Organometallic nucleoside analogues with ferrocenyl linker groups: Synthesis and cancer cell line studies

Article abstract of DOI:10.1021/jm500246h

Examples of organometallic compounds as nucleoside analogues are rare within the field of medicinal bioorganometallic chemistry. We report on the synthesis and properties of two chiral ferrocene derivatives containing a nucleobase and a hydroxyalkyl group. These so-called ferronucleosides show promising anticancer activity, with cytostatic studies on five different cancer cell lines indicating that both functional groups are required for optimal activity.

Full text of DOI:10.1021/jm500246h

Brief Article
pubs.acs.org/jmc
Organometallic Nucleoside Analogues with Ferrocenyl Linker
Groups: Synthesis and Cancer Cell Line Studies
Huy V. Nguyen,† Antoine Sallustrau,† Jan Balzarini,⊥ Matthew R. Bedford,‡ John C. Eden,§
Niki Georgousi,§ Nikolas J. Hodges,§ Jonathan Kedge,† Youcef Mehellou,∥ Chris Tselepis,‡
and James H. R. Tucker*,†
‡
§
†School of Chemistry, School of Cancer Sciences, College of Medical and Dental Sciences, School of Biosciences, College of Life
and Environmental Sciences, and ∥School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University
of Birmingham, Edgbaston, Birmingham, B15 2TT, U.K.
⊥Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B 3000
Leuven, Belgium
S
* Supporting Information
ABSTRACT: Examples of organometallic compounds as nucleo-
side analogues are rare within the field of medicinal
bioorganometallic chemistry. We report on the synthesis and
properties of two chiral ferrocene derivatives containing a
nucleobase and a hydroxyalkyl group. These so-called ferronu-
cleosides show promising anticancer activity, with cytostatic
studies on five different cancer cell lines indicating that both
functional groups are required for optimal activity.
ucleoside analogues have long been established as an
different structural features. Ferrocene has attracted active
interest in recent years within the field of medicinal and
bioorganometallic chemistry,3 with organometallic analogues
and derivatives of the antimalarial drug chloroquine (ferro-
quine) and the breast cancer drug tamoxifen (the ferrocifen
family) being the most widely known.4 At the same time there
has been a number of examples of other ferrocene containing
compounds that have shown anticancer,5 antibacterial, and
antifungal properties.6 However, although there are also some
recent examples of ferrocene-conjugated nucleobases7 and
hydroxylalkyl ferrocenes8 that exhibit anticancer activity, as far
as we are aware, nucleoside analogues of the type shown in
Figure 1 that are bridged solely by an organometallic linker
group and show biological activity have not been reported.9
As part of our program to develop novel metal-containing
analogues of DNA and its components,10 we recently reported
an organometallic nucleic acid oligomer designated as ferrocene
nucleic acid (FcNA).10b The monomeric components of the
reported form of FcNA consist of a tetrasubstituted ferrocene
unit containing two alkylhydroxyl groups to allow connectivity
via phosphodiesters, and two thymine nucleobases. We noticed
that these monomeric compounds have the required features
for a novel nucleoside analogue, where the five-membered
N
effective class of compound that exhibits antiviral or
anticancer activity.1 Two common structural features are a
nucleobase moiety and a hydroxylmethyl group (Figure 1),
Figure 1. Representation of the structural relationship between
thymidine and a nucleoside analogue that contains a variable linker
group connecting a hydroxymethyl group with a nucleobase, with AZT
(azidothymidine) as a specific example.
which together allow them to act as substrates that adversely
affect processes associated with nucleic acid synthesis. These
two components are typically connected by an organic linker
group that is a modification or a replacement of the sugar ring,
which can either be cyclic (e.g., AZT) or acyclic (e.g.,
acyclovir).2 Because of their structural similarities to natural
nucleosides, which can lead to resistance and side effects, there
is a continuing need for a diverse range of analogues with
Received: February 14, 2014
© XXXX American Chemical Society
A
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Journal of Medicinal Chemistry
Brief Article
sugar ring is substituted for a five-membered cyclopentadienyl
ring of a ferrocene unit. Accordingly we now report bis-
substituted ferrocenes 1 and 2 (so-called ferronucleosides) that
contain both a nucleobase (thymine or adenine) and a hydroxyl
group, along with various control compounds (Figure 2). The
cell line studies reported here demonstrate the promise of these
ferrocenyl derivatives as a novel class of nucleoside analogues
that show anticancer activity.
Scheme 1. Synthetic Route toward Ferrocene Nucleoside
Analogues 1 and 2
Figure 2. Ferronucleosides 1 and 2 and controls 3−6.
It was decided to first synthesize nucleoside analogues with a
1,2-disubstituted arrangement on one Cp ring, with the other
Cp ring unfunctionalized. This would enable us to utilize the
synthetic chemistry already developed within the group for
FcNA monomer synthesis.10b For the same reason, the
compounds would have a three-carbon hydroxyl linker (with
a methyl group on the α carbon to direct ortho-lithiation) and a
two-carbon linker to the nucleobase. The synthetic route taken
to make the ferronucleoside targets 1 and 2 is outlined in
Scheme 1. The chirally pure Ugi amine11 7 was treated with n-
BuLi and quenched with iodine to introduce the required
planar 1,2-disubstitution pattern. Subsequent functional group
interconversion gave 11, to provide the chain extension giving a
three carbon linker. Treatment of 11 with silyl enol ether,
catalyzed by the Lewis acid boron trifluoride, gave 12 in good
yield. Reduction of the ester followed by TBDPS protection
gave 14. Conversion to aldehyde 15 (via n-BuLi halogen
exchange and quenching with DMF) enabled a Wittig reaction
to be performed to form alkene 16, with subsequent
hydroboration−oxidation giving the monoprotected bis-alcohol
17 in high chiral purity (as checked by chiral HPLC analysis,
overall 97% ee). The conversion of 17 to the target compounds
1 and 2 proceeded via a Mitsunobu reaction with the
appropriate protected nucleobase, followed by deprotection
of the protecting groups. The family of compounds was also
extended by making the control compounds 3−6 (Figure 2) to
assess the role of the alcohol and nucleobase groups, noting
that 6 had previously been shown8 to display antineoplastic
activity against cervix carcinoma (HeLa) tumor cells.
