Formylation of a metathesis-derived: Ansa [4]-ferrocene: A simple route to anticancer organometallics

Article abstract of DOI:10.1039/d0dt01975e

Formylation of ansa[4]-ferrocene, obtained through the ruthenium-catalysed olefin metathesis, yields two separable, planar chiral 1,3-and 1,2-ansa-ferrocene aldehydes. Single-crystal X-ray structure analysis reveals that both regioisomers crystallize with spontaneous resolution of the racemate in the chiral P212121 space group with one molecule in the asymmetric unit. The major 1,3-isomer was further transformed into a conjugate with 1,2,3-triazole and uracil using click chemistry as the key synthetic step. This inorganic-organic hybrid displays anticancer activity (MCF-7, A549, MDA-MB-231 cell lines) with EC50 values comparable to those for cisplatin.

Full text of DOI:10.1039/d0dt01975e

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Dalton Trans., 2020, DOI: 10.1039/D0DT01975E.
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DOI: 10.1039/D0DT01975E
Formylation of a metathesis-derived ansa[4]-ferrocene: a simple route to anticancer
organometallics
[a]
[a]
[a]
Maria Mazur, Michał Mrozowicz, Włodzimierz Buchowicz,* Mariola Koszytkowska-
[a]
[b]
[c]
[c]
[c]
Stawińska, Radosław Kamiński, Zbigniew Ochal, Patrycja Wińska, Maria Bretner
[
[
[
a]
Faculty of Chemistry, Chair of Organic Chemistry, Warsaw University of Technology,
Noakowskiego 3, 00-664 Warsaw, Poland
b]
c]
Department of Chemistry, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw,
Poland
Faculty of Chemistry, Chair of Drug and Cosmetics Biotechnology, Warsaw University of
Technology, Noakowskiego 3, 00-664 Warsaw, Poland
Abstract
Formylation of ansa[4]-ferrocene, obtained through the ruthenium-catalysed olefin metathesis,
yields two separable, planar chiral 1,3- and 1,2-ansa-ferrocene aldehydes. Single-crystal X-ray
structure analysis reveals that both regioisomers crystallize with spontaneous resolution of the
racemate in the chiral P2 2 2 space group with one molecule in the asymmetric unit. The major
1
1 1
1
,3-isomer was further transformed into a conjugate with 1,2,3-triazole and uracil using the
click” chemistry as the key synthetic step. This inorganic-organic hybrid displays anticancer
activity (MCF-7, A549, MDA-MB-231 cell lines) with EC values comparable to those for
“
5
0
cisplatin.
Introduction
1
.
Ansa[n]-ferrocenes ([n]ferrocenophanes) are defined as iron complexes having the two
cyclopentadienyl rings connected by a bridge with variable length and structure ([n] denotes
the number of bridging atoms). A considerable variety of ferrocenophanes have been
synthesized up to date using different routes, to name among others the original “fly-trap”
1
2a
2b
method. Moreover, since the seminal reports by Locke et al. and Ogasawara et al., alkene
1

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metathesis in the metal coordination sphere has been recognized as a useful tool in the synthesis
DOI: 10.1039/D0DT01975E
of these compounds. Metathesis-derived ansa-metallocenes exhibit low ring-tilt and a rigid
bridge, and thus in many aspects resemble properties and reactivity of the parent
metallocenes.3,4
While numerous ferrocene derivatives were known to display promising biological activity,5,6
the potential of ansa-ferrocenes in medicinal chemistry has been discovered recently. A series
of bridge-functionalized [3]ferrocenophanes (Scheme 1a) with activity against cancer-cell lines
7
was obtained using the McMurry cross-coupling reactions. Since Plażuk et al. recognized that
the ferrociphenol analogue (Scheme 1a, compound A, R = OH) is more potent than its
7
a
7e
regioisomer A1 or the transposition product A2, much attention has been paid to structural
modifications of compounds A. The examination of several derivatives A in terms of their
cytotoxicity against hormone-independent MDA-MB-231 breast cancer cells revealed that
many of them displayed higher activity when compared to their flexible, non-bridged
analogues. This superiority was attributed to the rigid shape of the ferrocenophanes which
allows for their tight binding to a receptor, providing the molecules possess the proper
geometry.
a) Examples of reported derivatives
b) This work
R
R
R
R
H
N
O
O
Fe
N
R
Fe
O
linker
±)-B
Fe
Fe
(
A
A1
R
A2
Scheme 1. (a) Previous work, bridge-substituted [3]ferrocenophanes A, A1, and
[
4]ferrocenophanes A2 with cytotoxic activity (R = H, OH, NH , NHAc, Br, CN,
2
7
NHC(O)(CH ) C(O)NHOH). (b) This work, the target ring-substituted, metathesis-derived
2
6
[4]ferrocenophanes (±)-B.
2

