Metallo-nucleosides: Synthesis and biological evaluation of hexacarbonyl dicobalt 5-alkynyl-2′-deoxyuridines

Article abstract of DOI:10.1039/b713371e

Reactions of 5-alkynyl-2′-deoxyuridines with dicobalt octacarbonyl Co₂(CO)₈ in THF at room temperature gave hexacarbonyl dicobalt nucleoside complexes (77-93%). The metallo-nucleosides were characterized, including an X-ray structure

Full text of DOI:10.1039/b713371e

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Volume 6 | Number 1 | 7 January 2008 | Pages 1–204
ISSN 1477-0520
FULL PAPER
Roman Dembinski et al.
Metallo-nucleosides: synthesis and
biological evaluation of hexacarbonyl
dicobalt 5-alkynyl-2-deoxyuridines
1477-0520(2008)6:1;1-G

PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Metallo-nucleosides: synthesis and biological evaluation of hexacarbonyl
dicobalt 5-alkynyl-2ꢀ-deoxyuridines†‡
Craig D. Sergeant,a Ingo Ott,*b Adam Sniady,a Srinivasarao Meneni,a Ronald Gust,b Arnold L. Rheingoldc and
Roman Dembinski*a
Received 30th August 2007, Accepted 31st October 2007
First published as an Advance Article on the web 26th November 2007
DOI: 10.1039/b713371e
Reactions of 5-alkynyl-2ꢀ-deoxyuridines with dicobalt octacarbonyl Co2(CO)8 in THF at room
temperature gave hexacarbonyl dicobalt nucleoside complexes (77–93%). The metallo-nucleosides were
characterized, including an X-ray structure of a 1-cyclohexanol derivative. In crystalline form, the
Co–Co bond is perpendicular to the plane of the uracil base, which is found in the anti position. The
level of growth inhibition of MCF-7 and MDA-MB-231 human breast cancer cell lines was
examined and compared to results obtained with the alkynyl nucleoside precursors. The cobalt
compounds displayed good antiproliferative activities with IC50 values in the range of
5–50 lM. Interestingly, the coordination of the dicobalt carbonyl moiety to 5-alkynyl-2ꢀ-deoxyuridines
led to a significant increase in the cytotoxic potency for alkyl/aryl substituents at the non-nucleoside
side of the alkyne, but in the case of hydrogen (terminal alkyne) or a silyl group, a decrease of the
cytotoxic effect was observed. As demonstrated using examples for an active and a low active target
compound, the cytotoxicity was significantly influenced by the uptake into the tumor cells and the
biodistribution into the nuclei.
has been reported as bestowing a significant apoptosis-inducing
activity against BJAB tumor cells.15,16
Introduction
Hexacarbonyl dicobalt complexes of acetylenes,17 in addition to
material science, inorganic/organometallic or synthetic chemistry,
are employed in medicinal-related investigations.11,18 A biochem-
ical study of a cobalt derivative of 17a-ethynyltestosterone (5,
Fig. 1) showed that the compound is still recognized by the
androgen receptor even when the relative binding affinity is quite
low (0.5%).19 The cytotoxicity of dicobalt hexacarbonyl complexes
has alsobeenreported.20–24 Inparticular, anaspirincobaltcarbonyl
derivative (6, Fig. 1) was discovered to be antitumor active in vitro
against MCF-7 and MDA-MB-231 human mammary tumor
cells.22,23 In cell culture experiments hexacarbonyl[2-acetoxy-(2-
propynyl)benzoate]dicobalt 6 has been found to be more active
than cisplatin at each tested concentration. It has been demon-
strated that the presence of the cobalt carbonyl is essential to
achieve the cytotoxic effect, as the alkynyl precursor does not ex-
hibit any activity. More systematic structure–activity relationship
studies confirmed the aspirin derivative 6 as the lead compound
and suggested a mode of action in which cyclooxygenase inhibition
plays a major role.24
Bioorganometallic chemistry provides new tools for control
of biological interactions.1–8 In particular, organometallic com-
pounds may offer innovative solutions for medicinal chemistry.
Traditionally, platinum compounds have forged a path in this area,
principally for cancer treatment. Yet, more recently, attention has
encircled other transition metals and their carbonyl derivatives.
For example, rhenium and technetium complexes (1, Fig. 1)
show potential for breast cancer imaging and radiodiagnostics.9,10
Biological assays contrived with the aid of organometallic bio-
conjugates and IR spectroscopy (carbonyl metalloimmunoassay)
have been elaborated.11 One current exciting development includes
protein kinase inhibition by ruthenium complexes (such as 2,
Fig. 1).12 The medicinal potential of metal carbonyl derivatives has
been reviewed not long ago;3,13 their antitumor activity has also
been noted.8 An example includes a triosmium cluster (3, Fig. 1),
which exhibits anti-telomerase activity on semi-purified enzymes
in a cell-free assay but is inactive towards the breast cancer MCF-7
cell line.14 Recently, a nucleoside–iron carbonyl complex (4, Fig. 1)
aDepartment of Chemistry and Center for Biomedical Research, Oakland
University, 2200 N. Squirrel Rd., Rochester, Michigan 48309-4477, USA.
E-mail: dembinsk@oakland.edu
Modified nucleosides have already acquired an important role
as therapeutic agents.25–29 Cytotoxic nucleoside analogues were
among the first chemotherapeutic agents to be introduced for the
medical treatment of cancer. This family of compounds has grown
to include a variety of purine and pyrimidine nucleoside derivatives
with activity in both solid tumors and hematological malignancies.
These agents behave as antimetabolites, compete with physiologic
nucleosides, and consequently, interact with a large number of
intracellular targets to induce cytotoxicity.25 Potent biological
properties have arisen by substitution at the 5-position of the uracil
base.
bInstitute of Pharmacy, Free University of Berlin, Ko¨nigin Luise Str. 2 + 4,
14195 Berlin, Germany. E-mail: ottingo@zedat.fu-berlin.de
cDepartment of Chemistry and Biochemistry, University of California, San
Diego, La Jolla, California 92093-0358, USA
† Electronic supplementary information (ESI) available: Tables of com-
parison of 1H and 13C NMR signals for compounds 8a–h. 1H and 13C
NMR spectra for compounds 8a–c, e–h. Crystal and refinement data, and
packing diagrams for compound 8c. See DOI: 10.1039/b713371e
‡ CCDC reference number 646479. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b713371e
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Fig. 1 Structures of representative metal–carbonyl complexes investigated for medicinal potential.