highest cytostatic activity, with 1 and 2 exhibiting low
micromolar to submicromolar antiproliferative activity com-
parable with cisplatin (Table 1). In addition, 1 and 2 were
Table 1. Cytostatic activity of Compounds 1−4
a
IC50 (μM)
compd
L1210
0.78
CEM
0.9
HeLa
2.68
1
2
1.0
0.35
39
1.1
3
12
45
4
417
592
49
509
5
26
94
6
25
43
52
cisplatin
5-FU
1
0.9
18
1.2
0.33 0.17
5
0.54 0.12
a
50% inhibitory concentration, or compound concentration required
to inhibit tumor cell proliferation by 50%. Data are the mean of at least
two independent experiments.
almost equally as active as 5-FU in L1210 cell cultures, 2- to 5-
fold less active in HeLa cell cultures, but 20- to 50-fold more
active in CEM cell cultures. Compounds 1 and 2 proved to be
poorly toxic to nontumorigenic human embryonic lung (HEL)
fibroblast cell cultures (minimal cytotoxic concentration, >50
μM).
Cell growth studies carried out on an esophageal cancer cell
line revealed that 1 inhibited growth at 6.25 μM, whereas
control compounds 3 and 4 (Figure 3 and Supporting
Information, respectively) had much less or no effect, even
up to higher concentrations of 25 μM. The same trend was
The cytostatic activity of six ferrocene compounds was
evaluated in comparison to the established anticancer drugs
cisplatin and 5-fluorouracil (5-FU) using a proliferation activity
assay carried out on three tumor cell lines: murine leukemia
cells (L1210), HeLa, and human T-lymphocyte cells (CEM).
The data indicate that the concomitant presence of the
hydroxyl and nucleobase components is crucial to give the
B
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Journal of Medicinal Chemistry
Brief Article
novel bioorganometallic compounds involving an adverse effect
on nucleic acid synthesis, as is the case for nucleobase analogue
drugs containing organic linker groups.12 We are currently
planning to carry out further studies to reveal the mode of
action of these ferronucleosides and to highlight stereochemical
and structure−activity relationships for improving biological
activity and specificity.
EXPERIMENTAL SECTION
■
General Information. Unless stated otherwise, all reactions were
performed under an Ar atmosphere. Compound 6 was prepared as
described previously.8 All tested compounds had a purity of ≥95%, as
shown by HPLC (see Supporting Information for data and conditions
used).
(R,Sp)-1-(α-N,N-Dimethylaminoethyl)-2-iodoferrocene (8).
The Ugi amine 711 (4.00 g, 15.56 mmol) was dissolved in Et2O (50
mL) at room temperature. n-BuLi (12 mL, 30 mmol) was added and
the mixture stirred overnight. The mixture was cooled to −78 °C, and
iodine (9.52 g, 37.51 mmol), dissolved in THF (60 mL), was added
over 10 min. The mixture was stirred at −78 °C for 90 min before
being warmed to room temperature, at which point it was stirred for
an additional 90 min before being quenched at 0 °C with sodium
thiosulfate(aq) (50 mL, 25% w/v). After dilution with Et2O (30 mL),
the layers were separated and the aqueous layer was further extracted
with Et2O (3 × 50 mL). The combined organic fractions were dried
over MgSO4. The solvent was removed in vacuo before purification via
flash column chromatography (5% MeOH, 5% TEA in DCM) to yield
Figure 3. Growth curves for 1 (top) and 3 (bottom) at three different
concentrations (LC = 6.25 μM, MC = 12.5 μM, HC = 25 μM) over 4
days in cancer cell line OE 19 (n = 3 SD).
1
product (3.18 g, 55%). H NMR (400 MHz, CDCl3) δ 4.46 (dd, J =
observed for the adenine 2 and its control 5 (see Supporting
Information data). Once again the data indicate that both
functional groups (the hydroxyl and the nucleobase) are
required for the best cytostatic activities, which is comparable
to cisplatin under these conditions.
Assays of cellular viability (MTT assay) and cell proliferation
(BrdU assay) were then performed on colorectal cancer cell
lines. The results after a 48 h exposure (Figure 4) revealed that
2.4, 1.4 Hz, 1H), 4.24 (t, J = 2.6 Hz, 1H), 4.15 (dd, J = 2.7, 1.3 Hz,
1H), 4.12 (s, 5H), 3.62 (q, J = 6.8 Hz, 1H), 2.15 (s, 6H), 1.50 (d, J =
6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 90.21 (ipso Cp), 74.32
(Fc), 71.67 (Fc), 68.19 (Fc), 65.59 (Fc), 57.59 (CH*), 45.49 (ipso
Cp), 41.22 (CH3), 16.01 (CH3). MS (ES) (m/z) calcd for
C14H18N56FeI 382.9833, found 382.9820. IR (cm−1): 3078 (C−
H), 2931 (CH2), 2878 (CH2), 2809 (CH2), 1446 (CH3), 1371 (CH3),
1243, 1087, 821 (CHCH), 732 (CH Ar). Mp: 58−60 °C.