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DOI: 10.1039/D0DT01975E
The limited synthetic scope of compounds A encouraged us to develop a straightforward ring-
functionalization of a metathesis-derived ansa[4]-ferrocene as a facile route to novel conjugates
with biologically relevant molecules, such as uracil (Scheme 1b, compound B). Since
ferrocenecarboxaldehyde has been successfully used in the development of numerous ferrocene
8
bioconjugates, we focused our synthetic attempts on a formyl group as a versatile entry into
further connection with diverse building blocks. In the light of reports on anticancer activity of
compounds A, we were interested in evaluation of cytotoxic activity of the target compounds B.
2
.
Results and Discussion
2
.1. Synthesis and spectroscopic characterization
Ring-monosubstitution of a ferrocenophane in most cases yields two regioisomeric 1,3- and
,2-products (or β and α isomers), and results in molecules displaying planar chirality.9
1
Moreover, several disubstituted products could be also formed that usually were difficult to
identify and isolate. Consequently, reports on successful ring-functionalization of ansa-
ferrocenes have been rather limited. Notable examples include the Friedel-Crafts acetylation of
1
0
[
n]ferrocenophanes (n = 3-5) with acetyl chloride/AlCl , formylation of [n]ferrocenophanes
3
(
n = 3-4) or multibridged ferrocenophanes with DMF/POCl3,11 lithiation of 1,1´-
1
2
13
trimethyleneferrocene with n-BuLi/TMEDA, mercuration with subsequent halogenation,
1
4
and borylation with BBr . While in most reactions the β-isomer predominates for steric
3
reasons, the directed ortho metalation of a dimethylamino-substituted [3]ferrocenophane
1
5
provided selective route to the α-isomer. Taking into account those reports, in particular the
1
2
slow lithiation of 1,1´-trimethyleneferrocene, we focused our attempts on the formylation
under the Friedel-Crafts conditions reported for ferrocene.16
1
,1´-Diallylferrocene (1) readily undergoes ring-closing metathesis in the presence of the first
generation Grubbs catalysts to form ferrocenophane 2 in high yield, exclusively as the
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DOI: 10.1039/D0DT01975E
Z-isomer. Reactions of 2 with triethyl orthoformate and AlCl at room temperature cleanly
3
1
afforded two aldehydes, as judged from the H NMR spectra of the crude reaction mixtures
major CHO resonance at δ = 9.81 ppm, minor at δ = 10.07 ppm). The ratio of these two
(
products varied slightly from 3.3:1 to 2.9:1 in some consecutive runs. Thus, we tested also the
Vilsmeyer reaction (DMF/POCl3)17,11c to obtain the same products at the 4:1 ratio (Scheme 2).
a)
b)
Fe
Fe
Fe
+
Fe
O
O
1
2
(±)-3
(±)-4
Scheme 2. Synthesis of the (±)-3 and (±)-4 aldehydes: (a) [Ru(=CHPh)Cl (PCy ) ], CH Cl ,
2
3 2
2
2
reflux, 3 h (ref. 2); (b) CH(OEt) , AlCl , toluene, 0 °C to rt, 1 h; or DMF, POCl , CHCl , rt,
3
3
3
3
2
0 h.
The (±)-3 and (±)-4 regioisomers were isolated by column chromatography on silica gel in 47%
and 19% yields, respectively, and fully characterized, including X-ray crystallography
Figure 1 and Figure 2, respectively). While the H and 13C NMR spectra of 2 are
1
(
straightforward and feature four and five signals, respectively, incorporation of the ring
substituent renders all the proton and carbon atoms inequivalent. Consequently, the NMR
spectra of (±)-3 and (±)-4 are remarkably complex. Thus, the expected seven cyclopentadienyl
proton resonances were clearly observed. Interestingly, the olefinic and allylic protons signals
show significantly different patterns allowing to tentatively distinguish the 1,2- and 1,3-isomers
(Figure S1 and Figure S2 in the Supporting Information). Both (±)-3 and (±)-4 display chiral
planarity and were resolved into enantiomers on an analytical Chiralcel OD-H or AD-H column,
respectively (Figure S3 and Figure S4). For the preparative resolution of the racemic major
product (±)-3 (Scheme 3), the method originally reported by Kagan and co-workers was
adopted.18
4

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DOI: 10.1039/D0DT01975E
a)
b)
Fe
Fe
Fe
+
Fe
O
O
O
O
O
O
O
(±)-3
(±)-5
c)
H
H
HO
OH
6
Fe
O
(
+)-(S )-3
p
Scheme 3. Resolution of (±)-3 into enantiomers: (a) CH(OMe) , p-TsOH, 80-90 °C; (b) (S)-
3
(
-)-1,2,4-butanetriol, p-TsOH, CHCl , 60 °C, then crystallization from hexanes and 2-
3
propanol at 4 °C; (c) p-TsOH, CH Cl , H O, 60 °C.
2
2
2
The dimethyl acetal (±)-5, obtained from (±)-3 and triethyl orthoformate, reacted with
commercial (S)-(-)-1,2,4-butanetriol in chloroform using catalytic p-TsOH to yield the
diastereomeric acetals 6. The two diastereoisomers of 6 were clearly distinguishable with
1H NMR spectroscopy using the diagnostic O-CH-O signals at δ = 5.332 and δ = 5.326 ppm,
and were separated by repeated crystallizations. Acidic hydrolysis of the diastereoisomer that
crystallized from hexanes/2-propanol mixtures released the enantiomerically enriched (+)-(S )-
p
3
with [α]D20 = 167.5 (c = 0.08 in CHCl3).
In an attempt to show that the ansa-ferrocene aldehyde (±)-3 can be used in the synthesis of
bio-conjugates analogously to ferrocenecarboxaldehyde, reactions depicted on Scheme 4 were
1
9
carried out, resulting in inorganic-organic hybrids 9a and (±)-9.
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DOI: 10.1039/D0DT01975E
O
a)
b)
c)
N
Fe
Fe
Fe
N
N
N
Fe
N
O
HO
N3
N
H
O
O
7a
8a
9a
O
a)
b)
c)
N
Fe
Fe
Fe
N
Fe
N
O
HO
N3
N
H
(
±)-3
(±)-7
(±)-8
(±)-9
Scheme 4. Synthesis of 9a and (±)-9: (a) NaBH , MeOH, THF, rt, 24 h for 7a, 48 h for (±)-7;
4
(
b) NaN , CH COOH, 50 °C, 3 h; (c) 3-propargyluracil, CuSO × 5H O, sodium ascorbate,
3 3 4 2
EtOH, rt, 3 days for 9a, 4 days for (±)-9.
The aldehyde (±)-3 was reduced with NaBH in methanol/THF under conditions similar to
4
those for ferrocenecarboxaldehyde,20 albeit extended reaction time was required. Then,
nucleophilic substitution in (±)-7 with sodium azide in acetic acid afforded the azide (±)-8. The
Cu(I)-catalysed 1,3–dipolar cycloaddition of the azide with 3-propargyluracil was successfully
performed to yield the ansa-ferrocene-triazole-uracil conjugate (±)-9. The structure of (±)-7,
(±)-8 and (±)-9 was established by NMR, MS, and elemental analyses. Thus, for example the
1H NMR spectrum of (±)-9 features the diagnostic uracil doublets of doublets at δ = 5.72 and
7
6
.17 ppm, the triazole singlet at δ = 7.53 ppm, and unresolved olefinic multiplets at δ = 5.99-
.03 ppm.
2
.2. X-ray characterization
Slow crystallization of (±)-3 and (±)-4 from hexanes results in spontaneous resolution of the
enantiomers. Both compounds crystallize in the chiral P2 2 2 space group with one molecule
1
1 1
in the asymmetric unit. The absolute structure determination of the randomly selected crystals
leads to (R )-3 and (R )-4 configuration, as shown in Figure 1 and Figure 2, respectively (for
p
p
6

