Tuning of Oxidation Potential of Ferrocene for Ratiometric Redox Labeling and Coding of Nucleotides and DNA

Article abstract of DOI:10.1002/chem.201904700

Three sets of 7-deazaadenine and cytosine nucleosides and nucleoside triphosphates bearing either unsubstituted ferrocene, octamethylferrocene and ferrocenecarboxamide linked through an alkyne tether to position 7 or 5, respectively, were designed and synthesized. The modified dN^FcXTPs were good substrates for KOD XL DNA polymerase in primer extension and were used for enzymatic synthesis of redox-labelled DNA probes. Square-wave voltammetry showed that the octamethylferrocene oxidation potential was shifted to lower values, whilst the ferrocenecarboxamide was shifted to higher potentials, as compared to ferrocene. Tailed PEX products containing different ratios of Fc-labelled A (dA^Fc) and FcPa-labelled C (dC^FcPa) were synthesized and hybridized with capture oligonucleotides immobilized on gold electrodes to study the electrochemistry of the redox-labelled DNA. Clearly distinguishable, fully orthogonal and ratiometric peaks were observed for the dA^Fc and dC^FcPa bases in DNA, demonstrating their potential for use in redox coding of nucleobases and for the direct electrochemical measurement of the relative ratio of nucleobases in an unknown sequence of DNA.

Full text of DOI:10.1002/chem.201904700

A Journal of
Accepted Article
Title: Tuning of Oxidation Potential of Ferrocene for Ratiometric Redox
Labelling and Coding of Nucleotides and DNA
Authors: Anna Simonova, Ivan Magriñá, Veronika Sýkorová, Radek
Pohl, Mayreli Ortiz, Luděk Havran, Miroslav Fojta, Ciara
O'Sullivan, and Michal Hocek
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To be cited as: Chem. Eur. J. 10.1002/chem.201904700
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10.1002/chem.201904700
Chemistry - A European Journal
Tuning of Oxidation Potential of Ferrocene for Ratiometric Redox Labelling and Coding of
Nucleotides and DNA
Dr. Anna Simonova,a,b Ivan Magriñá,c Dr. Veronika Sýkorová,a Dr. Radek Pohl,a Dr. Mayreli
Ortiz,c Dr. Luděk Havran,d Prof. Dr. Miroslav Fojta,d,e* Prof. Dr. Ciara O'Sullivan,c,f* and Prof.
Dr. Michal Hoceka,b*
[a] Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech
Republic, Gilead & IOCB Research Centre, Flemingovo namesti 2, CZ-16610 Prague 6, Czech
Republic; hocek@uochb.cas.cz
[b] Department of Organic Chemistry, Faculty of Science, Charles University in Prague,
Hlavova 8, Prague-2 12843, Czech Republic.
[c] Departament d’Enginyeria Química, Universitat Rovira i Virgili, 26 Països Catalans, 43007,
Tarragona, Spain; ciara.osullivan@urv.cat
[d] Institute of Biophysics, Czech Academy of Sciences, Královopolská 135, 612 65 Brno,
Czech Republic; fojta@ibp.cz
[e] Central European Institute of Technology, Masaryk University, Kamenice 753/5, 625 00
Brno, Czech Republic
[f] Institució Catalana de Recerca i Estudis Avançats, Passeig Lluís Companys, 23, 08010,
Barcelona, Spain
1
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Abstract: Three sets of 7-deazaadenine and cytosine nucleosides and nucleoside
triphosphates bearing either unsubstituted ferrocene, octamethylferrocene and
ferrocenecarboxamide linked through an alkyne tether to position 7 or 5, respectively, were
designed and synthesized. The modified dNFcXTPs were good substrates for KOD XL DNA
polymerase in primer extension and were used for enzymatic synthesis of redox-labelled DNA
probes. Square-wave voltammetry showed that the octamethylferrocene oxidation potential
was shifted to lower values, whilst the ferrocenecarboxamide was shifted to higher potentials,
as compared to ferrocene. Tailed PEX products containing different ratios of Fc-labelled A
(dAFc) and FcPa-labelled C (dCFcPa) were synthesized and hybridized with capture
oligonucleotides immobilized on gold electrodes to study the electrochemistry of the redox-
labelled DNA. Clearly distinguishable, fully orthogonal and ratiometric peaks were observed
for the dAFc and dCFcPa bases in DNA, demonstrating their potential for use in redox coding of
nucleobases and for the direct electrochemical measurement of the relative ratio of
nucleobases in an unknown sequence of DNA.