(R,Sp)-1-(α-Acetoxyethyl)-2-iodoferrocene (9). Compound 8
(3.26 g, 8.51 mmol) and acetic anhydride (25.68 mL, 272.17 mmol)
were heated at 50 °C for 2 h. The acetic anhydride was removed under
high vacuum (0.1 mmHg) and the residue purified via flash column
chromatography (10% EtOAc in hexane) to yield the yellow-brown
1
oily product (2.94 g, 87%). H NMR (400 MHz, CDCl3) δ 5.89 (q, J
= 6.4 Hz, 1H), 4.51 (dd, J = 2.6, 1.4 Hz, 1H), 4.33 (dd, J = 2.8, 1.4 Hz,
1H), 4.28 (t, J = 2.6 Hz, 1H), 4.15 (s, 5H), 2.01 (s, 3H), 1.66 (d, J =
6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.30 (CO), 87.54
(ipso Cp), 75.63 (Fc), 71.76 (Fc), 69.71 (Fc), 68.94 (Fc), 65.80
(CH*), 44.03 (ipso Cp), 21.16 (CH3), 18.66 (CH3). MS (ES) calcd
for C14H15O256FeI 397.9466, found 397.9471. IR (cm−1): 3095 (C−
H), 2972 (CH2), 2928 (CH2), 2866 (CH2), 1729 (CO), 1445
(CH3), 1371 (CH3), 1085, 820 (CHCH), 703 (CH Ar).
(R,Sp)-1-(α-Hydroxyethyl)-2-iodoferrocene (10). Compound 9
(2.937 g, 7.37 mmol) was dissolved in EtOH (35 mL). NaOH(aq) (30
mL, 10% w/v) was added, and the mixture was heated at 95 °C for 15
min. After the mixture was cooled to room temperature, the organic
layer was extracted with EtOAc (2 × 40 mL). The organic layers were
dried over Na2SO4. The solvent was removed in vacuo and the residue
purified via flash column chromatography (25% EtOAc in hexane) to
Figure 4. Cellular viability (MTT, blue) and cell proliferation (BrdU,
red) assays on colorectal cell lines (48 h).
1
1 and 2 had antineoplastic activities approaching that 5-FU,
whereas the other compounds were less effective. Encourag-
ingly, an AMES assay to investigate the potential mutagenicity
of these ferrocenyl derivatives revealed that the compounds
were inactive.
In conclusion, novel ferrocenyl nucleoside analogues 1 and 2
appear to exhibit cytostatic activities that are comparable under
the conditions used to commercially establish anticancer drugs
such as cisplatin and 5-FU. Control studies indicate that the
presence of a hydroxyl and a nucleobase group is required for
optimal activity. This suggests a mechanistic role for these
yield the yellow oily product (2.43 g, 92%). H NMR (400 MHz,
CDCl3) δ 4.85 (qd, J = 6.5, 2.8 Hz, 1H), 4.46 (dd, J = 2.5, 1.4 Hz, 1H),
4.29 (dd, J = 2.7, 1.3 Hz, 1H), 4.25 (t, J = 2.6 Hz, 1H), 4.14 (s, 5H),
1.88 (d, J = 3.6 Hz, 1H), 1.62 (d, J = 6.5 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 91.61 (ipso Cp), 75.01 (Fc), 71.59 (Fc), 68.72 (Fc),
66.51 (Fc), 64.98 (CH*), 43.62 (ipso Cp), 21.31 (CH3). MS (ES)
(m/z) calcd for C12H13O56FeI 355.9361, found 355.9352. IR (cm−1):
3255 (OH), 3093 (C−H), 2967 (CH2), 2920 (CH2), 1445 (CH3),
1369 (CH3), 1099 (C−OH), 816 (CHCH), 684 (CHCH).
(R,Sp)-1-(α-Methoxyethyl)-2-iodoferrocene (11). Compound
10 (2.43 g, 6.83 mmol) was dissolved in a MeOH/AcOH (20 mL,
9:1) mixture, and the solution was stirred at room temperature for 48
C
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Journal of Medicinal Chemistry
Brief Article
t
h. The reaction was quenched with water (10 mL) and extracted with
DCM (2 × 20 mL). The combined organic fractions were dried over
MgSO4, the solvent was removed in vacuo, and the residue was
purified via flash column chromatography (25% EtOAc in hexane) to
30.03 (CH*), 26.94 (tBu), 19.24 (ipso Bu), 18.91 (CH3). MS (ES)
(m/z) calcd for C30H35O56FeISiNa 622.0851, found 622.0846. IR
(cm−1): 3071 (CH Fc), 2958 (CH2), 2929 (CH2), 2856 (CH2),
1472 (CH2), 1387 (CH3), 1361, 1106, 1085, 821 (CH Ar TBDPS),
700 (CC).
