Ruthenium(II)–arene and triruthenium-carbonyl cluster complexes with new water-soluble phopsphites based on glucose: Synthesis, characterization and antiproliferative activity

Article abstract of DOI:10.1016/j.jorganchem.2020.121312

New water-soluble 3,5,6-bicyclophosphite ligands based on glucose modified with uracil, 5-fluorouracil or thymine are reported. The phosphite ligands were subsequently reacted with bis[dichlorido(η⁶-p-cymene)ruthenium(II)] and trirutheniumdodecacarbonyl to afford monoruthenium analogues of RAPTA-C and triruthenium clusters with 1–3 phosphite ligands, respectively. The influence of ligands on the stability of the compounds and the antiproliferative activity of the compounds was investigated.

Full text of DOI:10.1016/j.jorganchem.2020.121312

Journal of Organometallic Chemistry 919 (2020) 121312
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Ruthenium(II)earene and triruthenium-carbonyl cluster complexes
with new water-soluble phopsphites based on glucose: Synthesis,
characterization and antiproliferative activity
Maria R. Gonchar a, Egor M. Matnurov a, Tatiana A. Burdina a, Oliver Zava b, Tina Ridel b,
,
*
Elena R. Milaeva a, Paul J. Dyson b, Alexey A. Nazarov a
a Lomonosov Moscow State University, Department of Medicinal Chemistry and Fine Organic Synthesis, Leninskie Gory 1/3, 119991, Moscow, Russia
Institut des Sciences et Ingenierie Chimiques, Ecole Polytechnique Federale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland
b
ꢀ
ꢀ
ꢀ ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
New water-soluble 3,5,6-bicyclophosphite ligands based on glucose modified with uracil, 5-fluorouracil
or thymine are reported. The phosphite ligands were subsequently reacted with bis[dichlorido(h
6-p-
Received 25 November 2019
Received in revised form
17 April 2020
Accepted 18 April 2020
Available online 5 May 2020
cymene)ruthenium(II)] and trirutheniumdodecacarbonyl to afford monoruthenium analogues of RAPTA-
C and triruthenium clusters with 1e3 phosphite ligands, respectively. The influence of ligands on the
stability of the compounds and the antiproliferative activity of the compounds was investigated.
© 2020 Elsevier B.V. All rights reserved.
Keywords:
Ruthenium(II)-arene compounds
Triruthenium-carbonyl clusters
Antiprolifirative activity
Water-soluble phopsphites
1. Introduction
in aqueous-organic biphasic catalysis and therapeutic applications,
has led to the development of amphiphilic and hydrophilic ana-
Phosphorus-based ligands (e.g. Xantphos, (S)-BINAP) are an
important class compounds with widespread uses in catalysis and
medicinal chemistry [1e7]. While many phosphorus-based ligands
are hydrophobic, their increasing use in aqueous environments, e.g.
logues, such as the classic sulfonated phosphines TPPMS (sodium
3-(diphenylphosphino) benzenesulfonate) and TPPTS (triphenyl-
phosphine-3,30,300-trisulfonic acid trisodium salt) [8e11].
* Corresponding author.
E-mail address: nazarov@med.chem.msu.ru (A.A. Nazarov).
https://doi.org/10.1016/j.jorganchem.2020.121312
0022-328X/© 2020 Elsevier B.V. All rights reserved.

2
M.R. Gonchar et al. / Journal of Organometallic Chemistry 919 (2020) 121312
The chemistry of Ru compounds with phosphorus ligands is
evaluated.
well developed and has found many applications in catalysis. As
examples, water-soluble ruthenium complexes containing TPPTS
catalyzes the selective reduction of the carbonyl group in
a
,b
-un-
2. Results and discussion
saturated aldehydes [12,13], RuCl2(TPPTS)3 has been used as a
catalyst for the hydrogenation of unsaturated hydrocarbons [14]
and in formic acid dehydrogenation [15e17]. The cage phosphine,
1,3,5-triaza-7-phosphaadamantane (PTA), first reported in 1974 by
Daigle is amphiphilic in character and has been extensively used in
the catalysis [18e20]. The complex [RuCl2(PTA)4] catalyzes the se-
lective reduction of carbonyl groups [21] and acts as a catalyst
precursor for hydrogenation of CO2 and bicarbonate in aqueous
solution [22]. The Ru-cyclopentadienyl complex CpRuCl(PTA)2
demonstrates regioselective catalytic activity for the hydrogenation
of unsaturated ketones under aqueous biphasic conditions [23],
and a related complex catalyzes nitrile hydration [24].