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details see the Supporting Information). Owing to the presence of the bridge the
DOI: 10.1039/D0DT01975E
cyclopentadienyl ligands are forced to adopt an eclipsed conformation (it is known the
staggered conformation is more energetically favoured and dominates across the phase diagram
2
1
of the parent ferrocene). As expected, the C13=C14 double bonds adopt the (Z)-configuration,
and the CHO groups lie approximately in the cyclopentadienyl ligand plane (O1–C1–C2–C3/6
torsion angles equal 12.7(15)° and 15.7(7)° for (R )-3 and (R )-4, respectively). The angles
p
p
between the two least-squares planes fitted for the cyclopentadienyl rings show that both
molecules are slightly bent towards the bridge (174.00(1)° and 177.25(4)° for (R )-3 and (R )-
p
p
4
, respectively). Overall, it can be concluded that the molecules are quite alike in terms of their
size and shape. This is reflected in the unit cell parameters for both structures being rather quite
similar (Table S1 in the Supporting Information). The overall weak interaction pattern is also
similar in both structures. Apart from numerous H…H contacts being present, some more
specific C–H…O interactions are formed between the CHO group and the nearest
cyclopentadienyl ligands or the alkyl bridge. On the other hand, the location of the CHO group
with respect to the bridge in one of the cyclopentadienyl rings results in the packing of the
molecules in crystal structures being overall rather different (Figure S7 and Figure S8).
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DOI: 10.1039/D0DT01975E
Figure 1. The molecular structure of (R )-3. Atomic thermal motion is represented as
p
ellipsoids (50% probability level), and hydrogen-atom labels are omitted for clarity.
Figure 2. The molecular structure of (R )-4. Atomic thermal motion is represented as
p
ellipsoids (50% probability level), and hydrogen-atom labels are omitted for clarity.
2
.3. Biological evaluation
The antitumor activity of newly obtained compounds was evaluated using hormone-dependent
human breast carcinoma cell line MCF-7, hormone-independent human breast carcinoma cell
line MDA-MB-231, as well as human Caucasian lung carcinoma cell line A549. Normal MRC-
5
human fetal lung fibroblasts were used as a reference cell line to study cytotoxicity of these
compounds (Table 1, Figure S9). Cisplatin was used as the reference antitumor agent.
Ferrocenylmethyl azide 8a was also tested as a control, and contrary to the reported
2
2
23
ferrocenylalkenyl azide (FcCH=CHCH N ), showed no activity. Compounds 9a and (±)-9
2
3
demonstrated antiproliferative activity towards the studied cell lines. In general, the ansa-
complex (±)-9 showed lower EC values than the unbridged complex 9a. This observation can
5
0
be tentatively explained in terms of the rigid structure of (±)-9, similarly to the
7
[
3]ferrocenophanes reported by Jaouen and co-workers. The EC values determined for
5
0
compound (±)-9 towards breast carcinoma cell lines were comparable to those for cisplatin
8

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DOI: 10.1039/D0DT01975E
(
MCF-7, 28.7 µM vs 32.9 µM for cisplatin; MDA-MB-231, 30.3 µM vs 23.0 µM for cisplatin).
Moreover, compound (±)-9 exhibited slightly lower activity against A549 cell line than
cisplatin (EC = 10.9 µM vs EC = 4.6 µM, respectively). Compound (±)-9 with EC = 45.9
5
0
50
50
µM also displayed much lower toxicity against normal MRC-5 cells than cisplatin (EC = 8.4
5
0
µM). Consequently, the low cytotoxicity of compound (±)-9 towards MRC-5 cells resulted in
higher therapeutic index (defined as a ratio of EC (MRC-5)/EC (A549)) than that for
5
0
50
cisplatin.
Table 1. The viability of MCF-7, A549, MDA-MB-231, and MRC-5 cell lines after 72 hours
treatment with the newly obtained compounds.
a
Cell viability/EC ± SD (μM)
5
0
Compound
MDA-MB-
31d
MCF-7b
A549c
MRC-5e
2
8
9
a
a
189.0
>100
> 200
-
47.7±1.1
28.7±2.0
32.9±0.8
28.5±2.2
10.9±1.7
4.6±1.4
89.6±7.5
30.3±4.3
23.0±4.6
91.8±4.4
45.9±1.5
8.4±0.4
(
±)-9
cisplatin
a
EC50 values were obtained from a MTT-based assay and an equation of Y = 100/(1+10^((LogEC50
-
b
c
X)*HillSlope))); MCF-7, hormone-dependent human breast carcinoma cell line; A549, human Caucasian
lung carcinoma cell line, MDA-MB-231, hormone-independent human breast carcinoma cell line, MRC-5,
human fetal lung fibroblasts cell line.
d
e
2
4
The anticancer activity of (±)-9 and 9a is comparable to that of ferrocene-modified uracils or
2
5
ferrocene-1,2,3-triazole hybrids. [3]Ferrocenophanes A and A1 (Scheme 1a), that represent
modifications of polyphenols with well-established cytotoxicity, are significantly more active
7
a
with IC values against MDA-MB-231 cells in the nanomolar range.
5
0
Ferrocene derivatives have recently been suggested as potent anticancer agents owing to their
2
6
ability to decrease proliferation by inducing senescence in cancer cells. To determine the
extent of senescence/cell death induced by the most active compounds, i.e. (±)-9 and 9a, β-
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galactosidase activity, a senescence marker, was detected in MCF-7 cell line. Etoposide, a
2
8
senescence inducing agent, was used as a positive control. The cells were cultured in the
presence of gradually increasing concentrations of the compounds (6.25, 12.5, 25 and 50 µM),
and assayed for the activity of β-galactosidase after 48 hours of treatment. The examined
compounds (±)-9 and 9a did not induce senescence in MCF-7 cells, in contrast to etoposide
(Figure S10). These findings suggest that other factors than the ability to induce senescence in
cancer cells play a role in the observed anticancer activity of compounds 9a and (±)-9.
Identification of these factors needs further studies.
3
.
Conclusions
We have shown that the ansa-ferrocene 2 was regioselectively formylated to give separable,
planar-chiral aldehydes (±)-3 and (±)-4 in 66% combined yield. The β-isomer (±)-3
predominated under the tested reaction conditions, most likely for steric factors. It was further
transformed in three straightforward synthetic steps into an ansa-ferrocene-triazole-uracil
conjugate (±)-9 that displayed anticancer activity (MCF-7, A549, and MDA-MB-231 cell lines)
with EC in the micromolar range. Our finding suggests that the activity is most likely related
5
0
to all structural motifs in bioferrocenes (±)-9 and 9a. Thus, a family of organometallics with
anticancer potential is reported.
4
.
Experimental
4
.1. General Methods
All reactions, except the synthesis of azide (±)-8, were carried out under an inert atmosphere of
2
9
argon using Schlenk tube techniques. Solvents were purified by conventional methods. 1,1´-
Diallylferrocene (1),2b 1,1´-(2-buten-1,4-diyl)ferrocene (2),2 ferrocenemethanol (7a),20
3
0
19
azidomethylferrocene 8a, 3-propargyluracil were prepared using published methods. AlCl
3
was sublimed under vacuum. All other compounds were obtained from commercial sources and
were used without further purification. The NMR spectra were recorded on a Varian VNMRS
1
0