Interest in the use of the ethynyl (acetylenic) fragment for
as well as the biological evaluation concerning cytotoxicity and
modification of nucleoside bases has resulted in a great number
of applications for 5-alkynyl uridines.30,31 Considering the anti-
tumor activity of 5-alkynyl-2ꢀ-deoxyuridines (7)30 and the high
activity of hexacarbonyl dicobalt species,20–24 a combination of
both structural features in new target compounds was pursued.
This strategy was further motivated by the significant apoptosis
inducing properties of iron nucleoside analogues.15 Similar to the
results obtained with aspirin-derived cobalt carbonyl complexes,
the activity depends on the presence of the iron carbonyl moiety
suggesting that metal carbonyls are useful functional groups for
the modification or inducement of biological activity.
However, up to this date only one alkynyl nucleoside has been
converted into its hexacarbonyl dicobalt complex, and its biolog-
ical evaluation has not been pursued.32 In our ongoing interest
in synthetic transformations of alkynyl-modified nucleosides33
we have communicated a conversion of 5-(p-tolylethynyl)-2ꢀ-
deoxyuridine (7d) into its hexacarbonyl dicobalt derivative (8d).32
Here, this methodology was extended to a series of 5-alkynyl-
2ꢀ-deoxyuridines, for which significant antiproliferative properties
have been recently reported.30 The preparation and structural char-
acterization of the corresponding Co2(CO)6 complexes is described
uptake into the tumor cells and nuclei.
Chemistry
The series of 5-alkynyl-2ꢀ-deoxyuridines 7a–h (with the following
groups: an alkyl, a cycloalkyl, a cycloalkanol, three alkylphenyls, a
trialkylsilyl, and a terminal alkyne) was synthesized, starting from
5-iodo-2ꢀ-deoxyuridine. Isolation in good yields (76–94%) was
carried out according to an improved, frequently chromatography-
free, larger scale protocol.30,34 Conversion to the respective cobalt
carbonyl derivatives 8 came next. As illustrated in Scheme 1, the
alkynyl nucleosides 7a–h were treated with Co2(CO)8 (1.2 equiv.)
in THF at room temperature (22 ◦C) for approx. 1 h. Quantitative
formation of 8 was observed by 1H NMR or TLC. Isolation
was accomplished by open-air standard silica gel column chro-
matography and gave brown or dark red nucleosides 8a–h in high
yield (77–93%). The functional groups of these nucleosides did
not require any protection. The presence of a branched carbon
next to the carbon–carbon triple bond did not affect the yield
of 8c significantly (77%). This was not surprising, since synthesis
of simple cobalt complexes with a 1-ethynylcyclohexan-1-ol motif
Scheme 1 Synthesis of dicobalt hexacarbonyl 5-alkynyl-2ꢀ-deoxyuridines 8.
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Table 1 Preparation and cytotoxic activity of hexacarbonyl dicobalt 5-alkynyl-2ꢀ-deoxyuridines 8a–h (IC50 values were obtained in two separate
experiments, each n = 6)
IC50/lM
Compound
R
Yield (%)
MCF-7
MDA-MB-231
8a
8b
87
93
19.5 ( 3.5)
12.6 ( 1.4)
29.1 ( 3.6)
36.9 ( 1.3)
8c
77
32.2 ( 4.0)
47.3 ( 3.3)
8d
8e
8f
92
80
86
13.3 ( 0.2)
8.5 ( 3.0)
6.8 ( 1.0)
22.4 ( 0.6)
8.6 ( 0.5)
10.6 ( 0.6)
8g
8h
84a
87
10.9 ( 2.0)
6.7 ( 4.6)
6.8 ( 3.2)
19.4 ( 4.5)
Cisplatinb
—
—
—
—
2.0 ( 0.3)
4.8 ( 0.6)
4.0 ( 1.5)
9.6 ( 0.3)
5-Fluorouracilb
a Forms CHCl3 solvate. b Ref. 24.
have been reported with comparable yields.35 Structures for 8a–h
are depicted in Table 1.
The dicobalt complexes were characterized by 1H and 13C NMR,
IR, and MS. The characteristic NMR (acetone-d6) chemical
shifts for 8a–h include the 1H signal of H-6 (8.29–8.57 ppm)
and 13C signals of C-5 (111.9–113.7, which reflects a downfield
shift as compared to the alkynyl precursors at 97.5–99.6), C≡C
(76.6–112.6), and CoCO (200.5–201.1 ppm).36 Tables comparing
all 1H and 13C NMR chemical shifts for 8a–h are provided in the
ESI† whereas a detailed characterization and similar comparison
for 7a–h is available in our earlier report.30 IR spectra showed a
CO stretching vibrational pattern characteristic for dicobalt hexa-
carbonyl alkynes (2096–2091, 2056–2050, and 2027–2021 cm−1).
Absorptions attributable to the nucleoside core were also observed
(usually three bands between 1702–1603 cm−1). Mass spectra for
8a–h exhibited intense molecular ions and a sequential fragmenta-
tion with a loss of consecutive carbonyl groups.37 Complexes 8 are
obtained as an amorphous powder that can be stored for months
in the freezer (−10 ◦C) under a nitrogen atmosphere without
1
noticeable decomposition, as confirmed by H NMR. They are
more susceptible to degradation, while in organic solvents in
an ambient atmosphere for an extended time (weeks), however,
no significant decomposition was noticed by H NMR when an
Fig. 2 An ORTEP view of the 8c with the atom-labeling scheme. Thermal
ellipsoids at the 50% probability level. Selected interatomic distances [A]:
C(5)–C(7) 1.456(4); C(7)–C(8) 1.347(4); C(8)–C(9) 1.520(4); Co(1)–Co(2)
2.4682(5); O(4) · · · H–O(9) 2.720(3). Key angles [deg]: C(5)–C(7)–C(8)
146.6(3); C(7)–C(8)–C(9) 141.3(2).