1
yield the yellow oily product (2.37 g, 94%). H NMR (400 MHz,
CDCl3) δ 4.49 (dd, J = 2.4, 1.4 Hz, 1H), 4.34 (q, J = 6.5 Hz, 1H),
4.29−4.25 (m, 2H), 4.13 (s, 5H), 3.26 (s, 3H), 1.64 (d, J = 6.5 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 89.78 (ipso Cp), 74.78 (Fc),
74.22 (Fc), 71.66 (Fc), 68.86 (Fc), 65.35 (CH*), 56.00 (CH3), 39.48
(ipso Cp), 19.63 (CH3). MS (ES) (m/z) calcd for C13H15O56FeI
369.9517, found 369.9513. IR (cm−1): 3094 (C−H), 2974 (CH2),
2926 (CH2), 2871 (CH2), 2815 (CH2), 1448 (CH3), 1371 (CH3),
1085 (C−O−C), 820 (CHCH).
(S,Sp)-1-[α-Methyl-(3-(tert-butyldiphenylsilyloxy)propyl)]-2-
formylferrocene (15). Compound 14 (2.182 g, 3.51 mmol) was
dissolved in Et2O (30 mL). The mixture was cooled to −78 °C, and n-
BuLi (2.32 mL, 7.01 mmol) was added. After 30 min, DMF (0.68 mL,
8.76 mmol) was added, and the mixture was stirred at −78 °C for
another 30 min before being allowed to warm to room temperature
before quenching with water (20 mL). The phases were separated, and
the aqueous layer was extracted with Et2O (2 × 20 mL). The
combined ethereal fractions were dried over Na2SO4. The solvent was
removed in vacuo and the residue purified via flash column
chromatography (10% EtOAc in hexane) to yield the red oily product
(S,Sp)-1-[α-Methyl(2-ethylpropanoate)]-2-iodoferrocene
(12). Compound 11 (2.37 g, 6.42 mmol) and 1-ethoxyvinyloxy-
trimethylsilane (8.234 g, 51.37 mmol) were dissolved in DCM (30
mL). The mixture was cooled to −78 °C, and BF3·OEt2 (1.77 mL,
14.12 mmol) was then added dropwise. The mixture was stirred for 15
min at −78 °C before being warmed to room temperature and
quenched with saturated NaHCO3 (40 mL). The organic layer was
separated, and the aqueous layer was further extracted with DCM (40
mL). The combined organic fractions were dried over MgSO4. The
solvent was removed in vacuo and the residue purified via flash column
chromatography (10% EtOAc in hexane) to yield the yellow oily
product (1.676 g, 61%). 1H NMR (400 MHz, CDCl3) δ 4.42 (dd, J =
2.4, 1.4 Hz, 1H), 4.18−4.08 (m, 7H + 2H), 3.14−3.05 (m, 1H), 2.53
(dd, J = 15.0, 3.7 Hz, 1H), 2.11 (dd, J = 15.0, 10.3 Hz, 1H), 1.43 (d, J
= 6.9 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 172.00 (CO), 94.07 (ipso Cp), 74.12 (Fc), 71.52 (Fc), 67.84
(Fc), 64.58 (Fc), 60.26 (CH2), 44.08 (ipso Cp), 43.19 (CH2), 30.72
(CH*), 18.90 (CH3), 14.27 (CH3). MS (ES) (m/z) calcd for
C16H19O256FeI 425.9779, found 425.9782.
1
(1.686 g, 92%). H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 7.68−
7.59 (m, 4H), 7.42−7.33 (m, 6H), 4.75 (dd, J = 2.7, 1.4 Hz, 1H), 4.48
(t, J = 2.6 Hz, 1H), 4.43 (dd, J = 2.6, 1.4 Hz, 1H), 4.21 (s, 5H), 3.61 (t,
J = 7.1, 2H), 3.21−3.10 (m, 1H), 1.73−1.50 (m, 2H), 1.34 (d, J = 6.9
Hz, 3H), 1.04 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 193.25 (C
O), 135.55 (Ph), 133.94 (ipso Ph), 133.80 (ipso Ph), 129.55 (Ph),
127.61 (Ph), 99.14 (ipso Cp), 76.31 (ipso Cp), 71.04 (Fc), 70.80 (Fc),
70.03 (Fc), 68.89 (Fc), 61.75 (CH2), 43.28 (CH2), 27.90 (CH*),
26.89 (tBu), 22.66 (ipso tBu), 19.17 (CH3). MS (ES) (m/z) calcd for
C31H36O256FeSiNa 547.1732, found 547.1727. IR (cm−1): 3071 (
CH Fc), 2958 (CH2), 2929 (CH2), 2856 (CH2), 1673 (CO), 1589
(CN), 1427 (CH2), 1376 (tBu), 1106 (Si-OR), 1086 (Si-OR), 821
(CH Ar Ph), 700 (CC).
(S,Rp)-1-[α-Methyl-(3-(tert-butyldiphenylsilyloxy)propyl)]-2-
vinylferrocene (16). Trimethylmethylphosphonium bromide (1.722
g, 4.82 mmol), potassium tert-butoxide (0.541 g, 4.82 mmol, and a
catalytic amount of dibenzo-18-crown-6-ether were dissolved in THF
(20 mL). The mixture was stirred for 30 min, and then 15 (1.686 g,
3.21 mmol), dissolved in THF (30 mL), was added to the mixture.
The mixture was stirred overnight at room temperature, before
quenching with water (10 mL) and extracting with Et2O (2 × 20 mL).