The 3,5,6-bicyclophosphites with uracil 8, 5-fluorouracil 9 or
thymine 10 moieties were prepared according to the route shown
in Scheme 1. In the first step 1 was treated with O,O0-bis(-
trimethylsilyl)-uracil (prepared in situ), O,O0-bis(trimethylsilyl)-5-
fluorouracil (commercially available) or O,O0-bis(trimethylsilyl)-
thymine (prepared in situ) in the presence of trimethylsilyltri-
fluoromethane sulfonate. The trimethylsilyl protecting groups were
removed by treatment with NaHCO3 and the pure compounds 2e4
obtained by column chromatography. This procedure leads to the
exclusive formation of the b-isomer, which affords one set of signals
in the 1H and 13C NMR spectra. In the 1H NMR spectra of 2e4 signals
from the uracil (in 2), 5-fluro-uracyl (in 3) or thymine (in 4) moi-
eties were observed. The propanoyl protecting groups were
removed by treatment of 2e4 with ammonia in methanol [49] to
afford the modified sugars 5e7. The 1H and 13C NMR spectra of 5e7
confirm the disappearance of signals attributable to the protecting
groups.
The Ru(h
6-p-cymene)Cl2PTA, termed RAPTA-C, is a pre-catalyst
for hydrogenation reactions [25], but is better known for its anti-
cancer properties [26e28], primarily when used in combination
with other drugs [29e33]. In addition to RAPTA-C, an extensive
range of RAPTA-type complexes has been studied encompassing Ru
with an arene ligand, PTA or modified PTA ligand and additional co-
ligands [34]. An alternative series of compounds are known in
which the PTA ligand is replaced by other phosphorus donor li-
gands. Examples include RAPTA analogues with phosphite-
carbohydrate ligands [35e38], which potentially target cancer
cells via the Warburg effect [39].
Interestingly, Ru-carbonyl clusters with the same ligand show
anticancer and anti-angiogenic activity [40]. However, the limited
solubility of the complexes and clusters in aqueous media repre-
sents a significant limitation of the compounds for pharmacological
applications. Consequently, we decided to prepare a new class of
water-soluble bicyclophosphites bearing uracil, 5-fluorouracil or
thymine moieties. Glucose modified compounds bearing natural or
artificial nucleobases can be seen as antimetabolites, known class of
active chemotherapeutic agents such as folic acid, pyrimidine or
purine analogues. Antimetabolites have similar structures as
naturally occurring molecules used in nucleic acid synthesis but
differ enough that they interfere with normal cell functions. These
agents are used for a variety of cancer therapies, including
leukaemia, breast, ovarian and gastrointestinal cancers [41,42].
5-Fluorouracil (5-FU) is a pyrimidine base containing a fluorine
atom at the 5-carbon position on the ring and inhibits DNA syn-
thesis due to mimicking the natural base. 5-FU is used for the
treatment of many malignancies, including in co-administration
with oxaliplatin [43,44]. Recently several reports were published
in which the activity of Ru complexes with 5-fluorouracil [45e47]
against several cancer cell lines, including HCT116 [48] was
reported.
Phosphorylation of 5e7 with hexaethylphosphoroustriamide
leads to the formation of the 3,5,6-bicyclophosphite ligands 8e10
[50]. 31P NMR spectroscopy was used to monitor the progress of the
reaction and, with time, a signal at ca. 119 ppm increases in in-
tensity which confirms the formation of the bicyclophosphite unit.
The 13C NMR spectra of 8e10 show the expected JC-P (C4eP~2 Hz,
C5eP~4 Hz, C6eP~5.6 Hz, C3eP<1 Hz) coupling constants con-
firming the formation of the product.
The 3,5,6-bicylophosphite ligands based on a sugar moiety re-
ported in the literature [51] are insoluble or only sparingly soluble
in water. Still, they are reasonably stable towards oxidation and
In this report, RAPTA-type complexes and Ru-carbonyl clusters
were prepared based on the new phosphite ligands and their
antiproliferative activity against several cancer cell lines was
Fig. 1. 31P NMR spectra 8 in water over 24 h.
Scheme 1. Synthesis of 3,5,6-bicylophosphite ligands 8e10.

M.R. Gonchar et al. / Journal of Organometallic Chemistry 919 (2020) 121312
3
Scheme 2. Synthesis of Ru(II)-arene complexes 11e13.
Table 1
moisture in comparison to noncyclic phosphites. In contrast, 8e10
have a much higher solubility in the polar solvents such as acetone
or water. The stability of 8e10 in water was studied by 31P NMR
spectroscopy (see Fig. 1 for the spectra of 8), with hydrolytic
decomposition taking place and ca. 30% decomposition observed
after 24 h.
Lipophilicity and solubility of cluster compounds 14e16.
Compound
LogP o/w
Solubility, mM
0.1% DMSO
0.3% DMSO
0.5% DMSO
14
15
16
5.25
4.17
3.89
297
70
115
910
85
128
1177
177
The reaction of 8e10 with bis[dichlorido(h
6-p-cymene)ruth-
202
enium(II)] in CH2Cl2 at room temperature afforded the Ru(II)-arene
complexes 11e13 in high yield (Scheme 2).
The characteristic change in the resonance in the 31P NMR
spectra were observed upon coordination of the phosphite ligands,
with the singlet shifting from ca. 119 ppm to ca. 135 ppm. Com-
plexes 11e13 are soluble in methanol, acetone, and water, with
their water solubility being at least five times higher than their
Table 2
Antiproliferative activity against human ovarian cancer cells.
