Effective repression of the fragmentation of a hexadentate ligand bearing an auto-immolable pendant arm by iron coordination

Article abstract of DOI:10.1002/ejic.200800419

A diamagnetic ferrous complex (1) (MRI silent) is presented that consists of a macrocyclic hexadentate ligand (7) bearing an auto-immolable arm, as seen in organic prodrug design. This arm constitutes a phenylogous N/O acetal "locked" by glycosylation. Enzymatic glycolysis is hypothesized to lead to a phenol intermediate (a phenylogous hemiaminal) that fragments spontaneously thereby liberating a paramagnetic ferrous complex (MRI active). This paper describes the synthesis of ligand 7 and complex 1, and their respective reaction with β-galactosidase, the target enzyme. While ligand 7 alone fragments swiftly to the pentadentate ligand dptacn (monitored by LCMS analysis) upon in vitro enzymatic conversion, the phenol resulting from glycosyl removal from complex 1 accumulates in the buffered reaction mixture without any apparent fragmentation. Two independent explanations are put forward: metal coordination leads to rigidification of the ligand skeleton with concomitant kinetic inhibition of fragmentation or to the liberation of enough extra free energy to shift the thermodynamic equilibrium towards the starting material. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejic.200800419

FULL PAPER
DOI: 10.1002/ejic.200800419
Effective Repression of the Fragmentation of a Hexadentate Ligand Bearing an
Auto-Immolable Pendant Arm by Iron Coordination
Vitalie Stavila,[a] Yvon Stortz,[a] Cécile Franc,[a] Delphine Pitrat,[a] Philippe Maurin,[a] and
Jens Hasserodt*[a]
Keywords: Iron / Macrocyclic ligands / Prodrugs / Auto-immolable spacer / Low-spin complex
A diamagnetic ferrous complex (1) (MRI silent) is presented
that consists of a macrocyclic hexadentate ligand (7) bearing
an auto-immolable arm, as seen in organic prodrug design.
This arm constitutes a phenylogous N/O acetal “locked” by
glycosylation. Enzymatic glycolysis is hypothesized to lead
to a phenol intermediate (a phenylogous hemiaminal) that
fragments spontaneously thereby liberating a paramagnetic
ferrous complex (MRI active). This paper describes the syn-
thesis of ligand 7 and complex 1, and their respective reac-
tion with β-galactosidase, the target enzyme. While ligand 7
alone fragments swiftly to the pentadentate ligand dptacn
(monitored by LCMS analysis) upon in vitro enzymatic con-
version, the phenol resulting from glycosyl removal from
complex 1 accumulates in the buffered reaction mixture
without any apparent fragmentation. Two independent ex-
planations are put forward: metal coordination leads to rigid-
ification of the ligand skeleton with concomitant kinetic inhi-
bition of fragmentation or to the liberation of enough extra
free energy to shift the thermodynamic equilibrium towards
the starting material.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
as a promising point of departure for the design of enzyme-
responsive MRI contrast agents that operate in an off/on
mode.[2]
Introduction
Molecular imaging is an immense and rapidly expanding
field dedicated to the elucidation of the molecular basis of
life and disease.[1] The mostly invasive, and often lethal,
nature of classical approaches, such as fixation (histology)
of the living species, renders the resulting observations
somewhat unreliable. It is therefore desirable to develop
methods for in vivo imaging with minimal interference with
the species under scrutiny. This would also allow for the
very useful temporal resolution of the results.
We set out to develop a molecular probe for a specific
enzymatic activity for magnetic resonance imaging
(MRI).[2] A number of smart contrast agents have already
been introduced, among them those that detect copper,
zinc, or calcium ions[3–6], as well as those that reveal a spe-
cific enzymatic activity.[7–12] They all have in common the
presence of a gadolinium(III) atom at their center that is a
permanently paramagnetic lanthanide ion. We have opted
for iron(II) as this paramagnetic center in order to capi-
talize on its exceptional property of adopting a diamagnetic
as well as a paramagnetic state depending on ligand-field
strength.[13,14] A pair of binary, mononuclear iron(II) com-
plexes in a low-spin and a high-spin state, respectively
([Fe-tptacn]II and [Fe-dptacn]II), have thus been identified
Monitoring enzymatic activity by MRI is a very attract-
ive perspective for a number of biomedical reasons.[15–19]
However, for two reasons it would also be appealing from
a technological viewpoint: (a) MRI suffers from low sensi-
tivity,[20,21] but the development of MRI-active probes that
are susceptible to a particular enzymatic activity will lead
to a more or less pronounced amplification effect according
to the in vivo turnover rate by the enzyme of such an artifi-
cial substrate, an effect that is exploited in diverse biotech-
nology applications such as ELISA, as well as in (organic)
prodrug design. The presence of one protein molecule thus
equals a vast number of activated imaging probes. (b)
Among the competing imaging techniques only optical
methods allow the design of enzyme-responsive agents;
ultrasound imaging, X-ray-based CT and PET (that detects
γ-ray emitting radioactive tracers) do not appear to lend
themselves to the development of tracers that show a signal
change induced by chemical (enzymatic) modification.