Graphic abstract
Orthogonal redox labelling of nucleobases with substituted ferrocenes with tuned redox
potential was developed for redox coding of DNA bases.
2
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Introduction
Redox labelling of DNA basesby attachment of some oxidisable or reducible groups is used for
diverse applications in bioanalysis and diagnostics.1,2 The redox active group can be attached
to 2’-deoxyribonucleoside triphosphate (dNTP) and used for polymerase mediated synthesis
of redox-labelled DNA for subsequent electrochemical detection2 with further possible
applications for construction of electrochemical genosensors.3 By using a combination of
several orthogonal redox labels with differing redox potentials, an attractive option of redox
coding of DNA bases4 can be envisaged for applications in sequencing. Previously, we and
others have reported the use of nitrophenyl,5 anthraquinone,4,6 benzofurazane7 and
azidophenyl8 as reducible labels, some of which (combination of nitrophenyl with either
benzofurazane or azidophenyl) were orthogonal and suitable for ratiometric redox coding of
two bases, but none of the organic oxidizable labels, i.e. aminophenyl,5 methylene blue,4,9
methoxyphenol,10 or phenothiazines,4,11 was truly ideal and orthogonal for combination with
another label(s). Ferrocene is a classical electrochemical standard12 that has been used as an
oxidizable electrochemical label for nucleotides and DNA13,14 and has been exploited in
sensors.3 In order to develop a set of fully orthogonal oxidizable redox labels for the use in
redox coding, herein we report the fine tuning of the oxidation potential of ferrocene by its
substitution with electron-donating or electron-withdrawing substituents.
Results and Discussion
Synthesis
In our design of modified ferrocene labels, we envisaged that multiple methylation of
ferrocene, as in octamethylferrocene, can be used as electron-donating substituents to
decrease the redox potential, whereas a substitution with an electron-withdrawing
carboxamide should increase the oxidation potential. To easily synthesise the modified
ferrocene-linked nucleosides and nucleotides through direct aqueous-phase Sonogashira
cross-coupling reactions,15 we designed the corresponding terminal alkynes: 1-ethynyl-
1',2,2',3,3',4,4',5-octamethylferrocene (FcMe)16 and propargylaminocarbonylferrocene
(FcPa)17 as suitable building blocks and prepared them as previously reported.
3
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The modified ferrocene-linked nucleosides were synthesized by Sonogashira cross-coupling
reactions of unprotected halogenated nucleosides (dAI or dCI) in the presence of Pd(PPh3)2Cl2
or Pd(OAc)2 catalyst, PPh3 or TPPTS (triphenylphosphine-3,3',3"-trisulfonate) ligand, CuI and
Et3N either in MeCN/water or in DMF to give labelled nucleosides dNFcMe or dNFcPa in high
yields (Table 1, Scheme 1).
Table 1. Synthesis of nucleosides and dNTPs bearing acetylene-linked ferrocene labels.
Starting
compound
Yield
(%)
Reagent
Catalyst
Solvent
Base
Product
dAI
dCI
dAFcMe
dCFcMe
90
Pd(OAc)2, CuI,
TPPTS
MeCN/H2O
(1/1)
Et3N
FcMe
86
98
dAI
dAFcPa
Pd(PPh3)2Cl2, CuI,
PPh3
Et3N
Et3N
FcPa
DMF
dCI
dCFcPa
97
dAITP
dCITP
dAITP
dCITP
dCITP
dAFcPa
dCFcPa
dAFcMe
dCFcMe
dAFcMeTP
dCFcMeTP
dAFcPaTP
dCFcPaTP
dCFcTP
38a
30a
13
Pd(PPh3)2Cl2, CuI,
PPh3
MeCN/H2O
(1/1)
FcMe
Pd(PPh3)2Cl2, CuI,
PPh3
MeCN/H2O
(1/1)
Et3N
Et3N
FcPA
16
Pd(OAc)2, CuI,
TPPTS
MeCN/H2O
(1/1)
ethynylferrocene
27
dAFcPaTP
dCFcPaTP
dAFcMeTP
dCFcMeTP
22
18
1) PO(OMe)3, POCl3, 0°C; 2) (NHBu3)2H2P2O7, Bu3N, DMF, 0°C;
3) TEAB (2M)
15a
20a
a isolated dNFcMeTPs were prone to oxidation on air
The corresponding modified dNTPs were prepared (Scheme 1, Table 1) either by
phosphorylation of modified nucleosides (Approach A) or by direct aqueous-phase cross-
coupling reactions of halogenated triphosphates dNITP with Fc-alkynes (Approach B). The
cross-coupling reactions were performed analogously to the reaction of nucleosides using
Pd(PPh3)2Cl2 catalyst in acetonitrile/water for 1 h. The reactions reached completion but, due
4
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10.1002/chem.201904700
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to partial hydrolysis of the triphosphates and difficulties in separation, the desired dNFcMeTP
or dNFcPaTP were isolated in moderate yields (13-38 %) after isolation by HPLC. The alternative
approach using triphosphorylation of nucleosides gave similarly moderate yields. In all cases,
the modified dNFcXTPs were prepared and isolated in sufficient quantities for the subsequent
biochemical and electrochemical experiments. The dNTPs bearing unsubstituted
ethynylferrocene were also synthesised for comparison. dAFcTPs was prepared as previously
reported14 and the related dCFcTP was prepared analogously through Sonogashira reaction of
dCITP with ethynylferrocene achieving a yield of 27 %.
