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Antitumor Activity and Reductive Stress by Platinum(II)
N-Heterocyclic Carbenes based on Guanosine**
Maria Inês P. S. Leitão,[a] Maria Turos-Cabal,[b] Ana Maria Sanchez-Sanchez,[b]
Clara S. B. Gomes,[c, d, e] Federico Herrera,*[f] Vanesa Martin,*[b] and Ana Petronilho*[a]
Abstract: Platinum(II) complexes bearing N-heterocyclic car-
benes based guanosine and caffeine have been synthesized
by unassisted CH oxidative addition, leading to the corre-
sponding trans-hydride complexes. Platinum guanosine de-
rivatives bearing triflate as counterion or bromide instead of
hydride as co-ligand were also synthesized to facilitate
correlation between structure and activity. The hydride
compounds show high antiproliferative activity against all cell
lines (TC-71, MV-4-11, U-937 and A-172). Methyl Guanosine
complex 3, bearing a hydride ligand, is up to 30 times more
active than compound 4, with a bromide in the same
position. Changing the counterion has no significant effect in
antiproliferative activity. Increasing bulkiness at N7, with an
isopropyl group (compound 6), allows to maintain the
antiproliferative activity while decreasing toxicity for non-
cancer cells. Compound 6leads to an increase in endoplasmic
reticulum and autophagy markers on TC71 and MV-4-11
cancer cells, induces reductive stress and increases gluta-
thione levels in cancer cells but not in non-cancer cell line
HEK-293.
Introduction
Platinum-based drugs are responsible for circa 50 % of all
anticancer therapies worldwide, either in combination with
other therapies or as standalone treatment.[1,2] The first platinum
anticancer agent, cisplatin, began its clinical use more than
40 years ago and marked a milestone in the discovery and use
of metallodrugs.[3] Alongside with carboplatin and oxaliplatin,
cisplatin continues to play a major role in contemporary
oncology.[2,3] Cisplatin arrests the cell cycle at G2/M transition,
the magnitude of this cytostatic effect being dependent on the
duration and concentration of the treatment.[4] Despite their
effectiveness, the use of cisplatin and other metallodrugs has
several limitations. Their coordination is not restricted to DNA
nucleobases, and their binding to other biological substrates is
at the core of severe undesired side effects.[3] Cancer cells often
adapt to these drugs and become resistant, and tumour
recurrence is therefore common.[2,3] Subsequently, intense
research has been dedicated to the development of novel
platinum drugs.[2,5] A promising strategy is the coordination of
the metal moiety to naturally occurring and/or bioactive
ligands, which can provide a higher degree of selectivity.[6] In
this sense, modified nucleosides, such as organometallic
nucleosides,[7–9] show a great potential to fill this role. Modified
nucleosides are widely used in chemotherapy, acting as
antimetabolites that disrupt the synthesis of nucleic acids.[10,11]
The accessible incorporation of nucleoside analogues into
nucleic acids by the DNA repair machinery makes them
interesting candidates for combination with DNA-damaging
agents, such as cisplatin.[12] Indeed, combination therapies of
nucleosides and metallodrugs have proven effective for a
variety of cancer treatments.[2,13]
Previous work from our lab has established new method-
ologies for the synthesis of guanosine complexes based on
palladium and platinum.[14] In these complexes, the guanosine
ligand is bound to the metal centre as an N-heterocyclic
[a] Dr. M. I. P. S. Leitão, Dr. A. Petronilho
Instituto de Tecnologia Química e Biológica António Xavier
Avd República, 2780-157 Oeiras (Portugal)
E-mail: ana.petronilho@itqb.unl.pt
[b] M. Turos-Cabal, Dr. A. M. Sanchez-Sanchez, Prof. V. Martin
Facultad de Medicina, Dpto. Morfología y Biología Celular
Universidad de Oviedo- Instituto Universitario de Oncología del Principado
de Asturias (IUOPA)
Universidad de Oviedo and Instituto de Investigación Sanitaria del
Principado de Asturias (ISPA)
C/ Julián Clavería 6, 33006, Oviedo, Asturias (España)
E-mail: martinvanesa@uniovi.es
[c] Dr. C. S. B. Gomes
LAQV-REQUIMTE, Department of Chemistry. Associate Laboratory i4 HB
NOVA Faculdade de Ciências e Tecnologias, Universidade Nova de Lisboa
2829-516 Caparica (Portugal)
[d] Dr. C. S. B. Gomes
Institute for Health and Bioeconomy. UCIBIO
NOVA Faculdade de Ciências e Tecnologias, Universidade Nova de Lisboa
2829-516 Caparica (Portugal)
[e] Dr. C. S. B. Gomes
Applied Molecular Biosciences Unit, Department of Chemistry
NOVA Faculdade de Ciências e Tecnologias, Universidade Nova de Lisboa
2829-516 Caparica (Portugal)
[f] Prof. F. Herrera
BioISI – Instituto de Biosistemas e Ciências integrativas, Dep. Química e
Bioquímica Faculdade de Ciências da Universidade de Lisboa Campo
Grande, 1749-016 Lisboa (Portugal)
E-mail: fherrera@fc.ul.pt
[**] A previous version of this manuscript has been deposited on a preprint
server (https://doi.org/10.26434/chemrxiv-2022-k8c22).