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5
00 MHz spectrometer at ambient temperature. The ESI MS were acquired on a Q-TOF Premier
DOI: 10.1039/D0DT01975E
or Thermo Q Exactive (TOF HR MS) spectrometers. The optical rotation was measured on an
-1
2
-1
Anton Paar MCP-150 polarimeter; the α value is given in 10 deg·cm ·g , concentration c in
g/(100 mL). The HPLC analysis were performed on Shimadzu CTO-10ASV chromatograph
equipped with a STD-20A UV detector and a Chiralcel OD-H or Chiralcel AD-H chiral column
(4.6 mm x 250 mm, from Daicel Chemical Ind., Ltd.) equipped with a pre-column (4 mm x 10
mm, 5 m). The wavelength of UV detection was set at 254 nm. The HPLC analyses were
executed in an isocratic and isothermal (30 °C) mode.
4
.2. Synthesis of (±)-3 and (±)-4
Triethyl orthoformate (1.68 mL, 9.90 mmol) and freshly sublimed AlCl (2.26 g, 16.95 mmol)
3
were added to a solution of 2 (390 mg, 1.64 mmol) in dry toluene (15 mL) at 0 °C. The reaction
mixture was stirred for 1 hour at room temperature, then it was poured into an ice-cold saturated
aq. Na S O solution (80 mL). The phases were separated, the aqueous phase was extracted
2
2
3
with diethyl ether. The combined organic phases were dried over anhydrous Na SO and
2
4
evaporated to dryness to give orange oil. It was dissolved in hexane and purified by column
chromatography on silica gel (hexanes:ethyl acetate 5:1). The first fraction was identified as
substrate 2; then compound (±)-4 (the 1,2-isomer) was eluted: red solid, yield 84.0 mg (0.31
1
mmol, 19%). H NMR (500 MHz, CDCl ): δ 2.89-2.94 (m, 1H, CH -CH=), 2.98-3.05 (m, 2H,
3
2
CH -CH=), 3.63 (ddd, J = 15.3 Hz, 7.6 Hz, 1.3 Hz, 1H, CH -CH=), 3.96-3.97 (m, 1H,
2
2
C H /C H ), 4.00-4.01 (m, 1H, C H /C H ), 4.20-4.22 (m, 1H, C H /C H ), 4.24-4.25 (m, 1H,
5
3
5
4
5
3
5
4
5
3
5
4
C H /C H ), 4.44 (t, J = 2.6 Hz, 1H, C H /C H ), 4.45 (app. s, 1H, C H /C H ), 4.65 (dd, J =
5
3
5
4
5
3
5
4
5
3
5
4
2
1
.6 Hz, 1.5 Hz, 1H, C H /C H ), 6.02-6.07 (m, 1H, CH=), 6.13-6.18 (m, 1H, CH=), 10.09 (s,
5 3 5 4
1
3
1
H, CHO) ppm. C{ H} NMR (126 MHz, CDCl ): δ 22.2 (CH -CH=), 23.9 (CH -CH=), 68.0
3
2
2
(C H /C H ), 69.6 (C H /C H ), 70.3 (C H /C H ), 71.4 (C H /C H ), 72.1 (C H /C H ), 73.7
5 3 5 4 5 3 5 4 5 3 5 4 5 3 5 4 5 3 5 4
(
C H /C H ), 89.2 (C H /C H ), 89.7 (C H /C H ), 130.2 (CH=CH), 130.8 (CH=CH), 194.3
5
3
5
4
5
3
5
4
5
3
5
4
1
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(
C=O) ppm. FT-IR (KBr) ν: 1658 cm (C=O). HRMS (ESI): m/z Found for C H FeO
15 15
DOI: 10.1039/D0DT01975E
+
[
M+H] 267.04643 (Calc. 267.04668). Anal. Found: C, 67.93; H, 5.24. Calc. for C H FeO:
1
5
14
C, 67.70; H, 5.30%. Chiral HPLC (Chiralcel AD-H, n-hexane:EtOH 98:2, 0.4 mL/min): 23.60
min (48.8%), 24.74 min (51.2%).
Compound (±)-3 (the 1,3-isomer) was eluted as the third coloured band: red solid, yield: 207.0
1
mg (0.78 mmol, 47%). H NMR (500 MHz, CDCl ): δ 2.84 ( ) and 2.91 ( ) (part AB of ABX
3
A
B
system, JAX = 8.0 Hz, JBX =7.5 Hz, JAB = 15.0, 2H, CH -CH=), 3.03 ( ) and 3.08 ( ) (part
2
A
B
AB of ABX system, JAX = 7.5 Hz, JBX =7.5 Hz, JAB = 15.0, 2H, CH -CH=), 4.01-4.02 (m, 1H,
2
C H /C H ), 4.16-4.17 (m, 1H, C H /C H ), 4.26-4.27 (m, 1H, C H /C H ), 4.28-4.29 (m, 1H,
5
3
5
4
5
3
5
4
5
3
5
4
C H /C H ), 4.48 (dd, J = 2.5 Hz, 1.4 Hz, 1H, C H /C H ), 4.65 (dd, J = 2.6 Hz, 1.3 Hz, 1H,
5
3
5
4
5
3
5
4
C H /C H ), 4.70-4.71 (m, 1H, C H /C H ), 5.99-6.10 (m, 2H, overlapped X parts of two ABX
5
3
5
4
5
3
5
4
1
3
1
systems, CH=), 9.84 (s, 1H, CHO) ppm. C{ H} NMR (126 MHz, CDCl ): δ 23.7 (CH -CH=),
3
2
2
6
1
4.1 (CH -CH=), 68.8 (C H /C H ), 69.3 (C H /C H ), 69.39 (C H /C H ), 69.43 (C H /C H ),
2 5 3 5 4 5 3 5 4 5 3 5 4 5 3 5 4
9.5 (C H /C H ), 71.0 (C H /C H ), 73.7 (C H /C H ), 89.2 (C H /C H ), 130.2 (CH=CH),
5
3
5
4
5
3
5
4
5
3
5
4
5
3
5
4
−
1
30.5 (CH=CH), 193.1 (C=O) ppm. FT-IR (KBr) ν: 1658 cm (C=O). HRMS (ESI): m/z Found
5
6
+
for C H FeO [M+H] 267.04635 (Calc. 267.04668). Anal. Found: C, 68.18; H, 5.27. Calc.
1
5
15
for C H FeO: C, 67.70; H, 5.30%. Chiral HPLC (Chiralcel OD-H, n-hexane:2-propanol 95:5,
1
5
14
0
.8 mL/min): 20.68 min (49.9%), 26.19 min (50.1%).
4
.3. The Vilsmeyer reaction of 2
DMF (104.2 mg, 113.0 µL, 1.46 mmol) and POCl (167.5 mg, 100.0 µL, 1.09 mmol) were
3
added to a solution of 2 (80.0 mg, 0.34 mmol) in chloroform (2.0 mL) The resulting solution
was stirred for 20 h at room temperature, then quenched with saturated aq. Na CO (10 mL)
2
3
solution and stirred for 0.5 h at room temperature. The organic phase was separated, the aqueous
phase was extracted with three times chloroform. The combined organic phases were washed
with brine and dried over anhydrous Na SO . After removal of the volatiles under vacuum, the
2
4
1
2