Scheme 1. Synthesis of modified nucleosides and dNTPs. Reagents and conditions: i) FcPA or
FcMe, Pd(PPh3)2Cl2 + PPh3 or Pd(OAc)2 + TPPTS, CuI, PPh3, DMF (75 °C, 1 h) or MeCN/H2O
(1:1) (50 °C, 40 min.); ii) 1. POCl3, PO(OMe)3, 0 °C, 3 h; 2. (NHBu3)2H2P2O7, Bu3N, DMF, 0 °C,
1.5 h; 3. TEAB; iii) FcPA or FcMe, Pd(PPh3)2Cl2, CuI, PPh3, MeCN/H2O (1:1), 60 °C, 1 h.
5
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Biochemistry
Figure 1. Primer extension with a KOD XL polymerase using either (A) 19-mer template
tempA or tempC and primrnd; or (B) 31-mer temprnd16 and primrnd: (P) primer (5'-6-FAM-
labelled); (A+, C+ or +) natural dNTPs; (A-) dCTP, dTTP, dGTP; (C-) dATP, dTTP, dGTP; (AFc)
dAFcTP, dCTP, dTTP, dGTP; (CFc) dCFcTP, dATP, dTTP, dGTP; (AFcMe) dAFcMeTP, dCTP, dTTP,
dGTP; (CFcMe) dCFcMeTP, dATP, dTTP, dGTP; (AFcPa) dAFcPaTP, dCTP, dTTP, dGTP; (CFcPa) dCFcPaTP,
dATP, dTTP, dGTP.
The Fc-modified dNFcXTPs were then tested as substrates for DNA polymerases in primer
extension (PEX) reactions using either a 19-mer (tempA or tempC) or 31-mer (temprnd16
)
template and 15-mer primer primrnd (for sequences of all oligonucleotides, see Table S1 in SI).
KOD XL DNA polymerase was selected based on previous reports7,8,11,18 on extensive use of
KOD DNA polymerase and its mutants for polymerase synthesis of base-modified DNA. Figure
1 shows the PAGE analysis confirming that in all cases, full-length PEX products containing
either 1 or 4 modified nucleotides were formed. The identity of most of the PEX products was
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also confirmed by MALDI analysis (Table 2) of single-stranded oligonucleotides (ssONs) after
PEX with biotinylated template and magnetoseparation. Only in the case of 31-mers
containing 4 dNFcMe bases the mass of the full-length products, was not observed, probably
due to the limited stability of the octamethylferrocene label, which is prone to oxidation in
air. We also studied the dNFcXTPs as nucleotide building blocks for PCR, however, similarly to
the previously reported dAFcTP,14 the PCR amplification in the absence of natural dATP (or
dCTP) did not work (Figure S13a in SI). On the other hand, when using the modified dNFcXTPs
in presence of the natural dNTP (ratio 60:40), we observed formation of partially labelled
amplicons (Figure S13b in SI), which can be used for electrochemical detection of the PCR
products similarly as in our recent work on Fc-based electrochemical genosensor.3
Table 4. List of MALDI data of PEX products bearing modified or non-modified Fc labels.