˚
1
acetone-d6 solution of 8f was stored in the freezer for 6 months.
A molecular structure of a representative nucleoside was
confirmed by X-ray crystallography.‡ Efforts to obtain diffraction
quality crystals have only been successful in the case of 8c so far, by
evaporation of a methanol–chloroform solution. Fig. 2 illustrates
the molecular structure of the cyclohexanol-substituted nucleoside
cobalt complex. It should first be noted that formation of a cobalt
complex changes the position of the R group relative to the base
since C–C≡C angles in cobalt complexes are of approximately
140–150◦ with the carbon atoms of the C–C≡C–C unit located
in one plane. The C2 carbonyl group of 8c adopted an anti
orientation towards the ribose ring in the crystalline form: the
glycosidic bond torsion angle v (O4ꢀ–C1ꢀ–N1–C2) is −126.7(2)◦.
The dihedral angle C(5)–C(7)–C(8)–C(9) of −4.21(7)◦ confirmed
coplanarity of the alkyne and attached carbons. The dicobalt
carbonyl unit is located syn to the ribose ring, with the Co–Co
bond perpendicular to the uracil plane. The cyclohexanol ring
adopted a staggered conformation across the C(8)–C(9) bond with
O(9) of the hydroxyl group anti to the O(4ꢀ) of the ribose. In
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relation to the cyclohexanol ring, the Co2(CO)6 unit in 8c occupies
the equatorial location. However, it is likely that the alkyne of non-
coordinated 7c prefers an axial position in the chair conformation,
which has been changed (with a ring flip) after incorporation of
cobalt carbonyl, similar to observations during conformational
studies of 1-ethynylcyclohexanols.35
We also noticed a hydrogen bond between pyrimidine O(4) and
cyclohexanol O(9), which is specific for compound 8c. Unlike the
structure reported for 5-ethynylferrocenyl-2ꢀ-deoxycytidine,38 8c
lacks Watson–Crick hydrogen bond motifs. This is due in part
to the intramolecular O(4) · · · H–O(9) contact and non-covalent
contacts between the sugar and base portions of 8c. Base N(3)
and each of the sugar OH groups participate in hydrogen bonds
that contribute to the organization of 8c. Packing diagrams are
available in the ESI.†
cells) to 47.3 lM (8c in MDA-MB-231 cells). Thus, the potency
of the more active target compounds is well within the range of
established anticancer drugs such as 5-fluorouracil and cisplatin or
the lead compound for cytotoxic hexacarbonyldicobalt complexes
6 (IC50 values in the range of 1–10 lM in this assay).24 With the
exception of 8g, MCF-7 cells were more sensitive towards the
action of metallo-nucleosides, which is in good agreement with the
results obtained with the non-coordinated alkynyl deoxyuridines
7a–h. Interestingly, 7a–d were inactive (IC50 values above 50 lM)
whereas their cobalt carbonyl derivatives 8a–d displayed activity
in both tumor cell cultures investigated (Fig. 3). The alkynyl
deoxyuridine 7f had shown significant selectivity towards MCF-
7 cells and was inactive in MDA-MB-231 cells. This selectivity
almost disappeared for the corresponding Co2(CO)6 derivative 8f
as good antiproliferative effects could be noted in MDA-MB-
231 cells. Concerning the alkyne precursors, derivatives with a
hydrogen or silyl group at one end of the alkyne moiety were most
active (IC50 values lower than 5 lM in all experiments with 7g and
7h). For the respective cobalt carbonyl species 8g and 8h the an-
tiproliferative activity was decreased (IC50 values 6.7 to 19.4 lM).
Obviously, the coordination of alkynes to Co2(CO)6 has a
strong influence on the biological activity of the respective
alkyne compounds. In general, the coordination process led to
a significant increase in the cytotoxic potency for alkyl/aryl
substituents at the non-nucleoside side of the alkyne, but in the
case of hydrogen (terminal alkyne) or a silyl group, a decrease of
the cytotoxic effect was observed.
Cytotoxicity
After completion of synthesis and characterization, the com-
pounds were investigated for their antitumor activity in vitro
against two different human breast cancer cultures MCF-7
and MDA-MB-231. The results are summarized in Table 1
and illustrated in comparison with the non-coordinated alkynyl
nucleosides 7a–h30 in Fig. 3.
Uptake into cells and nuclei
Previous experiments proved that the hexacarbonyl dicobalt
structure strongly increases the lipophilicity of alkyne species.24
Thus, derivatization of deoxyuridines as cobalt carbonyl deriva-
tives will alter their cellular uptake, intracellular distribution
and interaction with biomolecules such as DNA, which can be
considered the main target for novel nucleoside analogues. HPLC
experiments using a reversed phase stationary phase were carried
out for the selected alkyne/cobalt alkyne pairs 7g/8g and 7h/8h,
and confirmed the lipophilicity increase associated with addition
of the dicobalt hexacarbonyl unit (as indicated by the higher
retention times of the complexes compared to the free ligands,
see ESI for more details†).
One of the least active (8c) and one of the most active (8f)
target compounds were selected for further studies on the uptake
of the complexes into the tumor cells and into the nuclei of the
cells. For this purpose, an established analytical method based on
atomic absorption spectroscopy was applied. Fig. 4 shows the time
dependent uptake of 8c and 8f into MCF-7 and MDA-MB-231
tumor cells. In general, the cellular levels were significantly higher
for 8f than for 8c, which is in good agreement with the results from
the cytotoxicity studies. Complex 8f reached the highest levels
after 6 h exposure while 8c accumulated faster (maxima after 2 h
incubation). During 24 h the cellular cobalt contents decreased
for both complexes. This trend was less striking in the MCF-7
cell line and probably contributes to the higher overall sensitivity
of MCF-7 compared to MDA-MB-231 cells. Altogether these
results indicate that cellular uptake plays an important role for
the bioactivity of cobalt carbonyl nucleosides. It can be assumed
that the hydroxyl group positioned on the cyclohexanol moiety of
Fig. 3 Effect of the substituents of cobalt complexes 8 and their alkynyl
precursors 7 for the proliferation of MCF-7 (top) and MDA-MB-231
(bottom) human breast cancer cell lines.39
All target compounds displayed significant antiproliferative
effects with IC50 values in the range of 6.7 lM (8h in MCF-7
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may be a useful tool to convert inactive nucleosides into active
ones but does not necessarily improve the cytotoxicity of already
strong antiproliferative active derivatives. Explanations for this
discrepancy may be found by the investigation of the molecular
interactions with potential biological targets such as DNA or
DNA related enzymes, which is the subject of ongoing studies.