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202301078
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carbene, making the complex more stable.[15] These platinated
nucleosides were examined for their antiproliferative activity[14]
towards several human cell lines. Complex 1(Figure 1), bearing
an anionic guanosine derivative, has no relevant antiprolifer-
ative activity. By contrast, protic NHC complex 2(Figure 1) is
active for glioblastoma cell line U251, having a significant
activity when compared to cisplatin, while showing no cytotoxic
for non-cancer cells (HEK-293 cell line).[14]
We have recently reported the synthesis of a platinum
complex based on 7-methylguanosine by CH oxidative
addition leading to the formation of the hydride complex 3[15]
(Figure 1). Following our results previously described for
complex 2,[14] herein we report the antiproliferative activity of
compound 3. Additionally, and motivated by the results
obtained for 3, we examine the effect of synthetic variations at
the purine core on antiproliferative activity.
Results and Discussion
The anticancer activity of compound 3was evaluated via MTT
assay in four different human cancer cell lines (Figure 2), namely
TC-71 (Ewing’s sarcoma), MV-4-11 (myelomonocytic leukaemia),
U-937 (histiocytic lymphoma) and A-172 (glioblastoma). Com-
plexes 1and 2were active against the MV-4-11 cell line at
10 μM (2) and 100 μM (1), showing no activity against the three
other cell lines, even at the highest concentration tested. In
contrast, complex 3was active against the four cancer cell lines.
Differences in the antiproliferative activity between 1, bearing a
guanosynil ligand, and 2, with a guanosylidene ligand, were
previously reported by our group,[14] with complex 2with the
NHC ligand providing a higher antiproliferative activity. Since
the antiproliferative activity of 3is considerably higher than
that of 2, we hypothesized that the presence of the methyl
group and/or the presence of the hydride as co-ligands could
be responsible for the increased antiproliferative activity, in
addition to the beneficial effect of the NHC ligand.
To determine the main cause of the higher cytotoxicity, we
prepared complex 4. This complex bears a methyl group at N7
and a bromide instead of a hydride trans to the NHC. Complex
4is easily obtained by post-functionalization of compound 1
with methyl triflate (Scheme 1).
Characterization of 4by NMR spectroscopy shows similar-
ities with NHC 3, as expected. The most diagnostic feature is
found in the 13C{1H}, with the upfield of ca. 30 ppm of carbenic
carbon (C8) with respect to 3. In NHC 4, the C8 resonates as a
triplet at 155.3 ppm, while in NHC 3it resonates at 181.9 ppm.
This shift evidences the large differences in sigma donation of
the hydride versus bromide on C8 and the resulting trans
influence.[15] The antiproliferative activity was measured for
compound 4and the corresponding IC50 calculated and
compared with those of 3for the difference cell lines (Table 1).
Figure 1. Chemical structure of complexes 1–3.
Figure 2. Viability of four human cancer cell lines, namely MV-4-11, A-
172 TC-71 and U-937, after incubation with compounds A) 1, B) 2and C) 3,
for 48 h, assessed by evaluating its ability to metabolize MTT.