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residue was examined with H NMR (CDCl ) to reveal the presence of the two aldehydes (±)-
3
3
and (±)-4 at the 4.0:1.0 ratio.
.4. Synthesis of alcohol (±)-7
4
Aldehyde (±)-3 (100.0 mg, 0.376 mmol) was dissolved in THF (3.0 mL), then methanol (70
μL) and sodium borohydride (5.0 mg, 0.132 mmol) were added. The progress of the reaction
was monitored by TLC. After 24 h methanol (70 μL) and sodium borohydride (5.0 mg, 0.132
mmol) were added again and the mixture was stirred until the substrate was consumed as judged
from TLC (another 24 h). A saturated aqueous solution of NH Cl (50 mL) was added, the
4
mixture was diluted with ethyl acetate and water, and extracted with ethyl acetate. The organic
phase was washed with water and dried over MgSO . The solution was evaporated to dryness
4
and (±)-7 was isolated from a saturated solution in hexanes as yellow, viscous oil (80.5 mg,
1
0
.300 mmol, 80% yield). H NMR (500 MHz, CDCl ): δ 1.41 (bs, 1H, OH), 2.91 (bs, 4H, CH -
3
2
CH=), 3.97 (bs, 1H, C H or C H ), 4.08-4.21 (m, 8H, C H , C H and CH OH), 5.97-6.05 (m,
5
3
5
4
5
3
5
4
2
1
3
1
2
H, CH=) ppm. C{ H} NMR (126 MHz, CDCl ): δ 23.9 (CH -CH=), 24.0 (CH -CH=), 60.4
3 2 2
(CH OH), 67.3 (C H /C H ), 67.8 (C H /C H ), 68.2 (C H /C H ), 68.4 (C H /C H ), 68.7
2 5 3 5 4 5 3 5 4 5 3 5 4 5 3 5 4
(
C H /C H ), 88.3 (C H /C H ), 88.5 (C H /C H ), 130.4 (CH=CH), 130.6 (CH=CH) ppm.
5
3
5
4
5
3
5
4
5
3
5
4
5
6
+
HRMS (ESI): m/z Found for C H FeO [M] 268.05432 (Calc. 268.05451). Anal. Found C,
1
5
16
6
6.93; H 5.59. Calc. for C H FeO: C, 67.21; H 5.97%.
15 16
4
.5. Synthesis of azide (±)-8
Alcohol (±)-7 (100.0 mg, 0.373 mmol), sodium azide (145.0 mg, 2.230 mmol) and glacial acetic
acid (5.0 mL) were placed in a flask and stirred at 50 °C for 3 h, then the reaction mixture was
diluted with dichloromethane (5.0 mL) and saturated aq. NaHCO (50 mL) was added. The
3
phases were separated, the aqueous phase was extracted twice with dichloromethane. The
combined organic phases were dried over Na SO and purified by column chromatography on
2
4,
silica gel (hexanes:ethyl acetate 25:2). A yellow band was collected that provided azide (±)-8
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DOI: 10.1039/D0DT01975E
as an orange solid. Yield: 100.1 mg (0.341 mmol, 91%). H NMR (500 MHz, CDCl ): δ 2.93-
3
2
.95 (m, 4H, CH -CH=), 3.82-3.84 (m, 1H, C H /C H ), 4.03-4.15 (overlapping m, 8H, C H ,
2 5 3 5 4 5 3
1
3
1
C H and CH N ), 6.01-6.04 (m, 2H, CH=) ppm. C{ H} NMR (126 MHz, CDCl ): δ 23.9
5
4
2
3
3
(
(
(
CH -CH=), 24.0 (CH -CH=), 50.9 (CH N ), 68.0 (C H /C H ), 68.5 (C H /C H ), 68.7
2 2 2 3 5 3 5 4 5 3 5 4
C H /C H ), 68.8 (C H /C H ), 68.9 (C H /C H ), 69.9 (C H /C H ), 82.0 (C H /C H ), 88.2
5
3
5
4
5
3
5
4
5
3
5
4
5
3
5
4
5
3
5
4
C H /C H ), 88.5 (C H /C H ), 130.5 (CH=CH), 130.7 (CH=CH) ppm. HRMS (ESI): m/z
5
3
5
4
5
3
5
4
5
6
+
Found for C H FeN [M] 293.06073 (Calc. 293.06099). Anal. Found C, 61.93; H, 5.09; N,
1
5
15
3
1
4.11. Calc. for C H FeN : C, 61.48; H, 5.16; N, 14.33%.
15 15 3
4
.6. Synthesis of (±)-9
The azide (±)-8 (105.0 mg, 0.358 mmol) was dissolved in THF (8.0 mL) in a Schlenk flask and
purged with argon. A solution of copper sulfate pentahydrate (4.5 mg, 0.018 mmol) and sodium
ascorbate (21.3 mg, 0.011 mmol) in distilled water (2.0 mL) was added to the flask and degassed
for 30 min under argon. 3-Propargyluracil (70.0 mg, 0.470 mmol) was added and the resulting
mixture was stirred in the dark at room temperature for 4 days. Dichloromethane (15 mL) was
added. The reaction mixture was washed three times with water, dried with anhydrous Na SO ,
2
4
and the volatiles were distilled off under vacuum. The product crystalized from CHCl /hexanes
3
1
as a yellow solid (89.4 mg, 0.202 mmol, 56% yield). H NMR (500 MHz, CDCl ): δ 2.92 (d, J
3
=
6.9 Hz, 4H, CH -CH=), 3.77-3.79 (m, 1H, C H ), 4.05-4.14 (five multiplets, 5H, C H and
2 5 3 5 3
C H ), 4.17 (app. s, 1H, C H or C H ), 5.15 (s, 2H, N-CH ), 5.17 (s, 2H, N-CH ), 5.72 (dd, J
5
4
5
3
5
4
2
2
=
7.7, 1.4 Hz, 1H, 6-Ura), 5.99-6.03 (m, 2H, CH=CH), 7.17 (dd, J = 7.5, 5.7 Hz, 1H, 5-Ura),
1
3
1
7
.53 (s, 1H, CH triazole), 9.09 (bs, 1H, NH) ppm. C{ H} NMR (126 MHz, CDCl ): δ 23.96
3
(
CH -CH=), 24.01 (CH -CH=), 35.5 (CH ), 50.1 (CH ), 68.0 (C H /C H ), 68.3 (C H /C H ),
2 2 2 2 5 3 5 4 5 3 5 4
6
8
1
8.6 (C H /C H ), 68.8 (C H /C H ), 69.0 (C H /C H ), 69.2 (C H /C H ), 70.1 (C H /C H ),
5 3 5 4 5 3 5 4 5 3 5 4 5 3 5 4 5 3 5 4
0.8 (C H /C H ), 88.3 (C H /C H ), 88.8 (C H /C H ), 101.9 (CH Ura), 122.8 (CH triazole),
5
3
5
4
5
3
5
4
5
3
5
4
30.4 (CH=CH), 130.8 (CH=CH), 138.6 (CH Ura), 138.6 (C triazole) 151.9 (C=O Ura), 162.9
1
4