In general, the presented results are in line with the former
investigation of derivatives of benzoic acids, which showed that
small structural modifications of the ligand structure can cause
significant changes in the biological activity.24 Moreover, the
crystallographic data presented in this report underlined the
impact of Co2(CO)6 coordination on the three dimensional
structure of the nucleoside ligand. As demonstrated by means
of an active and a poorly active complex, the uptake into the cells
and intracellular biodistribution into the nuclei—parameters that
are strongly influenced by the presence of the cobalt carbonyl
complex—play an important role in the bioactivity of cobalt
metallo-nucleosides.
Previous studies on 6 showed a high chemical stability of the
Co2(CO)6-alkyne moiety,23 as well as an extremely low cellular
uptake of the precursor compound Co2(CO)8.24 Therefore, it can
be assumed that only intact complexes are accumulated inside the
cells where they supposedly interact with biological targets and/or
are transformed to active metabolites. The fate of the complexes
inside the cells remains to be elucidated in detail. However, as
indicated by evaluation of the cobalt content of the nuclei, some
amounts of the complexes reach the main location of the most
probable primary target DNA.
As an overall result, our studies showed that the alkyne cobalt
carbonyl organometallic fragment is a useful tool in medicinal
chemistry research concerning the modulation of the properties of
known drugs or bioactive compounds.
Fig. 4 Cellular uptake of complexes 8c and 8f into MCF-7 (top) and
MDA-MB-231 (bottom); results are expressed as nmol compound per mg
cellular protein (n = 6).
Table 2 Nuclear uptake of complexes 8c and 8f into MCF-7 and MDA-
MB-231 cells after exposure for 24 h; results are expressed as nmol
compound per mg nuclear protein (n = 2)
Experimental section
Nuclear uptake/nmol mg−1
General
Cell line
8c
8f
Commercial chemicals were treated as follows: THF distilled
from Na–benzophenone. Co2(CO)8 (Acros or Strem), silica gel
(J. T. Baker, 60–200 mesh), TLC plates Analtech GF, cat. number
2521 or Merck 60, cat. number 5715 used as received. 5-Alkynyl-
2ꢀ-deoxyuridines 7 were obtained as described.30,40 Other materials
not listed were used as received.
IR spectra were recorded on a Bio-Rad FTS-175C spectrometer.
NMR spectra were obtained on a Bruker Avance DPX-200
spectrometer (1H of 200 MHz and 13C of 50 MHz). Chemical
shift values (d) are in ppm and coupling constant values (J) are in
Hz. Mass spectra were recorded on a Micromass ZQ instrument;
m/z indicates the most intense peak of the isotope envelope.
Microanalyses were conducted by Atlantic Microlab.
MCF-7
MDA-MB-231
0.051 ( 0.020)
0.043 ( 0.014)
0.217 ( 0.096)
0.321 ( 0.159)
8c has a negative effect on cellular drug accumulation (due to a
decrease of lipophilicity) and influences excretion or metabolism.
In order to evaluate if the target compounds reached the cellular
location of their biological target DNA, the nuclei were isolated
and the drug amount was quantified after exposure for 24 h
(Table 2). The uptake into the nuclei increased in the same order
as the cytotoxicity and cellular uptake (8c < 8h). Thus, it can be
concluded that both the intracellular distribution into the nuclei
and the cellular uptake determine the antiproliferative properties
of the investigated target compounds.
Synthesis of hexacarbonyl dicobalt 5-alkynyl-2ꢀ-deoxyuridines (8).
General procedure:
Conclusions
A Schlenk flask was charged under a nitrogen atmosphere with
Co2(CO)8 (typically 0.36–0.46 mmol, 1.2 equiv.), THF (typically 4–
6 mL), and 7 (typically 0.30–0.38 mmol). The mixture was stirred
for ca. 1 h at room temperature (22 ◦C). The solvent was removed
by rotary evaporation and the residue was dried by oil pump
The present study shows that the concept of Co2(CO)6 derivati-
zation can be used to change the potency of bioactive nucleoside
compounds but a critical selection of the alkyne ligand remains an
important issue. As summarized in Fig. 3, the Co2(CO)6 moiety
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vacuum for 1 h. The solid was dissolved in a minimum amount
of CHCl3 (ca. 1 mL). Silica gel column chromatography (typically
25 × 2.5 cm; CHCl3–CH3OH 100 : 0 → 90 : 10) gave a red-
brown fraction. Solvent was removed by rotary evaporation and
the residue was dried by an oil pump vacuum to give the dicobalt
hexacarbonyl compounds 8a–h as a brown or dark red powder that
were stored, under a nitrogen atmosphere, in a freezer at −10 ◦C.
3ꢀ), 4.34 (br s, 1H, H-3ꢀ), 4.11–4.01 (m, 1H, H-4ꢀ), 3.92–3.70 (m,
2H, H-5ꢀ), 2.45–2.15 (m, 2H, H-2ꢀ), 2.00–1.45 (m, 9H, c-C6H10),
1.35–1.10 (m, 1H, c-C6H10); 13C 200.8 (CoCO), 162.9 (d, J = 9.6,
C-4), 150.3 (d, J = 8.0, C-2), 142.2 (d, J = 183.5, C-6), 113.1 (s,
C-5), 112.6 (dU–C≡C), 89.4 (d, J = 149.4, C-4ꢀ), 86.7 (d, J =
170.4, C-1ꢀ), 84.4 (d, J = 3.5, dU–C≡C), 73.2 (s, C-1ꢀꢀ), 73.0 (d,
J = 149.1, C-3ꢀ), 63.1 (d, J = 139.9, C-5ꢀ), 42.0 (t, J = 133.2, C-2ꢀ),
40.6 and 40.4 (2t, J = 132.1, C-2ꢀꢀ), 26.5 (t, J = 125.0, C-4ꢀꢀ), 23.9
and 22.8 (2t, J = 129.1, C-3ꢀꢀ).