The combined ethereal fractions were dried over Na2SO4, solvent was
removed in vacuo, and the residue was purified via flash column
chromatography (5% EtOAc in hexane) to yield the product as a
(S,Sp)-1-[α-Methyl-(3-(hydroxyl)propyl)]-2-iodoferrocene
(13). Compound 12 (1.592 g, 3.73 mmol) was dissolved in Et2O (50
mL), and the solution was cooled to 0 °C. After standing for 5 min,
diisobutylaluminum hydride (11.2 mL, 11.2 mmol) was added slowly
at that temperature. The mixture was stirred at 0 °C for 1 h before the
reaction was quenched with saturated sodium potassium tartrate in
water (30 mL). The layers were separated, and the aqueous layer was
further extracted with Et2O (30 mL). The combined organic fractions
were dried over Na2SO4, the solvent was removed in vacuo, and the
residue was purified via flash column chromatography (50% EtOAc in
1
yellow oil (1.497 g, 89%). H NMR (400 MHz, CDCl3) δ 7.69−7.63
(m, 4H), 7.44−7.33 (m, 6H), 6.62 (dd, J = 17.4, 10.8 Hz, 1H), 5.34
(dd, J = 17.5, 1.8 Hz, 1H), 5.01 (dd, J = 10.8, 1.7 Hz, 1H), 4.43 (dd, J
= 2.5, 1.4 Hz, 1H), 4.12 (t, J = 2.6 Hz, 1H), 4.06 (dd, J = 2.5, 1.4 Hz,
1H), 4.03 (s, 5H), 3.62 (dd, J = 7.2, 5.4 Hz, 2H), 2.94−2.86 (m, 1H),
1.72−1.61 (m, 1H), 1.45−1.37 (m, 1H), 1.30 (d, J = 6.8 Hz, 3H), 1.06
(s, 9H). 13C NMR (101 MHz, CDCl3) δ 135.59 (Ph), 134.08 (ipso
Ph), 134.02 (ipso Ph), 133.50 (CH vinyl), 129.49 (Ph), 127.56 (Ph),
110.96 (CH2 vinyl), 94.84 (ipso Cp), 81.37 (ipso Cp), 69.66 (Fc),
66.55 (Fc), 66.27 (Fc), 64.08 (Fc), 61.89 (CH2), 42.80 (CH2), 27.65
1
hexane) to yield the product (1.413 g, 99%). H NMR (400 MHz,
CDCl3) δ 4.42 (dd, J = 2.4, 1.4 Hz, 1H), 4.17 (td, J = 2.6, 0.6 Hz, 1H),
4.13 (s, 5H), 4.06 (dd, J = 2.7, 1.3 Hz, 1H), 3.59 (t, J = 6.6 Hz, 2H),
2.78−2.69 (m, 1H), 1.72−1.52 (m, 2H), 1.41 (d, J = 7.0 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ 95.87 (ipso Cp), 73.76 (Fc), 71.47 (Fc),
67.87 (Fc), 64.18 (Fc), 60.84 (CH2), 44.73 (ipso Cp), 42.09 (CH2),
29.81 (CH*), 19.69 (CH3). MS (ES) (m/z) calcd for C14H17O56FeI
383.9674, found 383.9678. IR (cm−1): 3282 br (OH), 3088 (CH
Fc), 2971 (CH2), 2932 (CH2), 2854 (CH2), 1556, 1452 (CH2), 1376
(CH3), 680 (CC). Mp: 96−98 °C.
(CH*), 26.89 (tBu), 19.23 (ipso Bu), 18.92 (CH3). MS (ES) (m/z)
t
calcd for C32H38O56FeSi 522.2041, found 522.2055. IR (cm−1): 3072
(CH Fc), 2958 (CH2) 2930 (CH2), 2857 (CH2), 1625 (Ar Ph),
1589, 1427 (CH2), 1388 (CH3), 1105 (Si-OR), 1086 (Si-OR), 821
(CH Ar), 699 (vinyl/CC).
(S,Sp)-1-[α-Methyl-(3-(tert-butyldiphenylsilyloxy)propyl)]-2-
iodoferrocene (14). Compound 13 (1.413 g, 3.67 mmol) was
dissolved in DCM (20 mL) at room temperature. TEA (0.77 mL, 5.52
mmol), tert-butyldiphenylsilyl chloride (1.44 mL, 5.51 mmol), and
DMAP (catalytic amount) were added to the mixture. The solution
was then stirred overnight at room temperature before quenching with
water (10 mL). The phases were separated, and the aqueous layer was
extracted with Et2O (2 × 20 mL). The combined organic fractions
were dried over Na2SO4, the solvent was removed in vacuo, and the
residue was purified via flash column chromatography (10% EtOAc in
(S,Rp)-1-[α-Methyl-(3-(tert-butyldiphenylsilyloxy)propyl)]-[2-
(hydroxyl)ethyl]ferrocene (17). Compound 16 (1.497 g, 2.87
mmol) was dissolved in THF (30 mL). BH3·THF (1 M, 8.2 mL, 8.2
mmol) was then added dropwise at room temperature and the mixture
stirred for 2 h. EtOH (9.76 mL), NaOH (3M, 9.76 mL, 29.28 mol),
and H2O2 (30 wt % in water, 7.17 mL, 63.24 mol) were then
successively added, and the mixture was stirred for 1 h at room
temperature. The reaction mixture was extracted with DCM (30 mL),
washed with brine (20 mL), and then dried over Na2SO4. The solvent
was removed in vacuo and the residue purified via flash column
chromatography (10% EtOAc in hexane) to yield the yellow oily
1
hexane) to yield a yellow oily product (2 g, 95%). H NMR (400
MHz, CDCl3) δ 7.70−7.65 (m, 4H), 7.43−7.32 (m, 6H), 4.38 (dd, J =