oligonucleotide
M calcd. (Da)
10445.5
10673.7
10449.5
10677.7
6182.0
M found (Da)
10447.0
10674.1
10451,9
10679.6
6183.2
31ON_4AFc
31ON_4AFcPa
31ON_4CFc
31ON_4CFcPa
19ON_1AFc
19ON_1AFcPa
19ON_1AFcMe
19ON_1CFc
6239.0
6294.0
6159.0
6216.0
6238.6
6295.4
6160.2
3389.4
19ON_1CFcPa
19ON_1CFcMe
6271.0
6272.3
Electrochemistry of nucleosides and nucleotides
The electrochemical behavior of Fc-modified nucleosides and dNTPs was studied using
Square-wave voltammetry (SWV) on a pyrolytic graphite electrode (PGE) in acetate buffer (pH
5.0). Samples of nucleosides dNFcX and triphosphates dNFcXTP show voltammetric peaks
corresponding to reversible oxidation of the ferrocene moiety (see Fig. S14-15 in SI for the
evidence of signal reversibility/irreversibility given by components of the SWV current). In the
case of 7-deazaadenine derivatives, an additional peak of irreversible oxidation of the
pyrrolopyrimidine moiety was observed at 1.03-1.10 V (vs Ag|AgCl). As expected and designed,
the substitution of ferrocene strongly influences the oxidation potential. The electron rich
octamethylferrocene is shifted to lower oxidation potentials by ca. 300 mV (Table 3). This
7
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10.1002/chem.201904700
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easier oxidation, however, leads to limited stability of these labels in air. On the other hand,
the electron-poor amide-linked ferrocene derivatives are shifted to higher potentials by ca.
100 mV. Compounds containing octamethylferrocene give an additional irreversible peak
(denoted as X in Figure 2) at 1.20 V.
Table 3. Redox potentials of FcX-labelled nucleosides and dNTPsa
Compound
FcX/V
A*ox/V
X/V
dAFc
0.470
0.160
0.550
0.380
0.060
0.470
0.325
0.115
0.550
0.325
0.070
0.440
1.100
1.040
1.030
1.030
1.050
1.080
dAFcMe
dAFcPa
1.280
dAFcTP
dAFcMeTP
dAFcPaTP
dCFc
-----
dCFcMe
dCFcPa
1.200
1.125
dCFcTP
dCFcMeTP
dCFcPaTP
a Peak potentials of net SWV signals measured at the PGE against Ag|AgCl|3M KCl. For more details
see Figure 2.
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Figure 2. Square-wave voltammograms of modified nucleosides (a, b) or 40 μM dNTPs (c, d)
measured at a pyrolytic graphite electrode in 0.2 M acetate buffer (pH 5.0).
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Design, synthesis and electrochemistry of modified DNA probes
Scheme 2. PEX synthesis of the modified DNA probes and their capture on electrode.
In order to study the electrochemistry of redox-labelled DNA, we initially tried to
synthesize FcX-modified ssONs by PEX with magnetoseparation and studied their SWV on
carbon paste electrodes (analogously to our previous works14). Unfortunately, we did not
observe any significant signals, probably because of low amounts of the modified ssONs and
problems with their adsorption on electrodes. Therefore, we applied our recently reported
approach3 based on the synthesis of tailed-PEX products and their capture on gold electrodes
(Scheme 2). Since the octamethylferrocene-labelled nucleotides and ONs were prone to
oxidation with air, we focused only on the stable unsubstituted ferrocene (Fc) and
carboxamidoferrocene (FcPa) labels.
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To test whether the Fc and FcPa labels can be distinguished and electrochemically
quantified, we designed two 55-mer and one 37-mer template bearing a 20-mer ON sequence
at the 3'-end separated through a –(CH3)3- (C3) spacer (Table S1). The two 55-mer tailed
templates were designed for the synthesis of PEX products containing either a combination of
8 dAFc and 2 dCFcPa (DNA_8AFc_2CFcPa) or a combination of 2 dAFc and 8 dCFcPa
(DNA_2AFc_8CFcPa). The shorter 37-mer template was designed for PEX synthesis of DNA
containing equimolar numbers of 4 dAFc and 4 dCFcPa (DNA_4AFc_4CFcPa). The role of the 3'-tail
was to facilitate hybridization of the PEX product to a complementary capture probe
immobilised on the gold electrode and the role of the C3 spacer was to prevent further
extension during the PEX, maintaining the tail as ssON.