Results and Discussion
In this paper we present the first MRI-silent (off) mole-
cule candidate (1) based on [Fe-tptacn]II that is hypothe-
sized to fragment upon enzymatic conversion. Figure 1 de-
picts 1 that may, by judicious molecular design, be rendered
susceptible to a number of mostly (but not exclusively) hy-
drolytic enzymatic activities. Compound 1 should be effec-
[a] Laboratoire de Chimie, UMR CNRS 5182, University of
Lyon – ENS,
46 Allée dЈItalie, 69364 Lyon, France
E-mail: jens.hasserodt@ens-lyon.fr
Supporting information for this article is available on the
WWW under http://www.eurjic.org or from the author.
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V. Stavila, Y. Stortz, C. Franc, D. Pitrat, P. Maurin, J. Hasserodt
FULL PAPER
Figure 1. Hypothesized enzymatic conversion and subsequent fragmentation from a low-spin to a high-spin ferrous complex.
tively converted by the targeted enzyme into intermediate cers usually employ well-established leaving groups as for
2, which, in return, is supposed to fragment spontaneously example carboxylates or carbamates.[8,12,24]
into an MRI-active species (3) via elimination of a fragment
In this initial work, the hydrolase activity that is targeted
containing one nitrogen coordination site. Consequently, is that of β-galactosidase (1, Figure 3). This enzyme is the
one coordination site on the iron center should be vacated, product of a prominent reporter gene system.[25,26] Synthesis
occupied by a water molecule, and 3 thus becomes an effec- of β-galactoside 1 was achieved by first preparing the halide
tive relaxation-modifying agent for neighboring water pro-
tons (see ref.[2] for values of the effective magnetic moment
µeff, the longitudinal relaxation time T1, and relaxivities r1
of 3 and a derivative of 1, respectively).
The hypothesis that 2 spontaneously fragments (Fig-
ure 1) is based on the fact that 2 contains a moiety (Fig-
ure 2, gray) that is reminiscent of a hemiaminal. Under rea-
sonably dilute conditions, the equilibrium of hemiaminal
formation is well known to be largely positioned on the
bimolecular side; in addition, establishment of this equilib-
rium is fast.[22,23] The moiety as utilized in 2 is in fact a
phenylogous hemiaminal, thus promising similar electronic
features but also allowing the enzymatic reaction with 1 to
proceed rather effectively as a consequence of the good phe-
nolic leaving group. However, an important difference with
a simple phenylogous hemiaminal is the fact that in 2 the
nitrogen fragment and the carbon fragment are actually
linked to one another via a three-membered (-C–N–Fe-)
buckle including the coordinative bond to the metal center.
It thus remains to be seen if spontaneous fragmentation
takes place in physiological media. The pendant arm in 1
Figure 3. Synthesis of 1. Reagents and conditions: (i) HBr 30%
may also be compared with auto-immolable spacers gener-
in AcOH, (ii) Ag2O, p-hydroxybenzaldehyde, (iii) 2-PyrMgBr, (iv)
SOCl2, (v) dptacn (9), K2CO3, AcCN, 80 °C, 84%, (vi) MeONa,
in the field of (organic) prodrug development. Yet such spa- MeOH, (vii) [Fe(H2O)6][BF4]2, degassed MeOH.
ating high-energy quinone–methide intermediates as found
Figure 2. Pendant arm consisting of a phenylogous hemiaminal and its homology to parent acetal chemistry.