2.4, 1.3 Hz, 1H), 4.10 (s, 5H + 1H), 4.00 (dd, J = 2.7, 1.3 Hz, 1H),
3.70−3.65 (m, 2H), 2.77−2.68 (m, 1H), 1.88−1.80 (m, 1H), 1.43−
1.34 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H), 1.05 (s, 9H). 13C NMR (101
MHz, CDCl3) δ 135.63 (Ph), 134.10 (ipso Ph), 134.05 (ipso Ph),
129.47 (Ph), 127.58 (Ph), 96.25 (ipso Cp), 73.81 (Fc), 71.38 (Fc),
67.61 (Fc), 64.27(Fc), 62.10 (CH2), 44.45 (ipso Cp), 41.60 (CH2),
1
product (1.434 g, 82%). H NMR (400 MHz, CDCl3) δ 7.68−7.64
(m, 4H), 7.43−7.36 (m, 6H), 4.11−4.09 (m, 1H), 4.05 (s, 5H), 4.00
(t, J = 2.5 Hz, 1H), 3.97 (dd, J = 2.5, 1.3 Hz, 1H), 3.75 (tq, J = 6.8, 2.6
Hz, 2H), 3.67−3.63 (m, 2H), 2.77−2.68 (m, 1H), 2.66−2.49 (m, 2H),
D
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Journal of Medicinal Chemistry
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1.74−1.66 (m, 1H), 1.43−1.32 (m, 1H), 1.26 (d, J = 6.8 Hz, 3H), 1.06
(s, 9H). 13C NMR (101 MHz, CDCl3) δ 135.56 (Ph), 133.96 (ipso
Ph), 129.59 (Ph), 127.63 (Ph), 95.01 (ipso Cp), 82.31 (ipso Cp),
69.03 (Fc), 67.36 (Fc), 65.39 (Fc), 65.15 (Fc), 63.00 (CH2), 61.98
(CH2), 42.43 (CH2), 30.93 (CH2), 27.51 (CH*), 26.91 (tBu), 19.37
(CH3), 19.22 (ipso tBu). MS (ES) (m/z) calcd for C32H40O256FeSiNa
563.2045, found 563.2039. IR (cm−1): 3378 br (OH), 3072 (CH
Fc), 2930 (CH2), 2857 (CH2), 1589, 1472 (CH3), 1427 (CH2), 1388
(tBu), 1361, 1105 (Si-OR), 1086 (Si-OR), 819 (CH Ar Ph), 705 (C
C). HPLC: retention time 16.85 min; chiral AD column, 1% IPA in
hexane, isocratic over 40 min (1 mL/min), 97% ee.
(S)-1-[α-Methyl-(3-(hydroxy)propyl)]ferrocene (3). (S)-3-
Ethoxy-1-methyl-3-oxopropylferrocene15 (220 mg, 0.733 mmol) was
dissolved in diethyl ether (10 mL). LiAlH4 (56 mg, 1.466 mmol) was
added carefully, and the resulting suspension was left to stir for 1 h.
The reaction was quenched with saturated sodium potassium tartrate
(10 mL), extracted with diethyl ether (2 × 20 mL), dried over MgSO4
and the solvent removed in vacuo. The residue was purified via flash
column chromatography to give the product as a yellow oil (100 mg,
1
58%). H NMR (300 MHz, CDCl3) δ 4.13 (s, 5H), 4.09−4.04 (m,
4H), 3.67 (q, J = 6.2 Hz, 2H), 2.74−2.53 (m, 1H), 1.85−1.61 (m,
2H), 1.27 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 95.41
(ipso Cp), 68.51 (CH Cp), 67.22 (CH Cp), 67.12 (CH Cp), 67.07
(CH Cp), 65.70 (CH Cp), 61.12 (CH2), 41.47 (CH2), 29.62 (CH),
20.64 (CH3). MS (ES) (m/z) calcd for C14H18O256Fe 258.0707, found
258.0708. IR (cm−1): 3512−3146 br (OH), 2933 (CH), 1052 (C−O).
1-(Thyminyl)ethylferrocene (4). Triphenylphosphine (348 mg,
1.30 mmol), N-3-benzoylthymine13 (223 mg, 1.04 mmol), and 2-
ferrocenylethanol16 (200 mg, 0.87 mmol) were dissolved in THF (10
mL) and stirred for 10 min at room temperature. The flask was then
covered with foil, and DIAD (0.28 mL, 1.30 mmol) was added at room
temperature before the mixture was heated at 65 °C for 2 h. The
solvent was then evaporated and the residue extracted with EtOAc (30
mL), washed with brine (20 mL) and water (20 mL), and dried over
Na2SO4, before the solvent was removed in vacuo. Deprotection was
achieved by treating the crude mixture with methylamine solution (33
wt % in ethanol, 5 mL) for 30 min. The solvent was then evaporated in
vacuo and the residue purified via flash column chromatography (40%
EtOAc in hexane) to give the product (176 mg, 60%). 1H NMR (300
MHz, CDCl3) δ 8.29 (s, 1H), 6.70 (d, J = 1.2 Hz, 1H), 4.15 (s, 5H),
4.13−4.09 (m, 2H), 4.04 (t, J = 1.8 Hz, 2H), 3.79 (t, J = 7.1 Hz, 2H),
2.73 (t, J = 7.1 Hz, 2H), 1.85 (d, J = 1.2 Hz, 3H). 13C NMR (101
MHz, CDCl3 trace of MeOD) δ 216.94 (ipso thymine), 193.73 (C
O), 181.71 (CO), 141.17 (CH-thymine), 83.57 (ipso-Cp),
68.63(CH-Cp), 68.37(CH-Cp), 67.94 (CH-Cp), 50.20 (CH2), 29.17
(CH2), 11.98 (CH3). MS (ES) (m/z) calcd for C17H18N2O256Fe
338.0718, found 338.0720. Mp: degraded at 235 °C. IR (cm−1): 3146
(NH), 2999 (CH), 1683 (CO), 1644 (NH bending).
