Straightforward synthesis of radioiodinated Cc-substituted o-carboranes: Towards a versatile platform to enable the in vivo assessment of BNCT drug candidates

Article abstract of DOI:10.1039/c5dt01049g

Due to their high boron content and rich chemistry, dicarba-closo-dodecaboranes (carboranes) are promising building blocks for the development of drug candidates with application in Boron Neutron Capture Therapy. However, the non-invasive determination of their pharmacokinetic properties to predict therapeutic efficacy is still a challenge. Herein, we have reported the unprecedented preparation of mono-[¹²⁵I] iodinated decaborane via a catalyst-assisted isotopic exchange. Subsequent reactions of the radiolabelled species with acetylenes in acetonitrile under microwave heating yield the corresponding ¹²⁵I-labelled, C_c-substituted o-carboranes with good overall radiochemical yields in short reaction times. The same synthetic strategy was successfully applied to the preparation of ¹³¹I-labelled analogues, and further extension to other radioisotopes of iodine such as ¹²⁴I (positron emitter) or ¹²³I (gamma emitter) can be envisaged. Hence, the general strategy reported here is suitable for the preparation of a wide range of radiolabelled C_c-substituted o-carborane derivatives. The labelled compounds might be subsequently investigated in vivo by using nuclear imaging techniques such as Single Photon Emission Computerized Tomography or Positron Emission Tomography.

Full text of DOI:10.1039/c5dt01049g

Dalton
Transactions
PAPER
Straightforward synthesis of radioiodinated
Cc-substituted o-carboranes: towards a versatile
platform to enable the in vivo assessment of
BNCT drug candidates†
Cite this: Dalton Trans., 2015, 44,
9915
K. B. Gona,a J. L. V. N. P. Thota,a Z. Baz,a V. Gómez-Vallejob and J. Llop*a
Due to their high boron content and rich chemistry, dicarba-closo-dodecaboranes (carboranes) are
promising building blocks for the development of drug candidates with application in Boron Neutron
Capture Therapy. However, the non-invasive determination of their pharmacokinetic properties to predict
therapeutic efficacy is still a challenge. Herein, we have reported the unprecedented preparation of
mono-[125I] iodinated decaborane via a catalyst-assisted isotopic exchange. Subsequent reactions of the
radiolabelled species with acetylenes in acetonitrile under microwave heating yield the corresponding
125I-labelled, Cc-substituted o-carboranes with good overall radiochemical yields in short reaction times.
The same synthetic strategy was successfully applied to the preparation of 131I-labelled analogues, and
further extension to other radioisotopes of iodine such as 124I (positron emitter) or 123I (gamma emitter)
can be envisaged. Hence, the general strategy reported here is suitable for the preparation of a wide
range of radiolabelled Cc-substituted o-carborane derivatives. The labelled compounds might be sub-
sequently investigated in vivo by using nuclear imaging techniques such as Single Photon Emission
Computerized Tomography or Positron Emission Tomography.
Received 16th March 2015,
Accepted 17th April 2015
DOI: 10.1039/c5dt01049g
www.rsc.org/dalton
death, while sparing healthy surrounding tissue and decreas-
ing unwanted off-target side effects.
Introduction
Binary approaches to cancer therapy, in which two non- or low-
Besides presenting low or no toxicity, an ideal BNCT drug
toxicity components of the treatment require co-localization in candidate should be able to deposit >20–35 µg 10B per g of
the tumour to become effective, are promising strategies to tumour to secure therapeutic efficacy, and guarantee tumour-
improve patient outcomes and reduce side effects. One such to-normal tissue and tumour-to-blood ratios greater than five
binary approach, boron neutron capture therapy (BNCT), to prevent damage to healthy tissue in the path of the neutron
was proposed almost 80 years ago by Locher,1 and involves the beam.2 In addition, it should ideally incorporate (or enable
accumulation of the non-radioactive nuclide, boron-10 (10B), the straightforward incorporation of) a positron or a gamma
into the targeted area, followed by local irradiation with low emitter to facilitate the determination of its pharmacokinetic
energy thermal neutrons, which results in the rapid nuclear properties using non-invasive, in vivo imaging techniques
7
reaction 10B(n,α,γ)7Li. Alpha particles and Li recoil ions have such as Positron Emission Tomography (PET) or Single
high linear energy transfer (LET) and path lengths in the range Photon Emission Computerized Tomography (SPECT), to allow
of 4 to 10 µm. Hence, their deposition energy is limited to the candidate-by-candidate screening to predict therapeutic
diameter of a single cell, leading to selective cell damage and efficacy.