3944 Eur. J. Inorg. Chem. 2008, 3943–3947
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Repression of the Fragmentation of a Hexadentate Ligand by Iron Coordination
of alcohol 5 in four steps from commercial β-galactose
pentaacetate. Bromination of the latter[27] and subsequent
coupling to p-hydroxybenzaldehyde by the Königs–Knorr
method[28] furnishes an aldehydic synthetic intermediate (4)
that is treated with pyridine magnesium bromide[29] to ob-
tain a secondary alcohol 5. Chlorination of the latter with
sulfonyl chloride preceded the coupling to the pentanitro-
gen macrocyclic ligand dptacn.[30] The glycoside unit in the
resulting hexadentate ligand 6 was deprotected by standard
methods using sodium methylate in methanol. The synthe-
sis of 1 was complete by reacting 6 with [Fe(H2O)6][BF4]2
under anaerobic conditions.
In order to be able to monitor the reaction of candidate
molecule 1 with target enzyme β-galactosidase under physi-
ological conditions, a powerful analysis method had to be
found that would ensure reliable identification of the start-
ing compound, any intermediates, and the desired final
complex. Metal complexes of the likes of 1 and 3 are gen-
erally identified and characterized by elemental analysis,
magnetic moment measurements, UV/Vis spectroscopy (less
often by IR) in organic solvents, X-ray analysis, and rather
rarely by NMR and Mössbauer spectroscopy. From the
outset, any detection method applied to the chemical trans-
formation of 1 in this project had to be compatible with the
Figure 4. Time-dependent conversion by β-galactosidase of (a) 1
and (b) 7, monitored by HPLC coupled with UV and mass analysis
more or less complex physiological nature of the sample.
Such a technique was recognized in the form of high per- (ESI). Enzyme assay conditions: see Supporting Information.
Chromatographic conditions: Zorbax Eclipse XDB-C8 5 mm
formance liquid chromatography coupled simultaneously to
4.6ϫ150. Mobile phase = 0.1% formic acid in H2O/AcCN (88:12)
UV analysis and mass spectrometry (LCMS).
isocratic, 0.5 mL/min, 25 °C. UV detection at 399 (a) and 270 nm
(b), respectively.
Candidate complex 1 (as well as its homologue [Fe-
tptacn]II[2]), intermediate 2, and target complex 3 were
found to be stable during HPLC analysis and to be ioniz-
able by electrospray ionization (ESI) and thus identifiable
by mass detection. Enzymatic conversion of 1 proceeded
efficiently as expected; one of its diastereomers (see the twin
peaks at 3.7 min in Figure 4a) showed a slightly higher con-
version rate than the other. The intermediate phenol 2 thus
produced accumulated in the sample without any apparent
willingness to fragment; no trace of the desired complex 3
was detected (Figure 4a).
When the same experiment was carried out with com-
pound 7 (being the underlying ligand of complex 1), frag-
mentation of intermediate 8 (Figure 5) to dptacn (9) was so
fast that any accumulation of 8 was not observed (Fig-
ure 4b). This illustrates the rarely explored stabilization ef-
fect of any metastable molecular species (such as a phen-
ylogous hemiaminal) if the two possible fragments are held
together by common coordination to the same metal center.
Here, severe rigidification may prevent the system from
adopting conformations leading to transition states with
reasonable energy barriers (kinetic inhibition). Alterna-
tively, additional free energy release upon coordination of
Figure 5. Spontaneous fragmentation of intermediate 8 into desired
pentadentate ligand 9 after its generation by enzyme-catalyzed
glycolosis of 7.
the two fragments to the metal center may be the cause, rapid enzymatic conversion. (b) The site of enzymatic re-
thus shifting the thermodynamic fragmentation equilibrium cognition is remote to the metal complex, likewise maximiz-
to the left.
ing enzyme kinetics. (c) The experimenter has control over
In spite of the lack of fragmentation of phenol 2, the here the choice of the molecular moiety coordinating the metal
applied intelligent spacer technology using a phenylogous and hence also over the electronic spin state and the absence
hemiaminal has been proved to contribute three advan- of any influence on the proton relaxation time by the re-
tages: (a) The phenolic character of the glycoside leads to sulting complex.