Compounds
IC50 (mM)
A2780
A2780R
dichlorido(
propylidene-
h
6-p-cymene)(3,5,6-bicyclophosphite-1,2-O-iso-
-glucofuranoside)ruthenium(II) analogues. Never-
6
9
>5000
>5000
>5000
>5000
a-D
11
12
13
14
15
16
477 23
659 117
579 67
1249 264
0.50 0.09
41 15
>100
theless, in aqueous solution 11e13 slowly hydrolyze, as observed
for related compounds [35], but at a much slower rate. After 8 h in
the water, about 50% of original complex remains present (deter-
mined by 31P NMR spectroscopy), whereas only 10% remains for the
previously reported compounds.
1227 119
537 118
0.87 0.03
45 14
81
3
Previously, triruthenium-carbonyl clusters derivatized with the
3,5,6-bicyclophosphite-1,2-O-isopropylidene-a-D-glucofuranoside
derivatized with the 3,5,6-bicyclophosphite-1,2-O-isopropylidene-
-glucofuranoside ligand and this can be attributed to use of new
water soluble ligand 8 [40].
ligand were shown to exhibit anticancer and antiangiogenic
properties depending on the number of phosphorus ligands coor-
dinated to the cluster core [40]. However, their low water solubility
complicated studies and limit applications. Triruthenium dodeca-
carbonyl, Ru3(CO)12, was reacted with varying stoichiometries of 8
to afford 14e16 (Scheme 3). Changing the stoichiometry of the
a-D
The antiproliferative activity of compounds 6, 9 and 11e16 was
studied against human ovarian cancer (A2780) cells and the
cisplatin-resistant variant (A2780R), see Table 2. The glucose and
phosphorylated derivatives of 5-fluorouracil, i.e. 6 and 9 respec-
tively, are inactive. The Ru(II)-arene complexes 11e13 are active
only at a high micromolar range and may be considered as essen-
tially non-toxic. The most cytotoxic was found to be triruthenium
cluster with one phosphorus ligand coordinated to the cluster core
followed by compounds with two and tree phosphite ligands. A
similar dependence of cytotoxicity on the number of coordinated
reactants
(ruthenium
carbonyl
cluster:trimethylamine-N-
oxide:bicyclophosphite ligand) allows one to three carbonyl li-
gands to be substituted by the phosphite ligand. The reactions were
monitored by 31P NMR spectroscopy with the singlet correspond-
ing to the free ligand at 119 ppm shifting to 150e152 ppm following
coordination to the ruthenium-carbonyl cluster. Clusters 14e16
(Table 1.) are approximately twice as water-soluble than those
Scheme 3. Synthesis of triruthenium-carbonyl clusters 14e16.

4
M.R. Gonchar et al. / Journal of Organometallic Chemistry 919 (2020) 121312
phosphorus ligands was observed for previously reported
ruthenium-carbonyl clusters [40,52].
optical density, which is directly proportional to the number of
surviving cells, was quantified at 540 nm using a multiwell plate
reader (iEMS Reader MF, Labsystems, USA) and the percentage of
surviving cells was calculated from the absorbance of untreated
cells.
3. Experimental
All solvents were purified and degassed prior to use. 1H, 13C{1H},
and 31P{1H} NMR spectra were recorded on a Bruker Avance II 400
spectrometer at room temperature. Spectra were referenced to the
1H signal of the NMR solvent or by the inclusion of an external
reference: H3PO4 for 31P{1H} NMR. ESI-mass spectra of the com-
pounds were obtained in MeOH on a ThermoFinnigan LCQ Deca XP
Plus quadrupole ion-trap instrument operated in positive ion mode
over a mass range of m/z 150e1000. The ionization energy was set
at 5.0 V and the capillary temperature at 150 ꢀC. Melting points
were determined with a Stuart Scientific SMP3 apparatus and are
uncorrected. Flash chromatography system Varian 971-FP and
prepacked Silica Gel columns (Luknova, US) were used for purifi-
cation. Elemental analyses were carried out at the microanalytical
3.3. 1-(5-Fluorouracil)-2,3,5,6-tetra-O-propanoyl-b-D-
glucofuranosyl 3
Trimethylsilyltrifluoromethanesulfonate (2.24 g, 10.07 mmol)
was added dropwise to a solution of 1,2,3,5,6-penta-O-propanoyl-
b-D
-glucofuranose (2.25 g, 4.89 mmol) and O,O0-bis(trimethylsilyl)-
5-fluorouracil (2.0 mL, 7.65 mmol) in acetonitrile (50 mL) at 0 ꢀC
under N2 atmosphere. The reaction mixture was refluxed for 5 h,
cooled down to 0 ꢀC and saturated solution of NaHCO3 (50 mL) was
added. The product was extracted with CH2Cl2 (4 ꢁ 30 mL) and the
combined organic fractions were washed with brine and dried over
MgSO4. The pure product was isolated by flash chromatography
(СHCl3:MeOH 99:1). Yield: 1.83 g (72.6%), mp: 49e50 ꢀC, elem.
anal. calcd (%) for C22H29N2O11F: C 51.16, H 5.66, N 5.42; found: C
laboratory EPFL. The bis[dichlorido(
h
6-p-cymene)ruthenium(II)]
-d-
[53], 1,2,3,5,6-Penta-O-propanoyl- -d-glucofuranose 1 [54], 1-
b
b
glucofuranosyluracil 5 [49] were synthesized according to litera-
ture procedures and all analytical data was similar to the reported
in the literature.