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(
C=O Ura) ppm. HRMS (ESI): m/z Found for C H FeN O [M] 443.10403 (Calc.
22 21 5 2
DOI: 10.1039/D0DT01975E
4
4
4
43.10392). Anal. Found C, 59.16; H, 5.09; N, 15.10. Calc. for C H FeN O : C, 59.61; H,
22 21 5 2
.78; N, 15.80%.
.7. Synthesis of 9a
Compound 9a was obtained similarly as described recently.19 1H NMR (500 MHz, CDCl ): δ
3
4
.17 (s, 5H, C H ), 4.21 (s, 2H, C H ), 4.28 (s, 2H, C H ), 5.16 (s, 2H, N-CH ), 5.22 (s, 2H, N-
5 5 5 4 5 4 2
CH ), 5.72 (d, J = 7.5 Hz, 1H, 6-Ura), 7.20 (app. t, 1H, 5-Ura), 7.52 (bs, 1H, CH triazole), 9.31
2
1
3
1
(
bs, 1H, NH) ppm. C{ H} NMR (126 MHz, CDCl ): δ 35.4 (CH ), 50.0 (CH ), 68.9 (C H ),
3 2 2 5 4
6
1
7.0 (C H ), 69.0 (C H ), 80.8 (C H ), 101.7 (CH Ura), 122.9 (CH triazole), 139.0 (CH Ura),
5 5 5 4 5 4
42.8 (C triazole), 152.2 (C=O Ura), 163.0 (C=O Ura) ppm. HRMS (ESI): m/z Found for
5
6
+
C H FeN O [M+H] 392.08004 (Calc. 392.08044).
1
8
18
5
2
4
.8. Crystal structure determination
Single-crystals of (R )-3 and (R )-4 suitable for X-ray analyses were grown from racemic
p
p
samples in hexanes at –20 ºC. The X-ray diffraction measurements of both compounds were
carried out on a Rigaku Oxford Diffraction SuperNova instrument equipped with microfocus
Cu X-ray source. During the measurements crystals were maintained at 100 K with the use of
Oxford Cryosystems nitrogen gas-flow device. Unit-cell parameter determination and raw
diffraction image processing were performed with the native diffractometer software. All
structures were solved using a charge-flipping method implemented in the SUPERFLIP
program31,32 and refined with the JANA package33 within the independent atom model
approximation. Scattering factors, in their analytical form, were taken from the International
3
4
Tables for Crystallography. Final crystal, data collection and refinement parameters for all
compounds are summarized in associated CIF files, which are present in the Supporting
Information, or can be retrieved from the Cambridge Structural Database35 (deposition
numbers: CCDC 1935549-50).
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4
.9. Biological studies
The MCF-7, MDA-MB-231, and A549 cell lines were cultured in DMEM with high glucose
medium (Lonza, Basel, Switzerland) supplemented with 10% fetal bovine serum (EuroClone,
Siziano, Italy), 2mM L-glutamine, antibiotics (100 U/ml penicillin, 100 μg/ml streptomycin,
Sigma-Aldrich, St. Louis, MO, USA) and 10 μg/ml of human recombinant insulin (Sigma-
Aldrich) for MCF-7 at 37 °C with 5% CO . MRC-5 human fibroblasts were cultured in MEME
2
(
Sigma-Aldrich) supplemented with 10% fetal bovine serum (EuroClone), 2mM L-glutamine,
antibiotics (100 U/ml penicillin, 100 μg/ml streptomycin) and non-essential amino acids
Sigma-Aldrich). The cell viability after exposure to the newly synthesized compounds were
(
tested by MTT assay. Before the treatment, cells were trypsinized in 0.25% trypsin-EDTA
3
solution (Sigma-Aldrich) and seeded into 96-well microplates at 6 x 10 cells/well. The cells
were treated with tested compounds at the appropriate concentrations in DMSO at 0.5% final
concentration 24 h after plating. After 72 h incubation with compounds or carrier, supernatants
were discarded and subsequently MTT stock solution (Sigma-Aldrich) was added to each well
to a final concentration of 1 mg/mL. After 1 h of incubation at 37 °C, water-insoluble dark blue
formazan crystals were dissolved in DMSO (200 µL) (37 °C/10 min incubation). Optical
densities were measured at 570 nm using BioTek microplate reader. All measurements were
carried out in tetraplicate and the results are expressed in percentage of cell viability relative to
control (cells without inhibitor in 0.5% DMSO).
The β-galactosidase activity was stained in MCF-7 cell line with used Senescence
β-Galactosidase Staining Kit (Cell Signaling Technology) according to manufacturer’s
protocol. Etoposide, used as a positive control, was obtained from Sigma-Aldrich. Images were
generated using bright field by Olympus inverted microscope (Olympus inverted microscope
CK X41, 20x objective, U-TV0.63XC Olympus Camera; Olympus, Tokyo, Japan).
Supporting Information
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6