Hexacarbonyl dicobalt 5-pent-1-yn-1-yl-2ꢀ-deoxyuridine (8a)
From 7a (0.0997 g, 0.339 mmol) and Co2(CO)8 (0.1390 g,
0.4065 mmol), in THF (6 mL). Dark brown solid of 8a (0.1711 g,
0.2949 mmol, 87%). Anal. (C20H18Co2N2O11) C, H: calcd, 41.40,
3.13; found, 41.40, 3.32%. IR (cm−1, KBr) mCoCO 2091 s, 2050 vs,
2021 vs; 1702 s, 1686 s, 1638 w. MS (ES+, AcOK, MeOH) 619
((M + K)+, 15%), 591 ((M − CO + K)+, 8%), 563 ((M − 2CO +
K)+, 6%), 535 ((M − 3CO + K)+, 8%), 507 ((M − 4CO + K)+, 6%),
333 ((M − Co2(CO)6 + K)+, 100%). NMR (acetone-d6):36 1H 10.28
(s, 1H, N-3), 8.37 (s, 1H, H-6), 6.39 (dd, J = 7.7, 6.2, 1H, H-1ꢀ),
4.58–4.48 (m, 1H, OH-5ꢀ), 4.43 (d, J = 3.7, 1H, OH-3ꢀ), 4.32 (t,
J = 4.8, 1H, H-3ꢀ), 4.04 (q, J = 2.2, 1H, H-4ꢀ), 3.90–3.75 (m, 2H,
H-5ꢀ), 3.09 (t, 2H, J = 7.9, H-1ꢀꢀ), 2.36–2.25 (m, 2H, H-2ꢀ), 1.71
Hexacarbonyl dicobalt 5-[(4-methylphenyl)ethynyl]-
2ꢀ-deoxyuridine (8d)
From 7d (0.1016 g, 0.2968 mmol) and Co2(CO)8 (0.1218 g,
0.3561 mmol), in THF (5 mL). Dark brown solid of 8d (0.1716 g,
0.2731 mmol, 92%). Anal. (C24H18Co2N2O11) C, H: calcd, 45.88,
2.89; found, 45.66, 3.36%. IR (cm−1, KBr) mCoCO 2092 s, 2055 vs,
2023 vs; 1690 s, 1603 w. MS37 (ES+, KCl, MeOH) 1295 ((2 M +
K)+, 36%), 667 ((M + K)+, 92%), 639 ((M + K − CO)+, 100%),
629 ((M + H)+, 12%). NMR (acetone-d6):36 1H 10.32 (s, 1H, N-
3), 8.43 (s, 1H, H-6), 7.53 (d, J = 8.0, 2H, o-C6H4C≡C), 7.19
(d, J = 8.0, 2H, m-C6H4C≡C), 6.43 (t, J = 6.9, 1H, H-1ꢀ), 4.52
(br s, 1H, OH-5ꢀ), 4.43 (d, J = 2.7, 1H, OH-3ꢀ), 4.24 (t, J = 4.5,
1H, H-3ꢀ), 4.06–4.02 (m, 1H, H-4ꢀ), 3.83–3.68 (m, 2H, H-5ꢀ), 2.32
1
(sextet, 2H, J = 7.7, H-2ꢀꢀ), 1.06 (t, 3H, J = 7.3, H-3ꢀꢀ); 13C{ H}
201.0 (CoCO), 161.5 (C-4), 150.8 (C-2), 140.2 (C-6), 113.3 (C-5),
104.8 (dU–C≡C), 89.3 (C-4ꢀ), 86.6 (C-1ꢀ), 85.6 (dU-C≡C), 73.0
(C-3ꢀ), 63.3 (C-5ꢀ), 41.9 (C-2ꢀ), 37.4 (C-1ꢀꢀ), 26.0 (C-2ꢀꢀ), 14.4 (C-3ꢀꢀ).
1
(s, 3H, CH3), 2.40–2.25 (m, 2H, H-2ꢀ); 13C{ H} 200.5 (CoCO),
160.8 (C-4), 150.8 (C-2), 139.8 (C-6), 138.8 (p-C6H4C≡C), 136.3
(i-C6H4C≡C), 130.6 (o-C6H4C≡C), 130.2 (m-C6H4C≡C), 113.6
(C-5), 96.7 (dU-C≡C), 89.2 (C-4ꢀ), 86.4 (C-1ꢀ), 86.2 (dU–C≡C),
73.1 (C-3ꢀ), 63.3 (C-5ꢀ), 41.9 (C-2ꢀ), 21.4 (CH3).