(S,Rp)-1-[α-Methyl-(3-(hydroxy)propyl)]-2-[(thyminyl)ethyl]-
ferrocene (1). Triphenylphosphine (137 mg, 0.516 mmol), 3-
benzoylthymine13 (95 mg, 0.447 mmol), and 17 (0.186 g, 0.344
mmol) were dissolved in THF (10 mL) and stirred for 10 min at room
temperature. The flask was then covered with foil, and DIAD (0.11
mL, 0.516 mmol) was added at room temperature before the mixture
was heated at 65 °C for 2 h. The mixture was evaporated, extracted
with EtOAc (30 mL), washed with brine (20 mL) followed by water
(20 mL), and dried over Na2SO4. The solvent was removed in vacuo
and the residue purified via flash column chromatography (30%
EtOAc in hexane) to give the fully protected product (219 mg, 85%).
Deprotection was achieved first by stirring the compound in 5 mL of
TBAF for 2 h before the solvent was removed. The mixture was then
redissolved in methylamine (33 wt % in ethanol, 2 mL) and stirred at
room temperature for an addition 30 min. The methylamine was
evaporated and the crude was purified via flash column chromatog-
raphy (5% MeOH in DCM) to give the product as a yellow oil (105
1
mg, 74%). H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 7.07 (d, J =
1.2 Hz, 1H), 4.16−4.02 (m, 8H), 3.99−3.88 (m, 1H), 3.74−3.55 (m,
3H), 2.96−2.47 (m, 4H), 1.95 (d, J = 1.1 Hz, 3H), 1.75−1.64 (m,
1H), 1.56−1.46 (m, 1H), 1.39 (d, J = 6.8 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 164.22 (CO), 151.11 (CO), 140.41 (CH-
thymine), 111.00 (ipso thymine), 95.36 (ipso Fc), 80.77(ipso Fc),
69.30 (CH Cp), 67.63 (CH Cp), 65.97 (CH Cp), 65.37 (CH Cp),
60.27 (CH2), 49.84 (CH2), 43.24 (CH2), 27.99 (CH2), 27.07 (CH),
19.25 (CH3 thymine), 12.30 (CH3). MS (ES) (m/z) calcd for
C21H26N2O3Na56Fe 433.1191, found 433.1182. IR (cm−1): 3520−
3291 br (OH), 2957 (CH), 1677 (CO).
1-[2-(Adenin-9-yl)ethyl]ferrocene (5). Triphenylphosphine
(0.383 g, 1.46 mmol), N,N-6,6-dibenzoyladenine14 (0.500 g, 1.46
mmol), and 2-ferrocenylethanol16 (0.201 g, 0.73 mmol) were
dissolved in THF (10 mL) and stirred for 10 min at room
temperature. The flask was then covered with foil, and DIAD (0.24
mL, 1.18 mmol) was added at room temperature before the mixture
was warmed to 65 °C for 2 h. The mixture was evaporated, extracted
with EtOAc (30 mL), washed with brine (20 mL) followed by water
(20 mL), and then dried over Na2SO4. The solvent was removed in
vacuo and purified via flash column chromatography (40% EtOAc in
hexane) to give the bis-protected product (0.134 g, 33%).
Deprotection was achieved by dissolving the compound (0.055 g,
0.1 mmol) in methylamine (33 wt % in ethanol, 3 mL) and stirring at
room temperature for 30 min. The methylamine was then evaporated
and the residue purified via flash column chromatography (95/5
DCM/MeOH) to give the product as a yellow solid (0.019 g, 58%).
1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.05 (s, 1H), 7.17 (s,
2H), 4.31 (dd, J = 8.2, 6.8 Hz, 2H), 4.15 (s, 5H), 4.08−4.02 (m, 4H),
2.85 (t, J = 7.5 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 155.89
(ipso adenine), 152.35 (CH adenine), 149.40 (ipso adenine), 140.76
(CH adenine), 118.73 (ipso adenine), 84.39 (ipso Cp), 69.00 (Fc),
68.55 (Fc), 43.75 (CH2), 29.34 (CH2). MS (ES) (m/z) calcd for
C17H18N556Fe 348.0912, found 348.0920 (M+ + H+). IR (cm−1): 3399
(NH2), 3316 (NH2), 3084 (CH Fc), 2980 (CH2), 2931 (CH2),
2907 (CH2), 1653 (CC), 1596 (NH2), 1435 (CH2), 1245, 797 (CH
Ar). Mp: 142 °C (dec).
(S,Rp)-1-[α-Methyl-(3-(hydroxy)propyl)]-2-[2-(-adenin-9-yl)-
ethyl]ferrocene (2). Triphenylphosphine (0.291 g, 1.109 mmol),
N,N-6-dibenzoyladenine14 (0.381 g, 1.109 mmol), and 17 (0.300 g,
0.555 mmol) were dissolved in THF (10 mL) and stirred for 10 min at
room temperature. The flask was then covered with foil, and DIAD
(0.24 mL, 1.109 mmol) was added at room temperature before the
mixture was warmed to 65 °C for 2 h. The mixture was evaporated,
extracted with EtOAc (30 mL), washed with brine (20 mL) followed
by water (20 mL), and dried over Na2SO4. The solvent was removed
in vacuo and the residue purified via flash column chromatography
(30% EtOAc in hexane) to give the protected product (0.343 g, 72%).
