount (1 mL) of CHCl3 and dried in vacuo. Yield: 0.610 g
Experimental section
General
If not otherwise mentioned, all reactions were carried out (69%) white powder.
under a dry nitrogen or argon atmosphere using standard
3 2
[Pt(1,2-dithio-4-carboxylic acid)(PPh ) ] (Pt1)
Schlenk techniques. The reagents were purchased from Acros,
Fisher Scientific, Merck, Umicore or Aldrich and were used This compound was prepared according to method A using
without further purification. Solvents were dried according to 30 mg (0.20 mmol) dihydroasparagusic acid and 111 mg
1
13
1
31
1
common procedures prior to use. H, C{ H} and P{ H} (0.80 mmol) [Pt(PPh )Cl ]. Yield: 50 mg (0.057 mmol, 29%)
3
2
1
NMR spectra were recorded on either a Bruker Avance 200,
3
H-NMR (400 MHz, CDCl ): δ = 3.02–3.44 (m, 5 H, HOOC–CH
Bruker Avance 400 or Bruker Avance 600 NMR spectrometer. and S–CH
H Se HMBC NMR measurements were performed on a 12 H; m-CH) ppm; C{ H}-NMR (100.6 MHz, CDCl ): δ = 25.79
2
), 7.14 (m, 12 H, o-CH), 7.28 (m, 6 H, p-CH), 7.40 (m,
1
77
13
1
3
Bruker Avance 400 NMR spectrometer. The NMR spectra were (s, S–CH
2
), 46.38 (s, HOOC–CH), 127.69 (m, m-CH), 130.41 (s,
calibrated with respect to the signal of the residual protons p-CH), 134.69 (m, o-CH), 177.52 (s, COOH) ppm, i-CH not
1
13
31
1
31
1
(
H) or the signal of the deuterated solvent ( C). For P{ H} detected; P{ H}-NMR (81 MHz, CDCl ): δ = 26.26 (s with
3
940 | Dalton Trans., 2019, 48, 936–944
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Paper
1
95
1
+
Pt-satellites, JPt–P = 2887 Hz) ppm; MS (ESI): 892 [M + Na]
(0.63 mmol) NaBH
4 3 2
and 158 mg (0.20 mmol) [Pt(PPh )Cl ].
+
+
−1
1
8
70 [M + H] 720 [M − Asp] ; C H O P PtS (869.868 g mol ): Yield: 63 mg (0.065 mmol, 33%); H-NMR (200 MHz, CDCl ):
4
0
36
2
2
2
3
calcd C 55.23, H 4.17, S 7.37; found C 54.36, H 4.39, S 7.34.
2
δ = 3.10–3.45 (m, 5 H, HOOC–CH and Se–CH ), 7.15 (m, 12 H,
o-CH), 7.29 (m, 6 H, p-CH), 7.45 (m, 12 H, m-CH) ppm;
[
Pt(1,2-dithio-4-carboxylic acid)(dppma)] (Pt2)
This compound was prepared according to method A using (s, HOOC–CH), 127.52 (m, m-CH), 130.31 (s, p-CH), 134.73 (m,
0 mg (0.20 mmol) dihydroasparagusic acid and 122 mg o-CH); 177.28 (s, COOH) ppm, iCH not detected, SeCH : n.z.;
Pt-satellites
13
1
C{ H}-NMR (50.3 MHz, CDCl ): δ = 25.79 (s, Se–CH ), 44.54
3
2
3
2
1
1
195
(
0.20 mmol) [Pt(dppma)Cl ]. Yield: 28 mg (0.038 mmol, 19%)
P{ H}-NMR (81 MHz, CDCl ): δ = 21.51 (s with
3
2
1
3
77
1
2
H-NMR (400 MHz, CDCl
3
): δ = 2.42 (t, JP–H = 10.2 Hz; 3 H; and Se-satellites; JPt–P = 2923 Hz, JSe–P = 49.3 Hz) ppm; MS
+
+
1
4
N–CH ), 2.91–3.37 (m, 5 H, HOOC–CH and S–CH
(
3
2
), 7.42–7.53 (DEI): 961 [M]
719 [M
−
Asp] ;
40 36 2 2 2
C H O P PtSe ·
1
3
1
−1
m, 12 H, o-CH and p-CH), 7.66 (m, 8 H, m-CH) ppm; C{ H}- CHCl (993 503 g mol ) calcd C 48.66, H 3.68; found C 48.58,
3
3 2
NMR (100.6 MHz, CDCl ): δ = 24.19 (s, S–CH ), 33.10 (s, H 3.51.
N–CH ), 49.56 (s, HOOC–CH), 129.11 (m, m-CH), 132.31 (s,
3
‘
[Pt(1,2-Diselenolane-4-carboxylic acid)(dppma)] (Pt6)
P{ H}-NMR This compound was prepared according to method B using
p-CH), 132.44 (s, p-C H), 132.77 (m, o-CH), 133.10 (m, o-C’H),
77.54 (s, COOH) ppm, i-CH not detected;
81 MHz, CDCl
Hz) ppm; MS (ESI): 767 [M
3
1
1
1
(
1
95
1
3
): δ = 37.19 (s with Pt-satellites, JPt–P = 2478 51 mg (0.21 mmol) diselenoasparagusic acid, 24 mg
+
+
+
Na] 745 [M
+
H] ; (0.63 mmol) NaBH and 133 mg (0.20 mmol) [Pt(dppma)Cl ].