Hexacarbonyl dicobalt 5-(cyclopropylethynyl)-2ꢀ-deoxyuridine (8b)
From 7b (0.1012 g, 0.3462 mmol) and Co2(CO)8 (0.1421 g,
0.4155 mmol), in THF (6 mL). Dark brown solid of 8b (0.1851 g,
0.3201 mmol, 93%). Anal. (C20H16Co2N2O11) C, H: calcd, 41.54,
2.79; found, 41.01, 2.90%. IR (cm−1, KBr) mCoCO 2091 s, 2051 vs,
2022 vs; 1702 s, 1686 s, 1637 w. MS (ES+, AcOK, MeOH) 617
((M + K)+, 30%), 589 ((M − CO + K)+, 11%), 561 ((M − 2CO +
K)+, 6%), 533 ((M − 3CO + K)+, 13%), 505 ((M − 4CO + K)+,
10%), 331 ((M − Co2(CO)6 + K)+, 100%). NMR (acetone-d6):36
1H 10.27 (s, 1H, N-3), 8.35 (s, 1H, H-6), 6.39 (dd, J = 7.6, 6.3,
1H, H-1ꢀ), 4.59–4.47 (m, 1H, OH-5ꢀ), 4.43 (d, J = 3.6, 1H, OH-3ꢀ),
4.31 (t, J = 4.6, 1H, H-3ꢀ), 4.08–3.98 (m, 1H, H-4ꢀ), 3.90–3.65
(m, 2H, H-5ꢀ), 2.62–2.41 (m, 1H, H-1ꢀꢀ), 2.38–2.21 (m, 2H, H-2ꢀ),
Hexacarbonyl dicobalt 5-[(4-pentylphenyl)ethynyl]-2ꢀ-deoxyuridine
(8e)
From 7e (0.1200 g, 0.3012 mmol) and Co2(CO)8 (0.1236 g,
0.3614 mmol), in THF (5 mL). Dark brown solid of 8e (0.1643 g,
0.2402 mmol, 80%). Anal. (C28H26Co2N2O11) C, H: calcd, 49.14,
3.83; found, 48.76, 3.93%. IR (cm−1, KBr) mCoCO 2092 s, 2056 vs,
2024 vs; 1700 s, 1686 s, 1606 w. MS (ES+, KCl, MeOH) 721 ((M +
K)+, 65%), 693 ((M − CO + K)+, 100%), 666 ((M − 2CO + K)+,
32%), 638 ((M − 3CO + K)+, 37%), 610 ((M − 4CO + K)+, 64%),
582 ((M − 5CO + K)+, 59%), 554 ((M − 6CO + K)+, 42%), 436
((M − Co2(CO)6 + K)+, 25%). NMR (acetone-d6):36 1H 10.34 (s,
1H, N-3), 8.43 (s, 1H, H-6), 7.56 (d, J = 8.2, 2H, o-C6H4C≡C), 7.22
(d, J = 8.2, 2H, m-C6H4C≡C), 6.43 (dd, J = 7.9, 6.2, 1H, H-1ꢀ),
4.58–4.48 (m, 1H, OH-5ꢀ), 4.46 (d, J = 3.6, 1H, OH-3ꢀ), 4.26 (t, J =
4.6, 1H, H-3ꢀ), 4.11–4.00 (m, 1H, H-4ꢀ), 3.90–3.67 (m, 2H, H-5ꢀ),
2.61 (t, J = 7.3, 2H, H-1ꢀꢀ), 2.42–2.18 (m, 2H, H-2ꢀ), 1.74–1.54 (m,
2H, H-2ꢀꢀ), 1.43–1.25 (m, 4H, H-3ꢀꢀ, H-4ꢀꢀ), 0.89 (t, J = 6.6, 3H, H-
1
1.24–1.06 and 0.95–0.65 (2 m, 2 × 2H, H-2ꢀꢀ and H-3ꢀꢀ); 13C{ H}
200.8 (CoCO), 161.3 (C-4), 150.8 (C-2), 139.6 (C-6), 113.2 (C-5),
109.2 (dU–C≡C), 89.2 (C-4ꢀ), 86.4 (C-1ꢀ), 85.0 (dU–C≡C), 73.0
(C-3ꢀ), 63.2 (C-5ꢀ), 41.8 (C-2ꢀ), 16.3 (C-1ꢀꢀ), 13.1 and 12.9 (C-2ꢀꢀ and
C-3ꢀꢀ).
Hexacarbonyl dicobalt 5-[(1-hydroxycyclohexyl)ethynyl]-2ꢀ-
deoxyuridine (8c)
1
5ꢀꢀ); 13C{ H} 200.6 (CoCO), 160.8 (C-4), 150.8 (C-2), 143.8 (C-6),
139.8 (p-C6H4C≡C), 136.5 (i-C6H4C≡C), 130.6 (o-C6H4C≡C),
129.5 (m-C6H4C≡C), 113.6 (C-5), 96.7 (dU–C≡C), 89.2 (C-4ꢀ),
86.4 (C-1ꢀ), 86.2 (dU–C≡C), 73.1 (C-3ꢀ), 63.2 (C-5ꢀ), 41.8 (C-2ꢀ),
36.4 (C-1ꢀꢀ), 32.3 (C-3ꢀꢀ), 31.8 (C-2ꢀꢀ), 23.2 (C-4ꢀꢀ), 14.3 (C-5ꢀꢀ).
From 7c (0.1332 g, 0.3802 mmol) and Co2(CO)8 (0.1560 g,
0.4562 mmol), in THF (6 mL). Dark brown solid of 8c (0.1850 g,
0.2912 mmol, 77%). Anal. (C23H22Co2N2O12) C, H: calcd, 43.42,
3.49; found, 43.41, 3.77%. IR (cm−1, KBr) mCoCO 2093 s, 2054 vs,
2025 vs; 1702 s, 1670 s, 1637 w. MS (ES+, AcOK, MeOH) 1311
((2 M + K)+, 12%), 675 ((M + K)+, 53%), 647 ((M + K − CO)+,
35%), 619 ((M − 2CO + K)+, 8%), 591 ((M − 3CO + K)+, 21%),
389 ((M − Co2(CO)6 + K)+, 100%). NMR (acetone-d6):36 1H 10.60
(s, 1H, N-3), 8.47 (s, 1H, H-6), 6.38 (dd, J = 7.9, 5.9, 1H, H-1ꢀ),
5.59 (s, 1H, HO–C6H10), 4.53 (br s, 1H, OH-5ꢀ), 4.45 (br s, 1H, OH-
Hexacarbonyl dicobalt 5-[(4-tert-butylphenyl)ethynyl]-2ꢀ-
deoxyuridine (8f)
From 7f (0.0622 g, 0.162 mmol) and Co2(CO)8 (0.0665 g,
0.194 mmol), in THF (4 mL). Dark brown solid of 8f (0.0935 g,
0.140 mmol, 86%). Anal. (C27H24Co2N2O11) C, H: calcd, 48.38,
78 | Org. Biomol. Chem., 2008, 6, 73–80
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©

3.61; found, 48.08, 3.63%. IR (cm−1, KBr) mCoCO 2091 s, 2055 vs,
2025 vs; 1702 s, 1686 s, 1637 w. MS (ES+, AcOK, MeOH) 709
((M + K)+, 100%), 681 ((M + K − CO)+, 71%), 653 ((M − 2CO +
K)+, 29%), 625 ((M − 3CO + K)+, 22%), 597 ((M − 4CO + K)+,
6%), 423 ((M − Co2(CO)6 + K)+, 48%). NMR (acetone-d6):36 1H
10.33 (s, 1H, N-3), 8.44 (s, 1H, H-6), 7.60 (d, J = 8.2, 2H, o-
C6H4C≡C), 7.44 (d, J = 8.2, 2H, m-C6H4C≡C), 6.44 (dd, J = 7.8,
6.2, 1H, H-1ꢀ), 4.58–4.47 (m, 1H, OH-5ꢀ), 4.43 (d, J = 3.7, 1H, OH-
3ꢀ), 4.21 (t, J = 4.6, 1H, H-3ꢀ), 4.10–4.00 (m, 1H, H-4ꢀ), 3.90–3.65
Crystallography
Light brown plates of 8c were grown by evaporation of a CHCl3–
MeOH (1 : 1 v/v) solution during 14 days, placed over molecular
sieves in a closed jar under a nitrogen atmosphere in a glove box.