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Both compounds are active against all cell lines, compound
3being significantly more active than cisplatin and compound
4for all cell lines tested. For cell line U-937, from a non-solid
tumour (histiocytic lymphoma), complex 3is 30 times more
active than 4. These results indicate that the higher activity
found for 3could stem from a combination of a bulkier
substituent at N7 (when compared to 2) and the presence of a
hydride as co-ligand. Complexes 3and 4have different
counterions that could also contribute to the observed activity.
Thus, we synthesized complex 5via anion exchange of 3in
dichloromethane, using silver triflate (Scheme 2, see Supporting
Information for characterization), and evaluated the corre-
sponding antiproliferative activity. The IC50 values found for 5
are similar to those of 3, without significant differences (S.I.
Table S1). These results suggest that the counterion has no
significant influence on the antiproliferative activity.
Complex 3showed high cytotoxicity against four human
cancer cell lines, with IC50 values between 1.92 and 2.39 μM.
Motivated by these results, we performed further modifications
at the purine core to ascertain the overall effect on the activity
of these compounds. Variations of the steric environment at N7
at the purine backbone and at N9 were introduced to produce
complexes 6,7,[15] and 8(Figure 3). Compounds 6and 8were
synthesized by CH oxidative addition of the corresponding
ligand precursors to Pt(0), following the synthetic strategy
employed for compound 3. Complex 7was previously reported
by our group using a similar methodology.
For the synthesis of compound 6, acetate-protected
guanosine was quaternized with an isopropyl group to increase
steric crowding specifically at N7. 7-iPrGAc was reacted with
Pt(PPh3)4in dimethylformamide at 100°C for 7 h, yielding
complex 6in 68 % isolated yield (Scheme 3). Metallation at
position 8 results in a significant upfield shift of circa 1.1 ppm
for both methyl groups from the isopropyl moiety. The hydride
signal for complex 6resonates at 6.90 ppm, a shift of
0.70 ppm with respect to 4, which is indicative of a higher
electronic donation of the isopropyl group.[16] In the 13C
{1H} NMR, the carbenic C8 undergoes resonates at 181.4 ppm, in
agreement with that of previous complexes.[14]
For the synthesis of compound 8we employed 9-meth-
ylcaffeinium iodide (9-MeCaff), a more oxidized purine moiety.
9-MeCaff was then reacted with Pt(PPh3)4in dimeth-
ylformamide at 60°C for 24 h, affording complex 8in 42 %
isolated yield. Complex 8was characterized by NMR spectro-
scopy in DMSO-d6. In the 1H NMR analysis, the platinum-bonded
hydride resonates at 6.20 ppm.[15,17] In the 13C{1H} NMR analy-
sis, the metallated C8 resonates at 185.0 ppm, in line with the
values described for 3and 6. Of note, all compounds are stable
in DMSO-d6solutions for at least one week, as determined by
NMR.
Crystals of 8were obtained from a saturated solution of 8in
DMSO-d6, allowing for their characterization by single-crystal X-
ray analysis (Figure 4). The crystal structure confirms the trans
orientation for the two phosphines. The N7C8N9 angle is
106.7(5)°, identical to other metal NHCs based on caffeine.[17–19]
The PtC8 bond length is 2.064(5) Å, longer than in the related
Scheme 1. Methylation of complex 1with methyl triflate, affording the NHC
4.
Table 1. IC50 �sd values (μM) for compounds 3 and 4 towards four human
cancer cell lines after incubation for 48 h, expressed as mean of at least
three separate determinations. sd – standard deviation
Cell line 3 4 Cisplatin
TC-71 2.10�0.26 59.26�6.90 4.30 �1.10
MV-4-11 1.92�0.19 32.26�6.75 6.39 �0.80
U-937 1.97�0.24 58.10�9.20 8.23 �1.01
A-172 2.39�0.17 23.47�2.70 17.38 �1.60
Scheme 2. Ion-exchange reaction of complex 3(I) with AgOTf, affording
complex 5(OTf).
Figure 3. Chemical structure of complexes 6–8.
Scheme 3. Synthesis of complex 6by CH oxidative addition of 7-iPrGAc to
Pt0.
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systems having chlorine and bromine as co-ligands,[20,21] prob-
ably due to the trans influence of the hydride.[15]
Anticancer activity
The anticancer activity of these compounds was then evaluated
in the same four cancer cell lines and in the non-cancer cell line
HEK-293. The IC50 values obtained for complexes 3and 6–8are
indicated in Table 2.