4
2
−
1
1
C
29
H
29NO
2
P
2
PtS
2
(744.702 g mol ): calcd C 46.77, H 3.93, Yield: 85 mg (0.101 mmol, 51%); H-NMR (400 MHz, CDCl
3
):
3
N 1.88; S 8.61; found C 46.87, H 3.95, N 1.88; S 8.73.
δ = 2.44 (t, JP–H = 10.4 Hz, 3 H, N–CH
3
), 3.10–3.35 (m, 5 H,
HOOC–CH and Se–CH ), 7.49 (m, 8 H, o-CH), 7.55 (m, 4 H,
2
[
Pt(1,2-Thiaselenolane-4-carboxylic acid)(PPh ) ] (Pt3)
13
1
3
2
p-CH), 7.71 (m, 8 H, m-CH) ppm; C{ H}-NMR (100.6 MHz,
This compound was prepared according to method B using CDCl ): δ = 16.31 (s, Se–CH ), 33.28 (s, N–CH ), 47.57 (s,
1 mg (0.21 mmol) monoselenoasparagusic acid, 24 mg HOOC–CH), 129.07 (m, m-CH), 132.28 (s, p-CH), 132.34 (s,
3
2
3
4
(
‘
0.63 mmol) NaBH
Yield: 56 mg (0.061 mmol, 31%) H-NMR (400 MHz, CDCl
δ = 3.12–3.46 (m, 5 H, HOOC–CH, S–CH and Se–CH ), 7.15 33.98 (s with
4 3 2
and 158 mg (0.20 mmol) [Pt(PPh )Cl ]. p-C H), 132.81 (m, o-CH), 132.98 (m, o-C’H), 177.54 (s, COOH)
1
31
1
3
3
): ppm, i-CH not detected; P{ H}-NMR (81 MHz, CDCl ): δ =
1
95
77
1
Pt-satellites and Se-satellites, JPt–P = 2465
2
2
2
+
(
m, 12 H, o-CH), 7.29 (m, 6 H, p-CH), 7.43 (m, 12 H, m-CH) Hz,
J
Se–P
=
34.6 Hz) ppm; MS (ESI): 839 [M] ;
1
3
1
1
4
−1
ppm; C{ H}-NMR (100.6 MHz, CDCl
3
): δ = 17.10 (s, Se–CH
2
),
C
29
H
29NO
2
P
2
PtSe
2
·
CHCl
3
(868.336 g mol ) calcd C 40.46,
2
1
1
9.29 (s, S–CH ), 45.59 (s, HOOC–CH), 127.51 (m, m-CH), H 3.40, N 1.61; found C 40.85, H 3.28, N 1.19.
2
27.72 (m; m-CH), 130.38 (s, p-CH), 134.4–134.9 (m, o-CH),
3
1
1
[Pt(1,2-Diselenolane-diethylester)(PPh ) ] (Pt7)
3 2
77.21 (s, COOH) ppm, i-CH not detected;
P{ H}-NMR
1
95
2
(81 MHz, CDCl ): δ = 22.53 (d with
Pt-satellites, JP–P
Pt-satellites, JP–P
=
=
This compound was prepared according to method B using
110 mg of the ligand mixture, 18 mg (0.47 mmol) NaBH and
)Cl ]. Yield: 86 mg (0.081 mmol,
3
1
195
2
1
1
9.4 Hz, JPt–P = 2896 Hz), 24.89 (d with
9.5 Hz, JPt–P = 2907 Hz) ppm; H– Se-HMBC (400/76.3 MHz, 119 mg (0.15 mmol) [Pt(PPh
4
1
1
77
3
2
+
+
1
3
CDCl ): 67 (m; 1 Se; Pt–Se); MS (ESI): 917 [M] 720 [M − Asp] ; 54%); H-NMR (200 MHz, CDCl ): δ = 1.11 (t, J
C
= 7.2 Hz,
H–H
3
3
−
1
195
3
40
H
36
O
2
P
2
2 3
PtSeS (916.763 g mol ) calcd C 52.40, H 3.96, 6 H, CH –CH ), 3.59 (d with Pt-satellites, JPt–H = 46 Hz, 4 H,
S 3.50; found C 51.33, H 4.38, S 4.04.