Deprotection was achieved first by stirring the compound in TBAF (5
mL, 1M) for 2 h. The solvent was then removed and the residue
redissolved in methylamine (33 wt % in ethanol, 2 mL) and stirred at
room temperature for an additional 30 min. The methylamine was
then evaporated and the crude mixture purified via flash column
chromatography to give the product as a yellow solid (170 mg, 73%).
1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.17 (s, 1H), 7.21 (s,
2H), 4.41−4.33 (m, 2H+1H (OH)), 4.11 (s, 5H), 4.02 (d, J = 2.4 Hz,
2H), 3.99 (t, J = 2.4 Hz, 1H), 3.42−3.28 (m, 2H), 2.97−2.75 (m, 2H),
2.75−2.67 (m, 1H), 1.53−1.45 (m, 1H), 1.32 (d, J = 6.8 Hz, 3H +
1H). 13C NMR (101 MHz, DMSO-d6) δ 155.95 (ipso adenine),
152.43 (CH adenine), 149.39 (ipso adenine), 140.71 (CH adenine),
118.75 (ipso adenine), 94.43 (ipso Cp), 81.89 (ipso Cp), 68.80 (Cp),
66.46 (Cp), 64.92 (Cp), 64.74 (Cp), 58.66 (CH2), 43.10 (CH2), 42.43
(CH2), 27.98 (CH2), 27.10 (CH*), 19.38 (CH3). MS (ES) (m/z)
calcd for C21H26N5O56Fe 420.1487, found 420.1484. IR (cm−1): 3348
br (OH), 3270 (NH2), 3240 (NH2), 3098 (CH Fc), 2955 (CH2),
2926 (CH2), 2871 (CH2), 1674 (CN), 1604 (NH2), 1574 (NH2),
1305 (OH), 1076 (C−O), 814 (CH Ar). Mp: 90 °C-92 °C.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for 1−5 and 8−17, HPLC data
for 1−6 and 17, cell study procedures, and cell growth data for
E
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Journal of Medicinal Chemistry
Brief Article
and antifungal ferrocene incorporated dithiothione and dithioketone
compounds. Appl. Organomet. Chem. 2006, 20, 112−116. (c) Patra,
M.; Gasser, G.; Wenzel, M.; Merz, K.; Bandow, J. E.; Metzler-Nolte, N.
Synthesis and biological evaluation of ferrocene-containing bioorga-
nometallics inspired by the antibiotic platensimycin lead structure.
Organometallics 2010, 29, 4312−4219. (d) Zaheer, M.; Shah, A.;
Akhter, Z.; Qureshi, R.; Mirza, B.; Tauseef, M.; Bolte, M. Synthesis,
characterization, electrochemistry and evaluation of biological activities
of some ferrocenyl schiff bases. Appl. Organomet. Chem. 2011, 25, 61−
69.
2, 4, and 5 on an esophageal cancer cell line. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: j.tucker@bham.ac.uk. Phone: +44 (0)121 414 4422.
■
Notes
The authors declare no competing financial interest.
(7) (a) Kowalski, K.; Koceva-Chyla, A.; Pieniazek, A.; Bernasinska, J.;
Skiba, J.; Rybarczyk-Pirek, J. A.; Jozwiak, Z. The synthesis, structure,
́
ACKNOWLEDGMENTS
■
J.H.R.T. acknowledges financial support from the EPSRC
(Leadership Fellowship EP/G007578/1), an ISSF grant from
the Wellcome Trust, and a grant from KU Leuven (Grant GOA
10/014).
electrochemistry and in vitro anticancer activity studies of ferrocenyl−
thymine conjugates. J. Organomet. Chem. 2012, 700, 58−68.
(b) Simenela, A. A.; Morozovaa, A. E.; Snegura, V. L.; Zykovaa, I.
S.; Kachalab, V. V.; Ostrovskayac, A. L.; Bluchterovac, V. N.; Fomina,
M. M. Simple route to ferrocenylalkyl nucleobases. Antitumor activity
in vivo. Appl. Organomet. Chem. 2009, 23, 219−224. (c) Kowalski, K.;
Skiba, J.; Oehninger, L.; Ott, I.; Solecka, J.; Rajnisz, A.; Therrien, B.
Metallocene-modified uracils: synthesis, structure, and biological
activity. Organometallics. 2013, 32, 5766−5733. (d) James, P.;
ABBREVIATIONS USED
■
DCM, dichloromethane; DIAD, diisopropyl azodicarboxylate;
DMSO, dimethyl sulfoxide; TEA, triethylamine; DMAP, 4-
dimethylaminopyridine; n-BuLi, n-butyllithium; MTT, 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; BrdU,
bromodeoxyuridine; THF, tetrahydrofuran
Neudorfl, J.; Eissmann, M.; Jesse, P.; Prokop, A.; Schmalz, H.-G.
̈
Enantioselective synthesis of ferrocenyl nucleoside analogues with
apoptosis-inducing activity. Org. Lett. 2006, 8, 2763−2766.
(8) Shago, F. R.; Swarts, C. J.; Kreft, E.; Van Rensburg, E. J. C.
Antineoplastic activity of a series of ferrocene-containing alcohols.
Anticancer Res. 2007, 27, 3431−3434.
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