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Additional figures and tables, HPLC traces, experimental details for the resolution of (±)-3,
crystallographic data.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors thank the National Science Centre for financial support of this work (grant No
2
015/17/B/ST5/00547) and Warsaw University of Technology. The X-ray diffraction
experiments were carried out at the Department of Physics, University of Warsaw, on the
Rigaku Oxford Diffraction SuperNova diffractometer, which was co-financed by the European
Union within the European Regional Development Fund (POIG.02.01.00-14-122/09).
References and notes
1
For reviews see: (a) W. Heo, T. R. Lee, J. Organomet. Chem., 1999, 578, 31-42; (b) D. E.
Herbert, U. F. J. Mayer, I. Manners, Angew. Chem. Int. Ed., 2007, 46, 5060-5087; (c) R. A.
Musgrave, A. D. Russell, I. Manners, Organometallics, 2013, 32, 5654-5667.
2
3
(a) A. J. Locke, C. Jones, C. J. Richards, J. Organomet. Chem., 2001, 637-639, 669-676; (b)
M. Ogasawara, T. Nagano, T. Hayashi, J. Am. Chem. Soc., 2002, 124, 9068-9069.
For general reviews on olefin metathesis in transition metal complexes, see: (a) E. B. Bauer, J.
A. Gladysz, in Handbook of Metathesis, ed. R. H. Grubbs, Wiley-VCH, Weinheim, 1st. edition,
2
003, Vol. 2, 2.11, pp. 403–431; (b) A. Pietrzykowski, W. Buchowicz, in Advances in
Organometallic Chemistry and Catalysis: The Silver/Gold Jubilee International Conference on
Organometallic Chemistry Celebratory Book, ed. A. J. L. Pombeiro, J. Wiley & Sons, 2014,
1
2, pp. 157–170; (c) T. Fiedler, J. A. Gladysz, in Olefin Metathesis: Theory and Practice, ed.
K. Grela, John Wiley & Sons, 2014, 9, pp. 311–328.
4
For recent examples of olefin metathesis in metallocenes see: (a) T. A. Tumay, G. Kehr, R.
Fröhlich, G. Erker, Dalton Trans., 2009, 8923-8928; (b) M. Ogasawara, S. Watanabe, K.
1
7

Dalton Transactions
Page 18 of 22
View Article Online
DOI: 10.1039/D0DT01975E
Nakajima, T. Takahashi, J. Am. Chem. Soc., 2010, 132, 2136-2137; (c) W. Buchowicz, A.
Furmańczyk, J. Zachara, M. Majchrzak, Dalton Trans., 2012, 41, 9269-9271; (d) M.
Ogasawara, W.-Y. Wu, S. Arae, K. Nakajima, T. Takahashi, Organometallics, 2013, 32, 6593–
6
1
598; (e) S. Arae, K. Nakajima, T. Takahashi, M. Ogasawara, Organometallics, 2015, 34, 1197-
202.
5
For recent reviews see: (a) A. Nguyen, A. Vessières, E. A. Hillard, S. Top, P. Pigeon, G. Jaouen,
Chimia, 2007, 61, 716-724; (b) C. Ornelas, New J. Chem., 2011, 35, 1973-1985; (c) S. S. Braga,
A. M. S. Silva, Organometallics, 2013, 32, 5626-5639; (d) R. Wang, H. Chen, W. Yan, M.
Zheng, T. Zhang, Y. Zhang, Eur. J. Med. Chem., 2020, 190, 112109.
6
Selected recent examples: (a) G. Tabbi, C. Casssina, G. Cavigiolio, D. Colangelo, A. Ghiglia,
L. Viano, D. Osella, J. Med. Chem., 2002, 45, 5786-5796; (b) P. James, J. Neudörfl, M.
Eissmann, P. Jesse, A. Prokop, H.-G. Schmalz, Org. Lett., 2006, 8, 2763-2766; (c) K.
Kowalski, A. Koceva-Chyla, A. Pieniążek, J. Bernasińska, J. Skiba, A. J. Rybarczyk-Pirek, Z.
Jóźwiak, J. Organomet. Chem., 2012, 700, 58-68; (d) A. Hottin, D. W. Wright, A. Steenackers,
P. Delannoy, F. Dubar, C. Biot, G. J. Davies, J.-B. Behr, Chem. Eur. J., 2013, 19, 9526-9533;
(e) H. V. Nguyen, A. Sallustrau, J. Balzarini, M. R. Bedford, J. C. Eden, N. Georgousi, N. J.
Hodges, J. Kedge, Y. Mehellou, C. Tselepis, J. H. R. Tucker, J. Med. Chem., 2014, 57, 5817-
5
2
822; (f) Y. Wang, P. Pigeon, S. Top, M. J. McGlinchey, G. Jaouen, Angew. Chem. Int. Ed.,
015, 54, 10230-10233.
7
(a) D. Plażuk, A. Vessières, E. A. Hillard, O. Buriez, E. Labbé, P. Pigeon, M.-A. Plamont, C.
Amatore, J. Zakrzewski, G. Jaouen, J. Med. Chem., 2009, 52, 4964-4967; (b) M. Gormen, D.
Plażuk, P. Pigeon, E. A. Hillard, M.-A. Plamont, S. Top, A. Vessières, G. Jaouen, Tetrahedron
Lett., 2010, 51, 118-120; (c) M. Görmen, P. Pigeon, S. Top, A. Vessières, M.-A. Plamont, E.
A. Hillard, G. Jaouen, Med. Chem. Commun., 2010, 1, 149-151; (d) M. Görmen, P. Pigeon, S.
Top, E. A. Hillard, M. Huché, C. G. Hartinger, F. de Montigny, M.-A. Plamont, A. Vessières,
1
8