Agarose gel electrophoresis (Figure 3) shows the PEX product formation using either
set of natural dNTPs (+) or combination of dAFcTP, dCFcPaTP with TTP and GTP (*Fc). In all
cases, the formation of the full-length PEX product was observed confirming that even the
combination of two Fc-modified dNTPs can be used for polymerase construction of double-
redox-labelled DNA. The labelled PEX products were then hybridized to the complementary
capture probe immobilised on gold electrode, washed and used for electrochemical
interrogation by SWV. Ca(NO3)2 was selected as the electrolyte solution due to the ability of
divalent cations to shrink, compact and bend DNA, whilst also shielding electrostatic
repulsions between neighbour DNA strands.19
The square-wave voltammograms (Figure 5) of the three individual labelled PEX
products show two clearly distinguishable peak maxima corresponding to the oxidation of Fc
(0.3 V vs Ag/AgCl) and FcPa (0.4 V vs Ag/AgCl), respectively. After peak deconvolution, the
ratios of the intensities of the two oxidation peaks correlated very well with the expected A/C
nucleobase ratio present in each PEX product: 3.6 ± 0.5 (DNA_8AFc_2CFcPa), 0.27 ± 0.02
(DNA_2AFc_8CFcPa) and 1.04 ± 0.15 (DNA_4AFc_4CFcPa).
11
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Figure 3. Agarose gel electrophoresis of PEX products using temp8A,2C, temp8C,2A or temp4C,4A
templates and Primer8/2_4/4 obtained in presence of (a) all four natural dNTPs (+), or
combination of dAFcTP, dCFcPaTP with TTP and GTP (*Fc). P/T corresponds to primer hybridized
to template in the absence of polymerase.
12
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Figure 4. Square wave voltammograms of the oxidation peaks of dAFc and dCFcPa on PEX
products and then hybridized to a complementary surface tethered thiol-end sequence for
detection. The black traces correspond to the experimental SWV signals for dAFc/dCFcPa ratios
equal to: 8:2 (A), 2:8 (B) and 4:4 (C). Red and blue traces correspond to the deconvoluted
signals of dAFc and dCFcPa respectively. SWVs were recorded in 0.1 M Ca(NO3)2 vs Ag/AgCl
reference electrode.
13
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Conclusions
We have designed and synthesized nucleosides and dNTPs bearing three differently
substituted ferrocene labels. Substitution with eight electron-donating methyl groups led to a
significant decrease of the oxidation potential of ferrocene (by 300 mV), whilst the attachment
of the electron-withdrawing carboxamide shifted the redox potential to 100 mV higher values.
The octamethyferrocene-linked nucleosides and nucleotides were insufficiently stable due to
their spontaneous oxidation in air. However, the unsubstituted ferrocene (Fc) and
ferrocenecarboxamide (FcPa) labels were stable and useful for electrochemical labelling. The
corresponding redox-labelled dNFcXTPs were good substrates for KOD XL DNA polymerase and
were efficiently used for the enzymatic synthesis of DNA probes containing either one or even
two redox-labelled nucleotides using PEX. The oxidation peaks associated with dAFc and dCFcPa
were clearly distinguishable and ratiometric. Thus, for the first time, we describe a set of two
fully orthogonal and ratiometric oxidizable labels for DNA suitable for the redox-coding of
nucleobases. The PEX using tailed templates and hybridization with capture probes on gold
electrodes is a very efficient and straightforward strategy to study the incorporation of the
two redox labels to DNA and thus directly measure the relative abundance of A and C in an
unknown target sequence of DNA. In the future, the combination of these two ferrocene-
based oxidizable labels (Fc, FcPa) with some of the previously reported reducible labels (e.g.
benzofurazane, nitrophenyl, azidophenyl)5-8 will be tested for completing of the full set of
orthogonal labels for redox coding and detection of all four nucleobases.
Experimental
Complete experimental procedures and methods, characterization of all compounds,
additional figures and copies of spectra are given in the Supporting Information.
Acknowledgement:
This work was supported by the the Academy of Sciences of the Czech Republic (Praemium
Academiae award for M. H.), by the European Regional Development Fund; OP RDE (No.
CZ.02.1.01/0.0/0.0/16_019/0000729 to M.H.) and institutional support from the IBP CAS (No.
68081707).
14
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