All the variations introduced for complexes 6–8improved
the activity in relation to complex 3. Specifically, the introduc-
tion of a bulkier group at N7 (the isopropyl in 6, instead of a
methyl in 3) provides a beneficial effect in the anticancer
activity. Compound 6is more active against all cancer cell lines:
although it is still cytotoxic for HEK-293 cells, the safety index
values are more favourable for complex 6than for complex 3.
Replacing the sugar with a methyl group at N9 (complex 7)
leads to an antiproliferative activity of circa two to three times
higher in the four cell lines. However, the effect is even more
prominent in non-cancer HEK-293 cells, since complex 7is
slightly more toxic for this cell line than for cancer lines TC-71
and A-172. Finally, a more oxidized purine ligand (complex 8)
had no relevant benefit. Compound 8is more active than
complex 3, but it is also more toxic for the non-cancer cell line
HEK-293, in a similar degree to that of complex 7.
All IC50 values of guanine- and caffeine-derived NHCs are
very similar for each cell line. Compound 6, bearing an
isopropyl group at N7, is slightly less active than compounds 7
and 8for all cancer cell lines. However, complex 6is
approximately three times less toxic for the non-tumour cell
line HEK-293 with an IC50 of 2.98 μM (while 7and 8showed an
IC50 of 1.10 μM and 0.99 μM against HEK-293, respectively).
Although all compounds are toxic for non-tumour cells, the
safety index is above 1 in most cases (Table 3), indicating that
they are more toxic for cancer cells than normal proliferating
cells. In particular, the presence of a bulkier group at N7 in
compound 6resulted in a more favourable ratio between
anticancer activity and a lower toxicity for non-cancer cells, a
characteristic that warrants further development.
MTT assays detect a decrease in the mitochondrial activity
indicative of a decrease in the number of viable cells. However,
it does not allow to determine whether this decrease is due to
antiproliferative or cytotoxic effects. Trypan blue exclusion assay
allows to determine the number of both dead and viable cells:
viable cells possess intact cell membranes and exclude the
trypan blue dye, whereas dead cells do not. Thus, we used
trypan blue exclusion assay to confirm that there was a
reduction in the total number of cells (Dead +viable cells,
Figure 5A) and that this reduction was due, at least in part, to
induction of cell death (% dead cells vs total number of cells,
Figure 5B). Consistently, compound 6was neither cytotoxic nor
antiproliferative for HEK-293 cells at 1 μM (Figure 5A and B). Cell
cycle distribution analysis upon treatment with compound 6or
cisplatin for 24 h indicated that, besides cytotoxicity, there is an
early antiproliferative component in the action of these drugs
(Figure 5C and D). While compound 6induced an increase in
the proportion of cells in the G0/G1 phase, cisplatin caused cell
cycle arrest at G2/M, consistent with previous reports.[4]
We next explored the antitumoral mechanism of compound
6. We evaluated oxidative stress, apoptosis, endoplasmic
reticulum stress and autophagy, four common mechanisms of
action of antitumoral drugs. We evaluated these parameters
after 24 h with compound 6, to determine the events before
the loss of viability and proliferation observed at 48 h.
Surprisingly, compound 6did not induce oxidative stress.
Instead, 6reduced significantly the intracellular levels of
reactive oxygen species in cancer cell lines, but not in normal
HEK-293 cells (Figure 5E). This decrease was accompanied by an
increase in the mitochondrial membrane potential (Figure 5F).
This difference between non-cancer and cancer cells is not
Figure 4. Molecular structure of complex 8obtained by X-Ray crystallog-
raphy (H atoms omitted for clarity).