1,2-Dicarba-closo-dodecaboranes (ortho-carboranes or o-car-
boranes) are polyhedral clusters containing boron, hydrogen
aRadiochemistry and Nuclear Imaging Group, CIC biomaGUNE, Paseo Miramón 182,
San Sebastián, 20009 Guipuzcoa, Spain. E-mail: jllop@cicbiomagune.es;
Tel: +34 943 00 53 33
and carbon atoms and were first reported in the early 1960s
simultaneously by two groups.3 The unique physico-chemical
properties of o-carboranes, i.e. rigid geometry, rich derivative
chemistry, thermal and chemical stability and exceptional
hydrophobic character, together with their high boron content,
make them suitable building blocks for the preparation of
bRadiochemistry Platform, CIC biomaGUNE, Paseo Miramón 182, San Sebastián,
20009 Guipuzcoa, Spain
†Electronic supplementary information (ESI) available: Spectroscopic data and
chromatographic profiles. See DOI: 10.1039/c5dt01049g
This journal is © The Royal Society of Chemistry 2015
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Dalton Transactions
candidates for BNCT drugs.4–6 Indeed, functionalized o-carbor-
anes have been proposed as targeted boron-rich drugs able to
selectively accumulate in tumour tissue.7
Cc-selectively functionalized o-carboranes can be obtained
by treatment of o-carborane with a strong base (e.g., alkyl
lithium salts) and subsequent reaction with an electrophile.
Unfortunately, monolithiation of o-carboranes at carbon
competes unfavourably with dilithiation, leading to complex
mixtures. Alternatives for the preparation of mono-substituted
o-carboranes, e.g. blocking one of the Cc positions with a
–Si(Me)2CMe3 (TBDMS)8 or by using dimethoxyethane as a
solvent,9 have been developed. Alternatively, the reaction of
decaborane‡ (B10H14) with a Lewis base to form a reactive
complex (B10H12L2),10 and further reaction with an alkyne can
be used for the preparation of Cc-functionalized o-carboranes.
This 2-step reaction usually offers variable chemical yields and
requires longer reaction times (from several hours to days) at
elevated temperatures, especially in the case of hindered
alkynes.3a Variants of the method including the use of ionic
liquids11 and the use of metal salts to enhance the yields have
been reported, with satisfactory results.12 These routes enable
the preparation of a large collection of o-carborane derivatives,
including BNCT drug candidates.13
Fig. 1 Schematic synthesis and purification of 1-iododecaborane and
radiolabelling by isotopic exchange using 125I. The same synthetic strat-
egy was used for the preparation of 131I-labelled derivatives.
the general strategy reported here might be used for the
efficient preparation of a variety of radiolabelled o-carboranes
by using the same radiolabelled precursor (125I-labelled or 131I-
labelled iododecaborane) and just modifying the alkyne.
Notably, translation of the methodology to other positron (124I)
or gamma (123I) emitters, more convenient for their use in
in vivo imaging, should be straightforward.
Very recently, we have reported the mono-[18F]fluorination
of o-carborane via nucleophilic substitution using the carbora-
nyl iodonium salt as the precursor, and subsequent mono-
functionalization at one of the Cc atoms by formation of the
lithium salt and reaction with an aldehyde.14 The incorpor-
ation of the positron emitter (18F) enables external tracking
after administration into living organisms using PET. Despite
Results and discussion
the usefulness and novelty of this strategy, post-radiolabelling The mono-iodination of decaborane under non-radioactive
chemical reactions and tedious work-up are required, limiting conditions was first undertaken. Experimentally, decaborane
the widespread application of this methodology.
was reacted with iodine monochloride and anhydrous AlCl3 in
Radioiodination represents an attractive alternative to dichloromethane to obtain two positional isomers (1- and
radiofluorination. The radioiodination of nido- and closo- 2-iododecaboranes, see Fig. 1), which were separated by recrys-
derivatives of monocarbon carboranes,15 dodecahydro-closo- tallization in hot heptane following a previously reported
dodecaborate (2-),16 nido-o-carborane17 and dicarba-nido-unde- method.19 Previous results suggest a higher propensity of
caborate18 have been reported in the literature. Here, in con- 2-iododecaborane to undergo deiodination,19 and hence
tinuation of these previous studies, and in pursuit of a general 1-iododecaborane was used in subsequent radiolabelling
strategy for the preparation of radiolabelled o-carboranes, experiments and preparation of o-carborane derivatives.