Data were collected as outlined in the ESI (Table S3).†
Biological evaluation
Experiments concerning cytotoxicity and uptake into the cells
and nuclei were performed according to recently described
procedures.24
(m, 2H, H-5ꢀ), 2.43–2.16 (m, 2H, H-2ꢀ), 1.35 (s, 9H, C(CH3)3); 13
C
200.5 (s, CoCO), 160.9 (d, J = 9.3, C-4), 151.8 (br s, p-C6H4C≡C),
151.0 (d, J = 7.4, C-2), 139.8 (d, J = 181.0, C-6), 136.3 (t, J = 7.8,
i-C6H4C≡C), 130.4 (dd, J = 159.8, 6.0, o-C6H4C≡C), 126.5 (dd,
J = 157.2, 6.6, m-C6H4C≡C), 113.6 (s, C-5), 96.5 (s, dU–C≡C),
89.2 (d, J = 147.3, C-4ꢀ), 86.4 (d, J = 169.6, C-1ꢀ), 86.2 (d, J =
4.8, dU–C≡C), 73.1 (d, J = 151.0, C-3ꢀ), 63.3 (t, J = 141.0, C-5ꢀ),
41.9 (t, J = 133.8, C-2ꢀ), 35.3 (s, C(CH3)3), 31.5 (qt, J = 126.0, 4.4,
C(CH3)3).
Acknowledgements
We thank the National Institutes of Health (NIH, grant
CA111329), the Deutsche Forschungsgemeinschaft (DFG, grant
FOR630), and the Oakland University Research Excellence
Program in Biotechnology for support of this research. The
Thompson Award for C.D.S. is acknowledged, and Prof. S. Szafert
and Prof. K. Wheeler for helpful discussions.
Hexacarbonyl dicobalt 5-[(trimethylsilyl)ethynyl]-2ꢀ-deoxyuridine
(8g)
References
From 7g (0.1000 g, 0.3083 mmol) and Co2(CO)8 (0.1266 g,
0.3700 mmol), in THF (5 mL). Dark brown solid of 8g·1/3(CHCl3)
(0.1680 g, 0.2584 mmol, 84%). Anal. (C20H20Co2N2O11Si)·
1/3(CHCl3): C, H: calcd, 37.56, 3.15; found, 37.66, 3.63%. IR
(cm−1, KBr) mCoCO 2090 s, 2052 vs, 2021 vs; 1700 s, 1685 s, 1638 w.
MS (ES+, KCl, MeOH) 648 ((M + K)+, 76%), 620 ((M − CO +
K)+, 61%), 592 ((M − 2CO + K)+, 37%), 564 ((M − 3CO + K)+,
11%), 536 ((M − 4CO + K)+, 65%), 508 ((M − 5CO + K)+, 6%),
480 ((M − 6CO + K)+, 51%), 409 ((M − 6CO − Si(CH3)3 + K)+,
57%), 363 ((M − Co2(CO)6 + K)+, 100%). NMR (acetone-d6):36
1H 10.38 (s, 1H, N-3), 8.29 (s, 1H, H-6), 6.38 (dd, J = 7.9, 5.9, 1H,
H-1ꢀ), 4.65–4.47 (m, 1H, OH-5ꢀ), 4.44 (d, J = 3.6, 1H, OH-3ꢀ), 4.26
(t, J = 4.7, 1H, H-3ꢀ), 4.05 (q, J = 2.2, 1H, H-4ꢀ), 3.95–3.75 (m,
1 Concepts and Models in Bioinorganic Chemistry, ed. H. B. Kraatz and
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1
2H, H-5ꢀ), 2.45–2.15 (m, 2H, H-2ꢀ), 0.37 (s, 9H, Si(CH3)3); 13C{ H}
201.1 (CoCO), 160.8 (C-4), 150.6 (C-2), 140.7 (C-6), 113.7 (C-5),
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´
12 (a) H. Bregman and E. Meggers, Org. Lett., 2006, 8, 5465–5468; (b) J. E.
Hexacarbonyl dicobalt 5-ethynyl-2ꢀ-deoxyuridine (8h)
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Knapp and E. Meggers, Angew. Chem., Int. Ed., 2006, 45, 1580–1585;
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13 T. R. Johnson, B. E. Mann, J. E. Clark, R. Foresti, C. J. Green and R.
Motterlini, Angew. Chem., Int. Ed., 2003, 42, 3722–3729.