Table 2. IC50 �sd values (μM) for compounds 3and 6–8towards four
human cancer cell lines after incubation for 48 h, expressed as mean of at
least three separate determinations. sd – standard deviation
Cell line 3678
TC-71 2.10�0.26 1.12�0.13 1.23 �0.15 0.83 �0.11
MV-4-11 1.92�0.19 1.24�0.19 0.79 �0.10 1.21 �0.23
U-937 1.97�0.24 0.61�0.09 0.61 �0.08 0.73 �0.08
A-172 2.39�0.17 1.66�0.30 1.49 �0.25 1.48 �0.16
HEK-293 4.10�0.15 2.98�0.32 1.10 �0.22 0.99 �0.10
Table 3. Safety index values of PtH compounds 3and 6–8for four cancer
cell lines, calculated from MTT assays after 48 h of incubation with the
different compounds.[a]
Cell line 3 6 7 8
TC-71 1.95 2.66 0.89 1.19
MV-4-11 2.14 2.40 1.39 0.82
U-937 2.08 4.89 1.80 1.36
A-172 1.73 1.80 0.74 0.67
[a] Range of the ratios between the IC50 for the non-cancer cell line (HEK-
293) and the IC50 value for each cancer cell line presented in Table 2.
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Figure 5. Compound 6 induces reductive stress and cell death in cancer cells. Human cancer cell lines TC-71, MV-4-11, U937 and A172, and normal
HEK293 cells were incubated with compound 6 (1 μM, white bars) or the vehicle (DMSO 0.1 % v/v, black bars). Incubation of cancer cells with compound 6 for
48 h induced a decrease in total cell number (A, dead cells +viable cells) partially explained by cell death (B, % of dead cells vs total number of cells), as
determined by trypan blue assays. After 24 h of incubation, C) compound 6 induced cell cycle arrest at G0/G1 phase, while D) Cisplatin (Cis-Pt) induced cell
cycle arrest at G2/M, suggesting different mechanisms of action. At the same time point, compound 6 induced a decrease in the levels of intracellular reactive
oxygen species (ROS), as E) determined by DCFHDA staining; an increase in mitochondrial membrane potential, as F) determined by 123-rhodamine staining;
and G) an increase in intracellular glutathione (GSH), H) CHOP and LC3-II levels; but not caspase activation. HEK293 cells did not respond to compound 6 as
cancer cells, with the exception of a slight increase in CHOP levels. I, Transient transfection of cells with LC3-EGFP (green) showed a dose-dependent
enlargement of autophagosomes induced by compound 6. Nuclei were counterstained with Hoechst (blue). Scale bar, 20 μm. Results are the mean �SEM of 3
independent experiments. *, significant vs. CON, p<0.05 (t-student test).
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unusual. Cancer cells often show higher basal levels of ROS, due
to an altered mitochondrial function.[22,23] What is more
uncommon is the co-existence of a reductive intracellular
environment and a higher mitochondrial potential, which we
found only once in the literature in conditions of reductive
stress.[24,25] Reductive stress is defined as a condition character-
ized by excessive and/or sustained accumulation of reducing
equivalents that jeopardizes cellular survival. Recent reports
have highlighted the potential of reductive stress as a mode of
action for the development of anticancer drugs, making use of
the so-called catalytic anticancer compounds. Reductive stress
can be promoted in cancer cells by selenium-containing
metabolites[26–28] or ruthenium complexes[29] and examples with
other metals have also been reported.[30–33]
Glutathione (GSH) is the most abundant intracellular
antioxidant, and its levels are often increased in reductive
stress.[34] Consistently, we found increased intracellular GSH
levels in two selected cancer cell lines upon incubation with
compound 6, but not in HEK293 cells (Figure 5G). Moreover,
Reductive stress is often associated with other forms of stress.
In TC71 and MV-4-11 cancer cells, compound 6increased the
levels of CHOP and LC3-II, two endoplasmic reticulum stress
and autophagy markers, respectively (Figure 5H). In contrast,
HEK293 cells showed a substantially lower increase in CHOP
expression and no change in LC3-II levels. Morphological
analysis of cells transfected with LC3-EGFP and treated with
compound 6showed a dose-dependent appearance of auto-
phagosomes and other vesicular structures in the cytoplasm,
consistent with autophagy (Figure 5I). The type of cancer cell
death induced by compound 6was not apoptotic, as indicated
by the absence of caspase-3 cleavage, necessary to execute
apoptosis.