we report an unprecedented strategy. Our approach relies on
125I-radiolabelling was carried out by adapting the pre-
the preparation of radiolabelled decaborane using 125I (a viously reported palladium catalyzed iodine exchange reaction
radioactive isotope which decays by electron capture with a on iodinated dicarba-closo-dodecaboranes.20 Briefly, 1-iodode-
half-life of nearly 59 days) and catalytic isotopic exchange caborane (4.04 μmol) in toluene (100 μl) was reacted with
(Fig. 1).
370 KBq (10 μCi) of Na[125I]I (solution in 0.1 M aqueous
Further reaction with alkynes using acetonitrile, which acts NaOH) in the presence of Hermann’s catalyst (HC, 0.1 mg in
both as a Lewis base and as the solvent, yields the corres- 100 μl of toluene) at 100 °C for 5 min (Fig. 1). Radiochemical
ponding radiolabelled o-carborane derivatives in a one-pot, conversion (RCC) values, as determined by high performance
one-step reaction. The same synthetic strategy could be suc- liquid chromatography (HPLC) using radiometric detection
cessfully translated to the preparation of analogues radio- were 70 4% (see Fig. S7A in the ESI† for an example of a chro-
labelled with 131I (a radioactive isotope which decays by beta matographic profile). Longer reaction times and higher temp-
and gamma emission, with a half-life of nearly 8 days). Hence, erature values led to a decrease in RCC, suggesting
a
progressive deiodination of the precursor and the labelled
species in competition with the isotopic exchange reaction.
The crude reaction mixture was finally purified by solid phase
extraction (SPE) to remove the unreacted Na[125I]I. With this
‡Decaborane is a powerful toxin affecting the central nervous system, and can
be absorbed through skin. It forms an explosive mixture with carbon tetrachlor-
ide. Special precaution must be taken for its manipulation.
9916 | Dalton Trans., 2015, 44, 9915–9920
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Dalton Transactions
Paper
aim, the reaction mixture was diluted with water and passed
through a C-18 cartridge, which was further rinsed with water.
The final elution with acetonitrile (1 mL) yielded pure 1-[125I]
iododecaborane in overall radiochemical yield of 58 7% (see
Fig. S7B† for the chromatographic profile of the purified
product).
The work reported herein was first conducted with 125I,
which was selected for convenience (it is widely available) and
economical reasons. However, the results can be translated to
other radioisotopes of iodine, more convenient for imaging
studies and with shorter half-lives such as 123I (a gamma
emitter with T1/2 = 13.2 h) or 124I (a positron emitter with T1/2
=
4.2 days). In order to prove the suitability of the strategy when
other iodine radioisotopes were used, the same procedure was
repeated but Na[131I]I (solution in 0.1 M aqueous NaOH) was
used as the labelling agent. Equivalent radiochemical yields
(56 4%) were achieved.
Fig. 2 Scheme of the reaction for the preparation of o-carborane
derivatives using microwave (MW) heating; route A: using ionic liquids;
route B: using acetonitrile both as the Lewis base and solvent.
In order to develop a methodology applicable to shorter
lived radioisotopes of iodine (such as the above mentioned
123I and 124I) we emphasized on developing a one-pot, one-
step, fast and efficient method for the reaction of 1-[125I]iodo- published data (Table 1).12 Unfortunately, the translation of
these conditions to the preparation of 125I-and 131I-labelled
decaborane (or 1-[131I]iododecaborane) with different alkynes
to obtain radiolabelled substituted o-carboranes. Generally, analogues of compounds 2–7 resulted in low RCC values as
strategies involving Lewis bases require two steps, and hence determined by radio-HPLC (<5% in all cases). Longer reaction
times (up to 20 min) only improved RCC values slightly up to
microwave heating. Despite not previously reported in the 5–10%.