From 7h (0.0802 g, 0.318 mmol) and Co2(CO)8 (0.1305 g,
0.3816 mmol), in THF (6 mL). Dark brown solid of 8h (0.1490 g,
0.2769 mmol, 87%). Anal. (C17H12Co2N2O11) C, H: calcd, 37.94,
2.25; found, 38.04, 2.46%. IR (cm−1, KBr) mCoCO 2096 s, 2055 vs,
2027 vs; 1702 s, 1686 s, 1638 w. MS (ES+, AcOK, MeOH) 577
((M + K)+, 58%), 549 ((M − CO + K)+, 34%), 521 ((M − 2CO +
K)+, 6%), 493 ((M − 3CO + K)+, 20%), 465 ((M − 4CO + K)+,
20%), 291 ((M − Co2(CO)6 + K)+, 100%). NMR (acetone-d6):36
1H 10.25 (s, 1H, N-3), 8.57 (s, 1H, H-6), 6.71 (s, 1H, C≡CH),
6.35 (t, J = 6.6, 1H, H-1ꢀ), 4.53 (br s, 1H, OH-5ꢀ), 4.44 (br s, 1H,
OH-3ꢀ), 4.36 (t, J = 4.2, 1H, H-3ꢀ), 4.10–3.93 (m, 1H, H-4ꢀ), 3.93–
3.72 (m, 2H, H-5ꢀ), 2.39–2.20 (m, 2H, H-2ꢀ); 13C 200.9 (s, CoCO),
161.5 (d, J = 9.3, C-4), 150.8 (d, J = 8.0, C-2), 141.0 (d, J =
179.5, C-6), 111.9 (s, C-5), 89.2 (d, J = 148.9, C-4ꢀ), 86.6 (d, J =
170.5, C-1ꢀ), 83.1 (s, dU–C≡C), 76.6 (d, J = 224.4, dU–C≡C),
72.5 (d, J = 150.3, C-3ꢀ), 62.9 (t, J = 140.5, C-5ꢀ), 41.9 (t, J =
133.7, C-2ꢀ).
14 D. Colangelo, A. Ghiglia, A. Ghezzi, M. Ravera, E. Rosenberg, F.
Spada and D. Osella, J. Inorg. Biochem., 2005, 99, 505–512.
15 D. Schlawe, A. Majdalani, J. Velcicky, E. Heßler, T. Wieder, A. Prokop
and H.-G. Schmalz, Angew. Chem., Int. Ed., 2004, 43, 1731–1734.
16 Selected representative recent reference of metal carbonyls attached to
nucleosides: L. Wei, J. Babich, W. C. Eckelman and J. Zubieta, Inorg.
Chem., 2005, 44, 2198–2209.
17 For electronic structure of the alkyne-bridged dicobalt hexacarbonyl
complex see: J. A. Platts, G. J. S. Evans, M. P. Coogan and J. Overgaard,
Inorg. Chem., 2007, 46, 6291–6298.
18 Peptide labeling using a dicobalt hexacarbonyl alkynyl complex has
been reported: M. A. Neukamm, A. Pinto and N. Metzler-Nolte, Chem.
Commun., 2008, DOI: 10.1039/b712886j.
19 (a) S. Top, H. El Hafa, A. Vessie`res, M. Huche´, J. Vaissermann and G.
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©

20 (a) I. Ott, B. Kircher and R. Gust, J. Inorg. Biochem., 2004, 98, 485–
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Pharm. Pharm. Med. Chem., 1997, 330, 173–176.
21 Hexacarbonyl dicobalt propargylfructopyranose: I. Ott, T. Koch, H.
Shorafa, Z. Bai, D. Poeckel, D. Steinhilber and R. Gust, Org. Biomol.
Chem., 2005, 3, 2282–2286.
32 N. Esho, B. Davies, J. Lee and R. Dembinski, Chem. Commun., 2002,
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33 M. S. Rao, N. Esho, C. Sergeant and R. Dembinski, J. Org. Chem.,
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34 The nucleoside 7h was prepared by desilylation of 7g.
35 N. M. Deschamps, J. H. Kaldis, P. E. Lock, J. F. Britten and M. J.
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22 K. Schmidt, M. Jung, R. Keilitz, B. Schnurr and R. Gust, Inorg. Chim.
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23 For interaction with proteins and stability see: I. Ott and R. Gust,
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24 I. Ott, K. Schmidt, B. Kircher, P. Schumacher, T. Wiglenda and R.
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25 (a) Deoxynucleoside Analogs in Cancer Therapy, ed. J. P. Godefridus,
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36 (a) We were not able to achieve an NMR spectral resolution comparable
to that of the 5-alkynyl-2ꢀ-deoxyuridines.30 This can likely be attributed
to the presence of cobalt. Thus, more advancedtechniques that would
help to facilitate complete assignments of signals were not pursued.
Doublet/broad singlet and multiplet peaks (acetone-d6) were assigned
to 3ꢀ- and 5ꢀ-OH, respectively. For 7, the 3ꢀ- and 5ꢀ-OH (also assigned
based upon multiplicity; doublet and triplet, DMSO-d6) exhibit
reversed relative positions of chemical shifts; (b) Pairs of o- and m-
of the phenyl rings 1H and 13C signals, C-1ꢀ and C-4ꢀ, and C≡C signals
were tentatively assigned following trends for 7,30 except the C≡C for
8h, where we were able to observe 1JC–H
.
37 MS ES+ (positive) data are given. We observed that negative spectra
also show consecutive fragmentations with a loss of CO. A representa-
tive ES− (negative) spectrum for 8d is available in the supplementary
materials of our earlier work32.
28 I. E. Smith, Lancet, 2002, 360, 790–792.
29 A representative collection of articles related to antiviral investigations
can be found in the special issue: Antiviral Res., 2006, 71, 75–414.
30 S. Meneni, I. Ott, C. D. Sergeant, A. Sniady, R. Gust and R. Dembinski,
Bioorg. Med. Chem., 2007, 15, 3082–3088, and references therein.
31 Selected recent representative examples: (a) R. E. Hudson and A.
Ghorbani-Choghamarani, Org. Biomol. Chem., 2007, 5, 1845–1848;
(b) W. A. Cristofoli, L. I. Wiebe, E. De Clercq, G. Andrei, R. Snoeck,
J. Balzarini and E. E. Knaus, J. Med. Chem., 2007, 50, 2851–2857.
38 A. R. Pike, L. C. Ryder, B. R. Horrocks, W. Clegg, B. A. Connolly and
A. Houlton, Chem.–Eur. J., 2005, 11, 344–353.
39 Corrected value for 7d/MCF-7 from the one given in ref. 30.
40 The equivalents reported in the general procedure in ref. 30 apply to
volatile alkynes. To produce 7c–f, 1.2 equiv. of a less volatile alkyne
may be used. For an alternate procedure utilizing volatile alkynes see:
S. Ghilagaber, W. N. Hunter and R. Marquez, Tetrahedron Lett., 2007,
48, 483–486.
80 | Org. Biomol. Chem., 2008, 6, 73–80
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The Royal Society of Chemistry 2008
©