51.07, H 5.77, N 5.27.1H NMR (400.13 MHz, CDCl3):
d
¼ 9.14 (d,
J ¼ 4.4 Hz, 1H, NH), 7.56 (d, J ¼ 5.9 Hz, 1H; CH]CF), 6.07 (tr,
J ¼ 1.7 Hz, 1H; H-1), 5.48 (d, J ¼ 2.9 Hz, 1H; H-3), 5.38 (m, 1H; H-5),
5.06 (d, J ¼ 2.0 Hz, 1H; H-2), 4.61 (dd, J ¼ 12.2; 2.4 Hz, 1H; H-6), 4.38
(dd, J ¼ 9.3; 2.9 Hz 1H; H-4), 4.13(dd, J ¼ 12.3; 4.9 Hz, 1H, H-60),
2.58e2.28 (m, 8H, CH2), 1.21e1.10 (m, 12H, CH3) ppm.13C{1H} NMR
3.1. Log P values measured by reversed-phase HPLC
The log P values were measured by reversed-phase HPLC on a
150 mm C-18 column following the method already described in
the literature [40,55e57]. The correlation between log Kw and log P
was established based on the compounds with known logP (4-
methoxyanilin: 0.95, 4-bromanilin: 2.26, naphthalene: 3.30, tert-
butylbenzene: 4.11, pyrene: 4.50). For solubility measurements
compounds were solubilized in DMSO and diluted with water to
(100.63 MHz, CDCl3):
d
¼ 173.9 (CO), 173.0 (CO), 172.5 (CO), 171.9
(CO), 156.7 (J ¼ 26.7 Hz, C(O)CF), 148.8 (CO),140.8 (J ¼ 238.5 Hz, CF),
123.5 (J ¼ 34.7 Hz, CH]CF), 89.3 (C-1), 80.0 (C-2), 78.8 (C-4), 72.9
(C-3), 66.7 (C-5), 62.7 (C-6), 27.3 (CH2), 27.2 (CH2), 27.1 (CH2), 27.0
(CH2), 8.9 (CH3), 8.7 (CH3), 8.6 (CH3), 8.5 (CH3) ppm. MS (ESIþ): m/z:
517 [MþH]þ.
achieve a final concentration of 300 mM. In all cases the precipita-
tion of compounds was observed, sample shacked for 30 min,
filtered and concentration of complexes in the aqeous phase was
estimated by HPLC. The calibration curve was plotted.
3.4. 1-(2,3,5,6-Tetra-O-propanoyl-b-D-glucofuranosyl) thymine 4
3.2. Cell culture experiments and conditions
1,1,1,3,3,3-Hexamethyldisilazane (15.4 mL, 73.5 mmol) was
added to a suspension of thymine (630 mg, 5 mmol) and (NH4)2SO4
(60 mg, 0.45 mmol) in CH2Cl2 (20 mL). The reaction mixture was
refluxed for 2 h and the resulting clear solution was concentrated in
vacuo to yield the O,O0-bis(trimethylsilyl)-thymine as a colourless
oil, which was redissolved in dry acetonitrile (25 mL) and 1,2,3,5,6-
Human A2780 and A2780cisR ovarian carcinoma cell lines were
obtained from the European Centre of Cell Cultures (ECACC, Porton
Down, Salisbury, UK). Human MCF-7 breast carcinoma was ob-
tained from the American Type Culture Collection (ATCC). These
cells are routinely grown in Dulbecco’s Modified Eagle Medium
containing 4.5 g/L glucose and glutamax and were supplemented
with 10% heat-inactivated fetal bovine serum and antibiotics. Cul-
tures were maintained at 37 ꢀC in a humidified atmosphere con-
taining 5% CO2. All cell culture reagents were purchased from
Gibco-BRL, Basel Switzerland. For cell viability experiments tests,
cells were grown in 96-well plates (Costar, Integra Biosciences,
Cambridge, MA, USA) as monolayers for 24 h in complete medium
with 10% FCS to reach sub-confluence. Then fresh complete me-
dium with 5% FCS was added together with the drugs, and the
culture was continued for another 72 h. The compounds were pre-
dissolved at 20 mM in DMSO and then added to the cell culture
medium at the required concentration with a maximum DMSO
content of 0.5 v/v% to be incubated for 72 h. At these concentra-
tions, DMSO does not affect cell viability. Cell viability was deter-
mined using the MTT assay, which quantifies the mitochondrial
activity in metabolically active cells, essentially as reported previ-
ously [58]. Briefly, following drug exposure, MTT (Sigma, final
concentration 0.2 mg/mL) was added to the cell culture medium for
the final 2 h, then the culture medium was aspirated and the violet
formazan precipitate dissolved in 0.1 M HCl in 2-propanol. The
penta-O-propanoyl-b-D-glucofuranose (1.3 g, 2.83 mmol) was
added. The reaction mixture was cooled down to 0 ꢀC and trime-
thylsilyltrifluoromethane sulfonate (1.12 g, 5.03 mmol) was added
dropwise. After 5 h of refluxing the mixture was cooled to 0 ꢀC with
an ice bath and a saturated solution of NaHCO3 (20 mL) was added
to quench the reaction. The product was isolated by extraction with
CH2Cl2 (4 ꢁ 20 mL) and purified by column chromatography
(CHCl3:MeOH 99:1). Yield: 1.0 g (69.0%), mp: 53e54 ꢀC, elem. anal.