our first attempts were performed with ionic liquids under
context of the preparation of o-carboranes in ionic liquids,
microwave heating was expected to significantly decrease
In pursuit of simple alternatives applicable to the prepa-
ration of radioiodinated o-carboranes, we assayed an experi-
reaction times. This was tested in model compounds using mental scenario based on a one-pot, one-step, microwave-
decaborane as the precursor (see Table 1). Experimentally, assisted synthetic route without using ionic liquids. Explora-
tory studies were initially conducted with non-labelled deca-
decaborane and the corresponding alkynes (1 : 3 molar ratio)
were dissolved in biphasic toluene/ionic liquid (1-butyl-3- borane; in a typical experiment, decaborane and alkyne
methylimidazolium chloride, bmimCl) in a microwave vial (1 : 3 molar ratio) were dissolved in acetonitrile in a microwave
vial and heated at 120 °C for 20 min under microwave
and heated at 140 °C under microwave irradiation for
1 minute (Fig. 2, method A). Overall yields after purification irradiation (Fig. 2, method B). Excellent yields were obtained
for the six compounds assayed (2–7) ranged from 68 6% to for the six alkynes assayed (65 4 to 76 3%, Table 1), while
reaction times could be significantly decreased when com-
85 7%, resulting in a significant reduction of the reaction
time when compared to conventional heating, according to pared to reported values using the conventional 2-step method
(e.g., 23 h for compound 2, 10 h for compound 3).
Despite the fact that this method proved successful for the
preparation of the substituted carboranes reported here, the
determination of the real scope of MW-assisted formation of
Table 1 Formation of o-carborane derivatives by reaction of decabor-
closo-carborane derivatives and the effect of different para-
meters (e.g. chemical properties of the alkynes, polarity, size,
etc.) on the reaction yield and formation of by-products would
require assays using a larger collection of alkynes and a more
systematic analysis. Such an investigation was out of the scope
of the current work.
As a proof of concept that this strategy is suitable for the
preparation of radiolabelled o-carboranes, these experimental
conditions were applied to the preparation of four 125I-labelled
o-carboranes (Fig. 3). Experimentally, the purified labelled
1-[125I]iododecaborane was dissolved in 100 μl of acetonitrile
in a 2 mL microwave vial. The corresponding alkyne (14 μmol),
was added and the mixture was heated under microwave
irradiation at 120 °C for 40 min. Good RCC values, as
anes with alkynes using ionic liquids (IL) and acetonitrile under micro-
wave heating
Compd
Alkyne
Y. ILa
Y. MeCNb
Y. CHc
2
3
4
5
6
7
1-Octyne
Phenylacetylene
1-Hexyne
1,8-Nonadiyne
4-Ethynyltoluene
Ethyl propiolate
85 7%
68 6%
71 6%
72 6%
75 8%
72 4%
75 7%
65 4%
72 9%
71 7%
76 3%
69 5%
91%
71%
NR
63%
NR
84 4%
a Yield obtained in this work: microwave heating, reaction time of
1 min, using ionic liquids. b Yield obtained in this work: microwave
heating, reaction time of 20 min, using MeCN both as the Lewis base
and solvent. c Yield reported in the literature, using ionic liquids under
conventional heating (CH) with reaction time of 7 min; NR: not
reported in the literature.
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Experimental section
General
Decaborane was purchased from Katchem Ltd (Prague, Czech
Republic); all other reagents (analytical grade purity) were pur-
chased from Aldrich Chemical Co. and used without further
purification. Dry solvents, stored over 4 Å molecular sieves,
were also purchased from Aldrich Chemical Co. 6-Heptyn-1-yl
p-toluenesulfonate was prepared following
a previously
described method.21 All reactions were carried out under a
nitrogen atmosphere and followed by thin-layer chromato-
graphy carried out on silica gel 60 F254 plates (Macherey-
Nagel). Visualization was accomplished with a UV source (254,
365 nm) and by treatment with an acidic solution of 1% PdCl2
in methanol. Carboranes were charred as black spots on TLC.
Microwave reactions were conducted using a Biotage Initiator
Exp Eu system, and a power of 400 W was used. All the reac-
tions were performed in the vials specified by the manufac-
turer. Manual chromatography was performed with silica gel
60 (70–230 mesh) from Scharlau. 1H, 11B and 13C-NMR spectra
were recorded on a 500 MHz Avance III Bruker spectrometer.
To explain the multiplicities, the following abbreviations are
used: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet.
Fig. 3 Scheme of the reaction for the preparation of 125I-labelled
o-carborane derivatives using microwave (MW) heating and acetonitrile
as the Lewis base and solvent in a one-step, one-pot reaction. The same
strategy was used for the preparation of 131I-labelled analogues.