Eur. J. Inorg. Chem. 2008, 3943–3947
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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V. Stavila, Y. Stortz, C. Franc, D. Pitrat, P. Maurin, J. Hasserodt
FULL PAPER
thionyl chloride (143 mg, 88 µL, 1.2 mmol) and stirred for 1 h. All
volatile components were then thoroughly evaporated, and the re-
sulting chloride was introduced into the next step as is. A solution
of 2-[chloro(4-tetraacetyl-β--galactopyranosyloxy)phenyl]methyl-
pyridine (356 mg, 0.6 mmol) and dptacn (9; 168 mg, 0.5 mmol) in
AcCN (10 mL) was treated with K2CO3 (1.5 g, 11 mmol). The re-
sulting suspension was stirred under argon at 50 °C overnight. The
mixture was filtered at room temp., and the solid was washed with
AcCN. The combined organic phases were evaporated, and the res-
idue was purified by silica gel chromatography (CH2Cl2/MeOH,
10:1 to CH2Cl2/MeOH/NH4OH, 4:1:0.1). Hexaamine 6 was thus
obtained as a yellow oil (327 mg, 74 %). 1H NMR (200 MHz,
CDCl3): δ = 8.48 (t, J = 4.4 Hz, 3 H), 7.63 (td, J = 7.6, 1.6 Hz, 3
H), 7.36 (d, J = 8.6 Hz, 2 H), 7.13 (m, 3 H), 6.89 (d, J = 8.6 Hz, 2
H), 5.42 (m, 2 H), 5.06 (dd, J = 7.9, 4.2 Hz, 1 H), 4.98 (d, J =
7.9 Hz, 1 H), 4.78 (s, 1 H), 3.97–4.22 (m, 3 H), 3.79 (s, 4 H), 2.96
(s, 4 H), 2.84 (d, J = 8.6 Hz, 4 H), 2.16 (s, 3 H), 2.03 (s, 3 H), 2.02
(s, 3 H), 2.00 (s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 179.3,
179.2, 170.1, 169.3, 163.0, 160.4, 155.8, 148.9, 137.2, 136.4, 136.2,
129.8, 123.2, 122.6, 121.8, 116.7, 99.5, 70.8, 68.6, 66.8, 64.6, 61.3,
55.8, 55.5, 54.0, 20.6 ppm.
Conclusions
Prodrug activation strategies for metal complexes are still
very rare and require considerable additional research ef-
forts on top of what has been invested in the development
of organic prodrugs. The results in this paper have illus-
trated the considerable stabilization effect contributed to
auto-immolable spacer units by metal complexation. This
influence should be countered by rendering the ligand ther-
modynamically more labile before its complexation with the
metal. Also, the issue of substitution kinetics[31] of the coor-
dinating imine moiety (pyridyl or other) by water needs to
be addressed.[32,33] To this end, studies of remote derivatives
of 1 are currently in progress.
Experimental Section
All reactions were conducted under an inert atmosphere using
Schlenk tubes and vacuum-line techniques. Solvents were degassed
using standard procedures.
1,4-Dipicolyl-7-[4-(β-
D
-galactopyranosyloxy)phenyl](pyridin-2-yl)-
(124 mg,
4-(Tetraacetyl-β-D-galactopyranosyloxy)benzaldehyde (4): Tetra-
methyl-1,4,7-triazacyclononane (7): Hexaamine
6
acetyl-α-bromogalactopyranose (4.11 g, 10.0 mmol) in distilled
AcCN (100 mL) was treated with Ag2O (10.0 g, 42.0 mmol) and p-
hydroxybenzaldehyde (1.22 g, 10.0 mmol). The mixture was stirred
for 4 h before the solvent was evaporated. The resulting residue was
taken up in ethyl acetate and filtered through a pad of silica gel to
remove the metallic components. After evaporation, yellow oil was
obtained that was purified by column chromatography (Et2O).
Compound 4 was obtained in crystalline form by slow evaporation
of the solvent (3.04 g, 67%). 1H NMR (200 MHz, CDCl3): δ = 9.93
(s, 1 H), 7.85 (d, J = 8.7 Hz, 2 H), 7.11 (d, J = 8.7 Hz, 2 H), 5.47
(m, 2 H), 5.17 (m, 2 H), 4.17 (m, 3 H), 2.19 (s, 3 H), 2.06 (s, 6 H),
2.02 (s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 190.6, 170.2,
170.1, 170.0, 169.2, 161.2, 131.7, 116.7, 98.5, 71.3, 70.6, 68.4, 66.7,
61.3, 20.6, 20.5 ppm. M.p. 116.4 °C. HRMS: calcd. for
C21H24NaO11 [M + Na] 475.12163; found 475.12166.
0.15 mmol) in MeOH (2 mL) was treated with NaOMe (9 mg,
0.15 mmol) under argon. LCMS monitoring indicated that the re-
action was complete after 4 h. The solvent was then evaporated
and the remaining residue treated with CHCl3 (2 mL) causing a
precipitate to form, which was filtered and washed with CHCl3.
The combined organic phases were then evaporated to yield 7
(78 mg, 79%). For LCMS purity analysis, see Supporting Infor-
mation.