calcd (%) for C23H32N2O11: C 53.90, H 6.29, N 5.47; found: C 53.85, H
6.63, N 5.13.1H NMR (400.13 MHz, CDCl3):
d
¼ 9.33 (s, 1H, NH), 7.56
(d, J ¼ 1.5 Hz, 1H; CH]CCH3), 6.11 (tr, J ¼ 2.3 Hz, 1H; H-1), 5.46 (d,
J ¼ 3.5 Hz, 1H; H-3), 5.38 (m, 1H; H-5), 5.05 (d, J ¼ 2.3 Hz, 1H; H-2),
4.62 (dd, J ¼ 12.3; 2.3 Hz,1H; H-6), 4.35 (dd, J ¼ 9.6; 3.2 Hz 1H; H-4),
4.09(dd, J ¼ 12.3; 5.3 Hz, 1H, H-60), 2.49e2.25 (m, 8H, CH2), 1.97 (d,
J ¼ 1.2 Hz, 3H, CH3), 1.23e1.06 (m, 12H, CH3) ppm.13C{1H} NMR
(100.63 MHz, CDCl3):
d
¼ 174.0 (CO), 173.1 (CO), 172.6 (CO), 171.8
(CO),163.5 (C(O)CCH3),150.1 (CO),134.9 (CCH3),111.9 (CH]C(CH3)),
88.9 (C-1), 80.4 (C-2), 78.4 (C-4), 73.3 (C-3), 66.8 (C-5), 62.9 (C-6),
27.4 (CH2), 27.3 (CH2), 27.2 (CH2), 27.1 (CH2), 12.7 (C(CH3)), 9.0
(CH3), 8.8 (CH3), 8.7 (CH3), 8.6 (CH3) ppm. MS (ESIþ): m/z: 535
[MþNa]þ.

M.R. Gonchar et al. / Journal of Organometallic Chemistry 919 (2020) 121312
5
3.5. 1-(5-Fluorouracil)-
b
-
D
-glucofuranosyl 6
80.3 (J ¼ 3.5 Hz, C-3), 79.7 (C-2), 74.3 (J ¼ 2.1 Hz, C-4), 71.7
(J ¼ 3.5 Hz, C-5), 67.1 (J ¼ 5.6 Hz, C-6) ppm.31P{1H}NMR
1-(5-Fluorouracil)-2,3,5,6-tetra-O-propanoyl-
b
-
D
-glucofur-
(161.98 MHz, d6-acetone):
[M ꢂ H]-.
d
¼ 120.2 ppm. MS (ESIꢂ): m/z: 319
anosyl (5.0 g, 9.68 mmol) was dissolved in saturated ammonia in
MeOH (100 mL) and left at room temperature for 24 h. The solvent
was removed at reduced pressure and the pure product was iso-
lated by flash column chromatography on silica gel
3.9. 3,5,6-Bicyclophosphite-1-
b-
D-glucofuranosylthimine 10
(CHCl3:CH3OH:NH3aq 84:15:1). Yield: 2.12
g (75.0%), mp:
186e187 ꢀC decomp., elem. anal. calcd (%) for C10H13N2O7F: C 41.10,
Similar to compound 8 starting from 1-
b-D-thimineglucofur-
H 4.48, N 9.59; found: C 41.19, H 4.54, N 9.47.1H NMR (400.13 MHz,
anosyl 4 (1.0 g, 3.47 mmol) and hexaethylphosphoroustriamide
(0.86 g, 3.47 mmol) compound 10 was synthesized. Yield: 0.76 g
(69.5%), mp: 241e242 ꢀC decomp., elem. anal. calcd (%) for
MeOH):
d
¼ 8.10 (d, J ¼ 7.0 Hz, 1H; CH]CF), 5.79 (t, J ¼ 1.4 Hz, 1H;
H-1), 4.18e4.15 (m, 2H; H-3, H-4), 4.14e4.10 (m, 2H; H-5, H-2), 3.84
(dd, J ¼ 11.7; 3.2 Hz, 1H; H-6), 3.69 (dd, J ¼ 11.7; 5.6 Hz, 1H, H-60)
C
11H13N2O7P: C 41.78, H 4.14, N 8.86; found: C 42.19, H 4.21, N
ppm.13C{1H} NMR (100.63 MHz, MeOH):
d
¼ 158.1 (J ¼ 26.8 Hz, C(O)
8.53.1H NMR (400.13 MHz, d6-acetone):
d
¼ 10.04 (s. 1H, NH), 8.03
CF), 149.4 (CO), 139.8 (J ¼ 231.0 Hz, CF), 125.8 (J ¼ 35.3 Hz, CH]CF),
92.2 (C-1), 82.9 (C-4), 81.0 (C-2), 74.8 (C-3), 69.3 (C-5), 63.8 (C-6)
ppm. MS (ESIþ): m/z: 315 [MþNa]þ.