Conclusions
In summary, the combination of steric hindrance at N7 and a
hydride trans to the NHC improves cytotoxicity against four
different cancer cell lines, with the best outcome found for
compound 6, bearing an isopropyl group at N7. The trypan
blue exclusion assay shows that for that the reduction in the
number of cells is due to cell death, but cell cycle arrest at G0/
G1 phase is also observed. Compound 6induces reductive
stress on cancer cells, with an increase in GSH levels and
endoplasmic reticulum and autophagy markers on TC71 and
MV-4-11 cancer cells (Ewing’s sarcoma and myelomonocytic
leukaemia, respectively). In contrast, non-tumour cells showed
neither signs of reductive stress, nor of autophagy, and the
putative increase in endoplasmic reticulum stress was lower
than in cancer cells. These platinated nucleosides thus show
anticancer activity with a different mode of action than that of
cisplatin, hence showing great potential to develop novel
metallodrugs able to circumvent the well know resistance
associated with cisplatin.
Experimental Section
Deposition Number: 2217136 (for 8) contain(s) the supplementary
crystallographic data for this paper. These data are provided free of
charge by the joint Cambridge Crystallographic Data Centre and
Fachinformationszentrum Karlsruhe Access Structures service.
Supporting Information
All experimental procedures, NMR and mass spectra, as well as
the crystallographic data, are included in the Supporting
Information. Additional references cited within the Supporting
Information.[35–39]
Acknowledgements
We thank Fernanda Murtinheira for the support on the
autophagy measurements. This work was supported by FCT –
Fundação para a Ciência e a Tecnologia, I.P., through MOSTMI-
CRO-ITQB R&D Unit (UIDB/04612/2020, UIDP/04612/2020) and
LS4FUTURE Associated Laboratory (LA/P/0087/2020). M.I.P.S.L.
was supported by fellowships PD/BD/135483/2018 and COVID/
BD/152502/2022 from FCT. A.P. acknowledges the contract
CEECINST/00102/2018. The NMR spectra were acquired at
CERMAX–ITQB, supported by Infrastructure Project No. 022161
(co-financed by FEDER through COMPETE 2020, POCI, PORL and
FCT through PIDDAC). C.S.B. Gomes acknowledges the XTAL –
Macromolecular Crystallography group for granting access to
the X-ray diffractometer. X-ray infrastructure financed by FCT-
MCTES through project RECI/BBBBEP/0124/2012. FH was sup-
ported by Centre grants from FCT to the BioISI Research Unit
(Refs. UIDB/04046/2020 and UIDP/04046/2020) and the Micro-
scopy facility at FCUL (as a node of the Portuguese Platform of
BioImaging, reference PPBI-POCI-01-0145-FEDER-022122), and
by individual grants through FCT (Ref. PTDC/FIS-MAC/2741/
2021) and the ARSACS Foundation (Canada). Maria Turos-Cabal
was supported by fellowship from the Spanish Association
Against Cancer (AECC, SV-19-AECC-FPI) and the Consejería de
Economía y Empleo del Principado de Asturias (FICYT, Severo-
Ochoa BP20-073).
Conflict of Interests
The authors declare no conflict of interest.
Data Availability Statement
X-ray crystallographic data in CIF format are available from the
Cambridge Crystallographic Data Centre (Deposition Number
2217136).
Keywords: anticancer agents ·CH activation ·organometallic
nucleosides ·platinum complexes ·reductive stress
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Manuscript received: April 4, 2023
Accepted manuscript online: April 27, 2023
Version of record online: ■■■,■■■■
Chemistry—A European Journal
Research Article
doi.org/10.1002/chem.202301078
Chem. Eur. J. 2023, e202301078 (7 of 7) © 2023 Wiley-VCH GmbH
15213765, 0, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202301078 by Cochrane Portugal, Wiley Online Library on [16/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
RESEARCH ARTICLE
Platinum(II) complexes bearing NHCs
based on guanosine undergo a sub-
stantial increase in antiproliferative
activity when changing the ligand
trans to the NHC from bromide to
hydride. Compound 6leads to an
increase in reductive stress and
increase in glutathione levels in
cancer cells but not in non-cancer
cells.
Dr. M. I. P. S. Leitão, M. Turos-Cabal,
Dr. A. M. Sanchez-Sanchez, Dr. C. S. B.
Gomes, Prof. F. Herrera*, Prof. V.
Martin*, Dr. A. Petronilho*
1 – 8
Antitumor Activity and Reductive
Stress by Platinum(II) N-Heterocyclic
Carbenes based on Guanosine
15213765, 0, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202301078 by Cochrane Portugal, Wiley Online Library on [16/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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