Table 2 Preparation of 125I-labelled o-carboranes using acetonitrile
acting both as the solvent and as the Lewis base, under microwave
heating
Compound
Alkyne
RCC (%)
RCY (%)
[
[
[
[
125I]8
Phenylacetylene
4-Ethynyltoluene
Ethyl propiolate
6-Heptyn-1-yl p-toluenesulfonate
69
89
84
70
4
3
4
5
22
33
31
36
3
2
3
4
125I]9
125I]10
125I]11
Synthetic procedure for microwave assisted alkyne-insertion to
decaborane in ionic liquid
In a clean and dry microwave vial, decaborane (1.636 mmol)
and alkyne (5.235 mmol) were solved in biphasic toluene
(8 ml)/bmimCl (0.818 mmol). The vial was purged with nitro-
determined by radio-HPLC, were obtained (see Table 2). Sub- gen, properly capped, and reacted under microwave heating
sequent purification using radio-HPLC yielded pure com- (140 °C, 1 min). After cooling, the organic layer was withdrawn
pounds with overall radio chemical yields (RCYs) of 22 3%, and the ionic liquid layer was extracted with ether (10 ml). The
33 2%, 31 3% and 36 4% for [125I]8, [125I]9, [125I]10 and combined organic layer was evaporated and the crude reaction
[
125I]11, respectively (Table 2). Compounds 8–11 were also pre- mixture was purified by silica gel column. The column was
pared using 131I, with equivalent radiochemical conversion eluted with hexane (except for compound 4, which was eluted
and yields. Identification of the labelled compounds was with 30% ethyl acetate in hexane), the product fractions were
carried out by radio-HPLC and co-elution using reference stan- combined and the solvent was evaporated using a rotary
dard compounds (Fig. S8–S11†).
evaporator.
It is worth mentioning that when the iodinated decaborane
is used (both in radioactive and in non-radioactive conditions),
the reaction with unsymmetrical acetylenes results in a
Synthetic procedure for microwave assisted alkyne-insertion to
decaborane in the absence of ionic liquid
mixture of two unavoidable positional isomers (see Fig. 3), In a clean and dry microwave vial, decaborane (1.636 mmol)
with the iodine atom attached to the 9- and 12-positions. Sep- and alkyne (5.235 mmol) were dissolved in acetonitrile (8 ml).
aration of these isomers was out of the scope of this work, The vial was purged with nitrogen gas, properly capped and
although it might be required for subsequent in vivo appli- reacted under microwave heating (120 °C, 20 min). After
cations. This could be achieved, for example, using chiral cooling, the solvent was evaporated and the residue was puri-
HPLC. In addition, the values of specific activity should also fied by silica gel column. The column was eluted with hexane
be taken into consideration, as they may gain relevance when (except for compound 4, which was eluted with 30% ethyl
moving to in vivo studies. Because the labelling strategy relies acetate in hexane), the product fractions were combined and
on isotopic exchange and low amounts of radioactivity were the solvent was evaporated using a rotary evaporator.
used, the final specific activity values were estimated to be
around 0.1 MBq µmol−1, taking into account that 10 µCi (0.37
Synthesis of 1-iododecaborane
MBq) of radioiodine were used to label 1 mg of 1-iododecabor- A previously described procedure was used.19 Briefly: in a
ane. These values may be increased significantly by using 100 ml SNRB flask, decaborane (5.00 g, 40.1 mmol) was dis-
higher amounts of radioactivity.
solved in anhydrous dichloromethane (35 mL). Anhydrous
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Paper
AlCl3 (0.546 g, 4.03 mmol) was added, the mixture was cooled B-40%; 30 min: A-60% & B-40%. Identification of the desired
to 0 °C and a solution of ICl (2.08 mL, 41.5 mmol) in 20 mL of products was achieved by co-elution using
anhydrous dichloromethane was added dropwise. The dark standard.