(d, J ¼ 1.2 Hz, 1H; CH]C(CH3)), 5.86 (d, J ¼ 0.9 Hz, 1H; H-1),5.24 (d,
J ¼ 4.1 Hz, 1H; HO), 5.12 (m, 1H; H-5), 4.62 (dd, J ¼ 9.4; 4.7 Hz, 1H;
H-6), 4.41 (m, 2H; H-3, H-4), 4.24 (brs, 1H; H-2), 4.02 (m, 1H, H-60),
1.88 (d, J ¼ 1.2 Hz, 3H; CH3) ppm.13C{1H} NMR (100.63 MHz, d6-
3.6. 1-b-D-Glucofuranosylthimine 7
acetone):
d
¼ 163.4 (C(O)), 150.4 (CO), 135.9 (CH]C(CH3)), 108.8
(CH]C(CH3)), 93.0 (C-1), 80.0 (C-2), 79.7 (J ¼ 3.5 Hz, C-3), 74.7 (C-
4), 71.7 (C-5), 67.1 (J ¼ 5.6 Hz, C-6), 11.8 (CH3) ppm.31P{1H}NMR
Similar to compound 6 starting from 1-(2,3,5,6-tetra-O-prop-
(161.98 MHz, d6-acetone):
[M ꢂ H]-.
d
¼ 120.0 ppm. MS (ESIꢂ): m/z: 315
anoyl-b-D-glucofuranosyl)thymine (2.0 g, 4.00 mmol) compound 7
was obtained. Yield: 0.89 g (77.4%), mp: 210e213 ꢀC decomp., elem.
anal. calcd (%) for C11H16N2O7: C 45.83, H 5.59, N 9.72; found: C
45.77, H 5.75, N 9.49.1H NMR (400.13 MHz, MeOH):
d
¼ 7.80 (d,
J ¼ 1.1 Hz, 1H; CH]CCH3), 5.80 (d, J ¼ 0.9 Hz, 1H; H-1), 4.20e4.10
(m, 4H; H-3, H-4, H-5, H-2), 3.83 (dd, J ¼ 11.7; 2.9 Hz, 1H; H-6), 3.68
(dd, J ¼ 11.7; 5.3 Hz, 1H, H-60) ppm. 13C{1H} NMR (100.63 MHz,
3.10. Dichlorido(((
glucofuranosyluracil) ruthenium(II) 11
h b-D-
6-p-cymene)(3,5,6-bicyclophosphite-1-
MeOH):
d
¼ 165.1 (J ¼ 26.8 Hz, CO), 151.0 (CO), 137.8 (J ¼ 231.0 Hz,
A
solution of bis[dichlorido(
(100 mg, 0.16 mmol) in dry CH2Cl2 (5 mL) was added to a sus-
pension of 3,5,6-bicyclophosphite-1- -D-glucofuranosyluracil
h
6-p-cymene)ruthenium(II)]
C(CH3)),109.0 (CH), 92.0 (C-1), 82.4 (C-4), 81.2 (C-2), 75.1 (C-3), 69.3
(C-5), 63.8 (C-6), 11.1 (CH3) ppm. MS (ESIþ): m/z: 311 [MþNa]þ.
b
(100 mg, 0.33 mmol) in dry CH2Cl2 (20 mL). The mixture was stirred
at room temperature for 12 h. The solvent was evaporated and the
crude product was dissolved in acetone (5 mL) and precipitated by
addition of ether, filtered, washed with ether (3 ꢁ 5 mL) and dried
under vacuum. Yield: 170 mg (85.0%), mp: >220 ꢀC decomp., elem.
anal. calcd (%) for C20H25N2O7PRuCl2: C 39.48, H 4.14, N 4.60; found:
3.7. 3,5,6-Bicyclophosphite-1-b-D-glucofuranosyluracil 8
Hexaethylphosphoroustriamide (0.9 g, 3.6 mmol) was added to
a solution of 1- -glucofuranosyluracil 5 (1.0 g, 3.6 mmol) in DMF
b-D
(50 mL) and the reaction mixture was stirred at 95e99 ꢀC for 5 h.