Se–CH ), 7.09 (m, 12 H, o-CH), 7.23 (m, 6 H, p-CH), 7.41 (m, 12
2
1
3
H, m-CH) ppm; C-NMR (100.6 MHz, CDCl ): 13.95 (s, CH ),
3
3
[Pt(1,2-Thiaselenolane-4-carboxylic acid)(dppma)] (Pt4)
23.55 (s, SeCH
2
), 58.97 (s, SeCH
2
–C), 60.89 (s, CH
3
–CH
2
),
This compound was prepared according to method B using 127.30 (m, m-CH), 129.94 (s, p-CH), 130.80 (m, i-C), 134.66 (m;
3
1
1
4
1 mg (0.21 mmol) monoselenoasparagusic acid, 24 mg o-CH) ppm; P{ H}-NMR (81 MHz, CDCl ): δ = 22.09 (s with
3
1
95
77
1
2
(
0.63 mmol) NaBH
H-NMR (400 MHz, CDCl
4
and 133 mg (0.20 mmol) [Pt(dppma)Cl
2
].
Pt-satellites and Se-satellites, JPt–P = 2902 Hz, JSe–P = 47.5
): δ = 2.46 (t, JP–H = 10.2 Hz, 3 H, Hz) ppm; H– Se-HMBC (400/76.3 MHz, CDCl ): δ = 85.5 (m,
1
3
1
77
3
3
+
+
N–CH ), 3.07–3.38 (m, 5 H, HOOC–CH, S–CH and Se–CH2), Se–CH2) ppm; MS (ESI): 1063 [M] , 719 [M
−
Asp] ;
(1063.75 g mol ) calcd C 50.81, H 4.17;
), 26.50 (s, found C 50.78, H 4.24.
S–CH ), 48.41 (s, HOOC–CH), 129.0 (m, m-CH), 130.38 (s, p-CH),
3
2
−1
7
.45–7.58 (m, 12 H, o-CH and p-CH), 7.70 (m, 8 H, m-CH) ppm;
45 44 4 2 2
C H O P PtSe
1
3
1
3 2
C{ H}-NMR (100.6 MHz, CDCl ): δ = 13.21 (s, Se–CH
2
Crystal structure determination
1
32.2–133.2 (m, o-CH), 177.29 (s, COOH) ppm, i-CH not detected;
3
2
2
1
1
195
P{ H}-NMR (81 MHz, CDCl
3
): δ = 33.87 (d with Pt-satellites, The intensity data were collected on a Nonius KappaCCD dif-
Pt-satellites, fractometer, using graphite-monochromated Mo-K radiation.
Pt–P = 2439 Hz) ppm; H– Se-HMBC Data were corrected for Lorentz and polarization effects;
1
195
JP–P = 50.3 Hz, J
J
= 2503 Hz), 37.21 (d with
Pt–P
1
α
1
77
P–P = 50.3 Hz,
J
(
400/76.3 MHz, CDCl
3
): 573.5 (m; 1 Se; Pt–Se). absorption was taken into account on a semi-empirical basis
8
2–84
using multiple-scans.
The structure was solved by direct methods (SHELXS ) and
This compound was prepared according to method B using refined by full-matrix least squares techniques against
[Pt(1,2-Diselenolane-4-carboxylic acid)(PPh ) ] (Pt5)
83
3
2
2
83
5
1 mg (0.21 mmol) diselenoasparagusic acid, 24 mg Fo (SHELXL-97 ).
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Dalton Trans., 2019, 48, 936–944 | 941

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Dalton Transactions
The hydrogen atoms bonded to the sulfur ligand of Pt1 regression analyses applying Hill-slope were run in GraphPad
were located by difference Fourier synthesis and refined isotro- 5.0 software.
pically. All other hydrogen atoms were included at calculated
positions with fixed thermal parameters. All non-hydrogen
8
5
atoms were refined anisotropically.
Conflicts of interest
g mol− , colourless prism, size 0.122 × 0.112 × 0.108 mm , There are no conflicts to declare.
2 2 3 r
Crystal data for Pt1. C40H36O2P PtS , CHCl , M = 989.21
1
3
monoclinic, space group C2/c, a = 27.8130(5), b = 19.4794(3),
3
c = 19.1878(3) Å, β = 130.220(1)°, V = 7937.8(2) Å , T = −140 °C,
−
3
−1
Z = 8, ρcalcd = 1.655 g cm , µ (Mo-K
scan, transmin: 0.5671, transmax: 0.7456, F(000) = 3920,
3 970 reflections in h(−36/28), k(−25/25), l(−24/24), measured Umicore AG & Co. KG is acknowledged for a generous gift of
in the range 2.09° ≤ Θ ≤ 27.48°, completeness Θmax = 99.7%, PtCl
075 independent reflections, Rint = 0.0526, 7484 reflections
with F > 4σ(F ), 484 parameters, 0 restraints, R1obs = 0.0425,
wR2obs = 0.0799, R1all = 0.0591, wR2all = 0.0864, GOOF = 1.085,
α
) = 39.59 cm , multi-
Acknowledgements
2
K
2
4
.
9
o
o
Notes and references
−
3
largest difference peak and hole: 1.136/−1.364 e Å
Crystal data for Pt7. C45 PtSe , 0.5·C
109.82 g mol− , yellow prism, size 0.05 × 0.05 × 0.05 mm ,
.
H
H
44
O
4
P
2
2
7
8
, M
r
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