brown reaction mixture was heated to reflux for 5 h. The reac-
a reference
tion mixture was filtered and the solvent was evaporated to
dryness. Recrystallization of the crude reaction mixture from
hot heptane gave pure 2-iododecaborane. 1-Iododecaborane
Conclusions
In conclusion, a straightforward methodology for the prepa-
ration of 125I- and 131I-labelled 1-iododecaborane is reported
for the first time. Subsequent reactions with alkynes using
acetonitrile as the solvent under microwave heating results in
the formation of the corresponding radiolabelled o-carborane
derivatives through a one-pot, one-step reaction, with excellent
yields in short reaction times. The experimental conditions
might be directly translated to the preparation of radiolabelled
carborane analogues using other radioisotopes of iodine such
as 124I or 123I, which are more appropriate to conduct sub-
sequent in vivo imaging studies. Hence, the combination of
the methodologies developed herein may enable the prepa-
ration of a wide range of radioiodinated o-carborane deriva-
tives, whose potential suitability as BNCT drug candidates
might be easily investigated using non-invasive, in vivo
imaging techniques such as PET and SPECT. The preparation
of radiolabelled carborane-bearing biomolecules is currently
being explored using the methodology reported here. Notably,
the presence of a tosyl group in compound 11 may enable sub-
sequent functionalization for the incorporation of biologically
active moieties and achievement of more complex structures.
was isolated by recrystallization of mother liquor.
Synthetic procedure for microwave assisted alkyne-insertion to
1-iododecaborane
In a cleaned and dry microwave vial, 1-iododecaborane
(1.636 mmol) and alkyne (5.235 mmol) were dissolved in
acetonitrile (8 ml). The vial was purged with nitrogen gas,
properly capped and reacted under microwave heating (120 °C,
60 min). After cooling, the solvent was evaporated and the
residue was purified by silica gel column chromatography. The
column was eluted with 4% ethyl acetate/hexane, the product
fractions were combined and the solvent was evaporated using
a rotary evaporator.
Synthesis of 125I- and 131I-labelled 1-iododecaborane
All the solvents were degassed for 10 minutes before use. 1 μL
[
125I]NaI (solution in 0.1 M NaOH, Perkin Elmer) or [131I]NaI
(solution in 0.1 M NaOH, Perkin Elmer) and 200 μL of aceto-
nitrile (Sigma-Aldrich) were introduced in a 2.5 mL vial. The
vial was heated at 100 °C for 5 min under a constant helium
flow to evaporate all the solvents. After complete evaporation,
1 mg of the precursor dissolved in 100 μL of toluene and
0.1 mg (0.101 μmol) of Herrmann’s catalyst (trans-bis(acetato)
bis[o-(di-o-tolylphosphino)benzyl] dipalladium(II), HC) dis-
solved in 100 μL of toluene were added. Reaction conditions
were: T = 100 °C, and t = 5 min. After completion of the reac-
tion, the solvent was removed by a constant helium flow and
the radiochemical conversion was determined by radio-HPLC.
Analytical conditions were: stationary phase: Mediterranea
SEA18 column (15 × 0.46 cm); mobile phase A: 0.1 M
ammonium formate (AMF) buffer pH = 3.9, B: acetonitrile;
flow rate = 1 mL min−1. The following gradient was used:
initial: A-80% & B-20%; 2 min: A-80% & B-20%; 12 min: A-20%
& B-80%; 16 min: A-20% & B-80%; 17 min: A-80% & B-20%;
20 min: A-80% & B-20%). Injected volume was 20 µL.
Acknowledgements
The authors would like to thank Dr Javier Calvo and Dr Daniel
Padró for providing assistance in LC-MS and NMR, respect-
ively, as well as the Departamento de Industria, Comercio y
Turismo of the Basque Government and the Ministerio de
Ciencia e Innovación (Grant number CTQ2009-08810) for
financial support.
Notes and references
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Synthesis of 125I- and 131I-labelled o-carboranes
In a clean and dry microwave vial, 125I- or 131I-labelled 1-iodo-
decaborane and alkyne (2 μL) were dissolved in acetonitrile
(100 μL). The vial was purged with nitrogen, properly capped
and reacted under microwave heating (120 °C, 60 min). After
completion of the reaction, RCC was determined by radio-
HPLC, using the same experimental conditions as explained
above. For compound 11, analytical conditions were: stationary
phase: Mediterranea SEA18 column (25 × 1.0 cm); mobile
phase A: 0.1 M ammonium formate (AMF) buffer pH = 3.9, B:
acetonitrile; flow rate = 5 mL min−1; the following gradient was
used: initial: A-60% & B-40%; 6 min: A-60% & B-40%; 12 min:
A-20% & B-80%; 24 min: A-20% & B-80%; 28 min: A-60% &
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9920 | Dalton Trans., 2015, 44, 9915–9920
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