The solvent was removed at reduced pressure and the pure com-
pound was isolated by column chromatography with the ethyl ac-
etate as eluent. Yield: 0.7 g (64.0%), mp: 177e179 ꢀC decomp., elem.
anal. calcd (%) for C10H11N2O7P: C 39.75, H 3.67, N 9.27; found: C
C 39.33, H 4.48, N 4.85.1H NMR (400.13 MHz, d4-MeOH):
d
¼ 11.40
(brs, 1H, NH), 7.83 (d, J ¼ 8.3 Hz, 1H; CH]CH), 6.23 (d, J ¼ 4.4 Hz,
1H; H-1), 5.91 (s, 1H, OH), 5.87 (d, J ¼ 5.9 Hz, 1H; HAr), 5.83 (d,
J ¼ 5.9 Hz, 1H; HAr), 5.73 (d, J ¼ 4.9 Hz, 1H; HAr), 5.71 (d, J ¼ 4.9 Hz,
1H; HAr), 5.62 (d, J ¼ 8.3 Hz, 1H; CH]CH), 5.21 (m, 1H; H-5), 4.74 (t,
J ¼ 10.3 Hz, 1H; H-6), 4.65 (s, 1H; H-3), 4.40 (s, 1H; H-4),4.24 (m, 1H,
H-60), 4.14 (d, J ¼ 3.9 Hz,1H; H-2), 2.66 (m,1H, CH), 2.02 (s, 3H, CH3),
1.12 (d, J ¼ 4.9 Hz, 6H; CH3) ppm. 31P{1H}NMR (161.98 MHz, d4-
40.06, H 4.00, N 9.25.1H NMR (400.13 MHz, d6-acetone):
d
¼ 10.10
(brs, 1H, NH), 8.17 (d, J ¼ 7.8 Hz, 1H; CH]CH), 5.84 (s, 1H; H-1), 5.72
(d, J ¼ 8.3 Hz, 1H; CH]CH), 5.28 (brs, 1H, OH), 5.11 (m, 1H; H-5),
4.62 (dd, J ¼ 9.3; 4.4 Hz, 1H; H-6), 4.42e4.39 (m, 2H; H-3, H-4), 4.26
(s, 1H; H-2), 4.01 (dd, J ¼ 9.3; 6.4 Hz, 1H, H-60) ppm.13C{1H} NMR
MeOH):
d
¼ 134.9 ppm. MS (ESIþ): m/z: 573 [M ꢂ Cl]þ.
(100.63 MHz, d6-acetone):
d
¼ 162.7 (CO), 150.8 (CO), 140.0 (CH),
100.8 (CH), 93.3 (C-1), 79.9 (C-2, C-3), 74.6 (J ¼ 2.1 Hz, C-4), 71.6
(J ¼ 4.4 Hz, C-5), 67.1 (J ¼ 5.9 Hz, C-6) ppm. 31P{1H}NMR
(161.98 MHz, d6-acetone):
[MþNa]þ.
d
¼ 120.2 ppm. MS (ESIþ): m/z: 325
3.11. Dichlorido(
flurouracyl)- -glucofuranosyl) ruthenium(II) 12
h
6-p-cymene)(3,5,6-bicyclophosphite-1-(5-
b-D
3.8. 3,5,6-Bicyclophosphite-1-(5-fluorouracil)-
b
-
D
-glucofuranosyl 9
Similar to compound 11 starting from bis[dichlorido(
cymene)ruthenium(II)] (100 mg, 0.16 mmol) and 3,5,6-
bicyclophosphite-1-(5-fluorouracil)- -glucofuranosyl (104 mg,
h
6-p-
Similar to compound 8 starting from 1-(5-fluorouracil)-
b-
D
-
b-D
glucofuranosyl 3 (0.9 g, 3.08 mmol) and hexaethylphosphorous-
triamide (0.76 g, 3.08 mmol) compound 9 was synthesized. Yield:
0.62 g (62.8%), mp: 242e243 ꢀC decomp., elem. anal. calcd (%) for
0.33 mmol) compound 12 was obtained with yield: 184 mg (89.0%),
mp: >220 ꢀC decomp., elem. anal. calcd (%) for C20H24N2O7PFRuCl2:
C 38.34, H 3.86, N 4.47; found: C 38.01, H 4.23, N 4.42.1H NMR
C
10H10N2O7FP: C 37.51, H 3.15, N 8.75; found: C 37.62, H 3.27, N
(400.13 MHz, DMSO‑d6):
d
¼ 10.54 (brs, 1H, NH), 8.10 (d, J ¼ 6.4 Hz,
8.73.1H NMR (400.13 MHz, d6-acetone):
d
¼ 8.37 (d, J ¼ 7.3 Hz, 1H;
1H; CH]CF), 5.92 (s, 1H; H-1), 5.78 (tr, J ¼ 5.9 Hz, 2H; HAr), 5.66 (d,
J ¼ 6.4 Hz, 1H; HAr), 5.62 (d, J ¼ 5.9 Hz, 1H; HAr), 5.30 (m, 1H; H-5),
4.82e4.74 (m, 2H; H-6, H-3), 4.56 (s,1H; H-4), 4.45 (s,1H; H-2), 4.35
(m, 1H, H-60), 2.81 (m, 1H, CH), 2.12 (s, 3H, CH3), 1.12 (d, J ¼ 6.9 Hz,
6H; CH3) ppm. 31P{1H}NMR (161.98 MHz, DMSO‑d6):
CH]CF), 5.80 (s, 1H; H-1), 5.17 (m, 1H; H-5), 4.64 (ddd, J ¼ 9.3; 4.7,
0.6 Hz, 1H; H-6), 4.46 (m, 1H; H-3), 4.43 (m, 1H; H-4), 4.31 (s, 1H; H-
2), 4.03 (ddd, J ¼ 9.3; 5.3, 1.5 Hz, 1H, H-60) ppm.13C{1H} NMR
(100.63 MHz, d6-acetone):
d
¼ 156.7 (J ¼ 26.8 Hz, C(O)CF), 148.9
(CO), 140.1 (J ¼ 230.8 Hz, CF), 124.3 (J ¼ 36.0 Hz, CH]CF), 93.4 (C-1),
d
¼ 134.5 ppm. MS (ESIþ): m/z: 591 [M ꢂ Cl]þ.