Page 19 of 22
Dalton Transactions
View Article Online
DOI: 10.1039/D0DT01975E
G. Jaouen, ChemMedChem, 2010, 5, 2039-2050; (e) M. Görmen, P. Pigeon, E. A. Hillard, A.
Vessières, M. Huché, M.-A. Richard, M. J. McGlinchey, S. Top, G. Jaouen, Organometallics,
2
012, 32, 5856-5866; (f) Y. L. K. Tan, P. Pigeon, S. Top, E. Labbé, O. Buriez, E. A. Hillard,
A. Vessières, C. Amatore, W. K. Leong, G. Jaouen, Dalton Trans., 2012, 41, 7537-7549; (g) J.
de Jesus Cázares-Marinero, O. Buriez, E. Labbé, S. Top, C. Amatore, G. Jaouen,
Organometallics, 2013, 32, 5926-5934; (h) M. Beauperin, S. Top, M.-A. Richard, D. Plażuk,
P. Pigeon, S. Toma, V. Poláčková, G. Jaouen, Dalton Trans., 2016, 45, 13126-13134.
D. R. van Staveren, N. Metzler-Nolte, Chem. Rev., 2004, 104, 5931-5985.
8
9
(a) K. Schlögl, in Topics in Stereochemistry, ed. N. L. Allinger, E. L. Eliel, Wiley, Hoboken,
1
967, Stereochemistry of Metallocenes, pp. 39-91; (b) D. Schaarschmidt, H. Lang,
Organometallics, 2013, 32, 5668-5704.
1
1
0 T. H. Barr, E. S. Bolton, H. L. Lentzner, W. E. Watts, Tetrahedron, 1969, 25, 5245-5253.
1 (a) M. Hisatome, T. Sakamoto, K. Yamakawa, J. Organomet. Chem., 1976, 107, 87-101; (b) R.
G. Sutherland, J. R. Sutton, W. H. Horspool, J. Organomet. Chem., 1976, 122, 393-401; (c) M.
Hisatome, N. Watanabe, T. Sakamoto, K. Yamakawa, J. Organomet. Chem., 1977, 125, 79-93.
2 M. Hillman, L. Matyevich, E. Fujita, U. Jagwani, J. McGowan, Organometallics, 1982, 1, 1226-
1
1
229.
1
1
1
3 D. R. Talham, D. O. Cowan, Organometallics, 1987, 6, 932-937.
4 A. Reichert, M. Bolte, H.-W. Lerner, M. Wagner, J. Organomet. Chem., 2013, 744, 15-23.
5 C. Nilewski, M. Neumann, L. Tebben, R. Fröhlich, G. Kehr, G. Erker, Synthesis, 2006, 13,
2
191-2200.
6 J.-H. Jia, X.-M. Tao, Y.-J. Li, W.-J. Sheng, L. Han, J.-R. Gao, Y.-F. Zheng, Chem. Phys. Lett.,
011, 514, 114-118.
1
2
1
9

Dalton Transactions
Page 20 of 22
View Article Online
DOI: 10.1039/D0DT01975E
1
7 (a) G. D. Broadhead, J. M. Osgerby, P. L. Pauson, J. Chem. Soc., 1958, 650-656; (b) S.
Movahhed, J. Westphal, M. Dindaroğlu, A. Falk, H.-G. Schmalz, Chem. Eur. J., 2016, 22,
7
381-7384.
1
1
8 O. Riant, O. Samuel, H. B. Kagan, J. Am. Chem. Soc., 1993, 115, 5835-5836.
9 A. Kasprzak, M. Koszytkowska-Stawińska, A. Nowicka, W. Buchowicz, M. Popławska, J. Org.
Chem., 2019, 84, 15900-15914.
2
0 P. V. Solntsev, K. L. Spurgin, J. R. Sabin, A. A. Heikal, V. N. Nemykin, Inorg. Chem., 2012,
5
1, 6537-6547.
2
2
1 D. Paliwoda, M. Hanfland, A. Katrusiak, J. Phys. Chem., 2019, C 123, 25719-25723.
2 A. Hottin, A. Scandolera, L. Duca, D. W. Wright, G. J. Davies, J. B. Behr, Bioorg. Med.
Chem. Lett., 2016, 26, 1546-1549.
2
3 Taking into account that ferroquine (a 1,2-unsymetrically disubstituted planar-chiral ferrocene
derivative) has been usually applied in biological studies as a racemate, we decided to test
racemic (±)-9. We presume that the main role of the ferrocenyl moiety is production of reactive
oxygen species. Thus, we do not expect a significant chiral effect.
2
4 (a) K. Kowalski, J. Skiba, L. Oehninger, I. Ott, J. Solecka, A. Rajnisz, B. Therrien,
Organometallics, 2013, 32, 5766-5773; (b) J. Skiba, K. Kowalski, A. Prochnicka, I. Ott, J.
Solecka, A. Rajnisz, B. Therrien, J. Organomet. Chem., 2015, 782, 52-61.
2
2
5 M. Maschke, M. Lieb, N. Metzler-Nolte, Eur. J. Inorg. Chem., 2012, 5953-5959.
6 (a) G. Jaouen, A. Vessières, S. Top, Chem. Soc. Rev., 2015, 44, 8802-8817; (b) Y. Wang, P. M.
Dansette, P. Pigeon, S. Top, M. J. McGlinchey, D. Mansuy, G. Jaouen, Chem. Sci., 2018, 9,
7
0-78.
2
7 A. Litwiniec, A. Grzanka, A. Helmin-Basa, L. Gackowska, D. Grzanka, J Cancer Res Clin
Oncol, 2010, 136, 717-736.
2
0

Page 21 of 22
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DOI: 10.1039/D0DT01975E
2
2
3
3
3
8 Y. Wang, Y. Wang, S. Liu, Y. Liu, H. Xu, J. Liang, J. Zhu, G. Zhang, W. Su, W. Dong, Q. Guo,
Biomed Pharmacother, 2018, 107, 606-614.
9 D. D. Perrin, W. L. F. Armarego, Purification of Laboratory Chemicals, Pergamon Press, New
York, 1988.
0 J. M. Casas-Solvas, A. Vargas-Berenguel, L. F. Capitán-Vallvey, F. Santoyo-González, Org.
Lett., 2004, 6, 3687-3690.
1 (a) G. Oszlányi, A. Sütő, Acta Cryst. Sect. A, 2004, 60, 134-141; (b) G. Oszlányi, A. Sütő, Acta
Cryst. Sect. A, 2005, 61, 147-152.
2 (a) L. Palatinus, G. Chapuis, J. Appl. Cryst., 2007, 40, 786-790; (b) L. Palatinus, Acta Cryst.
Sect. B, 2013, 69, 1-16.
3
3
3 V. Petříček, M. Dušek, L. Palatinus, Z. Kristallogr., 2014, 229, 345-352.
4 E. Prince, in International Tables for Crystallography, Volume C: Mathematical, physical and
chemical tables, International Union of Crystallography, Chester, UK, 2006.
5 C. R. Groom, I. J. Bruno, M. P. Lightfoot, S. C. Ward, Acta Cryst. Sect. B, 2016, 72, 171-179.
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Table of contents entry
Ansa-ferrocenealdehyde, obtained by formylation of a metathesis-derived ansa-ferrocene, was
transformed into a conjugate with triazole and uracil with anticancer activity.
O
N
Fe
N
N
Fe
N
N
H
O
anticancer activity
MCF-7, A549,
MDA-MB-231 cells
(micromolar range)