Complex 1: A solution of 6 (139 mg, 0.21 mmol) in degassed
MeOH (0.15 mL) was treated via cannula and under argon with a
solution of Fe(BF4)2·6H2O (68 mg, 0.18 mmol) in degassed MeOH
(1 mL). A dark brown color appears instantaneously, and the mix-
ture was then stirred for another 10 min before the solvent was
fully evaporated. The remaining residue was taken up in a minimal
amount of pure water and filtered through a RP-C18 cartridge
using water as the eluent. Lyophilization of the fractions containing
the product as detected by LCMS yielded 1 as a yellow solid
[4-(Tetraacetyl-β-D-galactopyranosyloxy)phenyl](pyridin-2-yl)-
methanol (5): 2-Bromopyridine (948 mg, 574 µL, 6.0 mmol) in THF
(8 mL) was treated dropwise with isopropylmagnesium bromide
(3.0 mL, 6.0 mmol, 2  in THF) under argon at 50 °C for 2 h. The
resulting solution was added at a rate of 0.5 mL/2 h to 4 (2.26,
5.0 mmol) in THF (18 mL) at room temperature, and the reaction
mixture was stirred until complete consumption of 4. The reaction
was quenched with sat. NH4Cl, extracted with CH2Cl2, and the
combined organic phases dried with Na2SO4. Purification of the
resulting residue by silica gel column chromatography yielded a
colorless solid that was recrystallized in pure diethyl ether (yield
1.94 g, 73%). 1H NMR (200 MHz, CDCl3): δ = 8.57 (d, J = 4.7 Hz,
1 H), 7.63 (td, J = 7.6, 1.4 Hz, 1 H), 7.30 (d, J = 8.6 Hz, 2 H), 7.21
(t, J = 4.7 Hz, 1 H), 7.13 (d, J = 7.6 Hz, 1 H), 6.97 (d, J = 8.6 Hz,
2 H), 5.72 (d, J = 4.2 Hz, 1 H), 5.43–5.47 (m, 2 H), 5.19 (d, J =
4.2 Hz, 1 H), 5.08 (dd, J = 7.9, 4.2 Hz, 1 H), 5.01 (d, J = 7.9 Hz,
1 H), 3.97–4.22 (m, 3 H), 2.17 (s, 3 H), 2.05 (s, 3 H), 2.03 (s, 3 H),
2.00 (s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 169.6, 169.5,
169.4, 168.66, 160.1, 155.9, 147.2, 137.6, 136.2, 127.7, 121.8, 120.6,
116.4, 99.0, 73.7, 70.3, 70.1, 68.0, 66.2, 60.7, 20.0 ppm. M.p.
138.2 °C. HRMS: calcd. for C26H29NO11 [M + H] 532.18189;
found 532.18186.
1
(103 mg, 65%). H NMR (200 MHz, D2O): δ = 7.34–7.95 (m, 19
H), 5.21 (m, 2 H), 4.50–5.00 (m), 4.22–4.43 (m, 1 H), 2.32–4.05 (m,
12 H) ppm. 13C NMR (50 MHz, D2O): δ = 166.0, 165.5, 165.3,
157.4, 154.7, 154.3, 154.2, 137.2, 136.8, 134.3, 132.3, 125.3, 125.1,
125.0, 122.4, 116.5, 116.1, 100.0, 75.3, 75.0, 72.1, 70.1, 68.0, 66.3,
65.9, 62.7, 61.3, 60.3, 58.9, 58.4, 51.9 ppm.
Enzyme Assay Conditions: Phosphate buffer at pH = 7.3 + EDTA
[1 m]; 35 °C; substrate concentration: 1 mg/mL; total volume =
1 mL; addition of 50-µL enzyme stock solution at 1UE/µL.
Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR, 13C NMR, and 13C NMR DEPT 135 spectra for
compounds 1 and 6; LCMS characterization of compounds 1 and
7; LCMS monitoring of the two enzyme assays.
Acknowledgments
Financial support from the CNRS, the French Ministry of Re-
search, the Rhone-Alpes Genopole, and Eumorphia are gratefully
acknowledged.
1,4-Dipicolyl-7-[4-(tetraacetyl-β-D-galactopyranosyloxy)phenyl]-
(pyridin-2-yl)methyl-1,4,7-triazacyclononane (6): Compound 5
(600 mg, 1.1 mmol) in CH2Cl2 (15 mL) was treated dropwise with
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Received: April 24, 2008
Published Online: July 25, 2008
Eur. J. Inorg. Chem. 2008, 3943–3947
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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