6
M.R. Gonchar et al. / Journal of Organometallic Chemistry 919 (2020) 121312
3.12. Dichlorido((
glucofuranosylthimine) ruthenium(II) 13
h
6-p-cymene)(3,5,6-bicyclophosphite-1-
b-
D-
(161.98 MHz, d6-acetone):
[MþNa]þ.
d
¼ 150.93 ppm. MS (ESIþ): m/z: 1486
Similar to compound 11 starting from bis[dichlorido(
cymene)ruthenium(II)] (100 mg, 0.16 mmol) and 3,5,6-
bicyclophosphite-1- -glucofuranosylthimine (104 mg,
0.33 mmol) compound 13 was obtained with yield: 180 mg (88.0%),
mp: >220 ꢀC decomp., elem. anal. calcd (%) for C21H27N2O7PRuCl2: C
40.52, H 4.37, N 4.50; found: C 40.36, H 4.41, N 4.28.1H NMR
h
6-p-
4. Conclusions
b
-D
l
In conclusion, we have prepared and characterized a series of
stable and water-soluble phosphites based on the glucose and
utilized those new ligands in the synthesis of RAPTA-type Ru(II)-
arene compounds and Ruclusters. Ru(II)-arene compounds do not
show any significant antiproliferative activity, while for the cluster
compounds a change in the number of phosphorus ligands
completely switch antiproliferative activity.
(400.13 MHz, DMSO‑d6):
d
¼ 7.59 (d, J ¼ 1. Hz, 1H; CH]CCH3), 6.31
(d, J ¼ 4.7 Hz, 1H; H-1), 6.06 (d, J ¼ 2.6 Hz, 1H; O), 5.92 (m, 2H; HAr),
5.78 (tr, J ¼ 7.0 Hz, 2H; HAr), 5.29 (m, 1H; H-5), 4.88 (tr, J ¼ 9.4 Hz,
1H; H-6), 4.78 (d, J ¼ 2.0 Hz, 1H; H-3), 4.47 (q, J ¼ 2.6 Hz,1H; H-4),
4.43 (m, 1H, H-60), 4.34 (dd, J ¼ 4.7, 2.6 Hz,1H; H-2), 2.80 (m, 1H,
CH), 2.12 (s, 3H, CH3), 1.99 (s, 3H, CH3), 1.22 (d, J ¼ 6.7 Hz, 6H; CH3)
Declaration of competing interest
ppm. 31P{1H}NMR (161.98 MHz, DMSO‑d6):
(ESIþ): m/z: 587 [M ꢂ Cl]þ.
d
¼ 134.2 ppm. MS
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
3.13. Ru3(CO)11(3,5,6-bicyclophosphite-1-b-D-glucofuranosyluracil)
14
Acknowledgements
A solution of 3,5,6-Bicyclophosphite-1-b-D-glucofuranosyluracil
ꢀ
We thank the Russian Foundation for Basic Research (grant N .
8 (100 mg, 0.33 mmol), in CH2Cl2 (5 mL) was added to a solution of
Ru3(CO)12 (211 mg, 0.33 mmol) in CH2Cl2 (10 mL) under nitrogen at
room temperature. The reaction mixture was stirred for 5 min and
Me3NO (24.8 mg, 0.31 mmol) was added. The reaction was stirred
for 12 h and the solvent was removed and the compound isolated
by flash chromatography (eluent CH2Cl2:Et2O 4:1). Yield 100 mg
(33%), m.p. 160e167 ꢀC decomp., elem. anal. calcd.(%) for
19-53-12042, E.M.M, E.R.M, A.A.N synthesis and stability study)
ꢀ
and Russian Science Foundation (grant N 19-13-00084, E.R.M,
A.A.N biological tests) for financial support.
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3,5,6-Bicyclophosphite-1- -glucofuranosyluracil (200 mg,
b
-D
8
0.66 mmol), Ru3(CO)12 (211 mg, 0.33 mmol) and Me3NO (74.4 mg,
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