Water-Soluble Rhenium Phosphine Complexes Incorporating the Ph2C(X) Motif (X = O-, NH-): Structural and Cytotoxicity Studies

Article abstract of DOI:10.1021/acs.inorgchem.9b03239

Reaction of [ReOCl₃(PPh₃)₂] or [ReO₂I(PPh₃)₂] with 2,2′-diphenylglycine (dpgH₂) in refluxing ethanol afforded the air-stable complex [ReO(dpgH)(dpg)(PPh₃)] (1). Treatment of [ReO(OEt)I₂(PPh₃)₂] with 1,2,3-triaza-7-phosphaadamantane (PTA) afforded the complex [ReO(OEt)I₂(PTA)₂] (2). Reaction of [ReOI₂(PTA)₃] with dpgH₂ led to the isolation of the complex [Re(NCPh₂)I₂(PTA)₃]·0.5EtOH (3·0.5EtOH). A similar reaction but using [ReOX₂(PTA)₃] (X = Cl, Br) resulted in the analogous halide complexes [Re(NCPh₂)Cl₂(PTA)₃]·2EtOH (4·2EtOH) and [Re(NCPh₂)(PTA)₃Br₂]·1.6EtOH (5·1.6EtOH). Using benzilic acid (2,2′-diphenylglycolic acid, benzH) with 2 afforded the complex [ReO(benz)₂(PTA)][PTAH]·EtOH (6·EtOH). The potential for the formation of complexes using radioisotopes with relatively short half-lives suitable for nuclear medicine applications by developing conditions for [Re(NCPh₂)(dpg)I(PTA)₃] (7)[ReO₄]^- in a 4 h time scale was investigated. A procedure for the technetium analog of complex [Re(NCPh₂)I₂(PTA)₃] (3) from ^99mTc[TcO₄]^- was then investigated. The molecular structures of 1-7 are reported; complexes 3-7 have been studied using in vitro cell assays (HeLa, HCT116, HT-29, and HEK 293) and were found to have IC₅₀ values in the range of 29-1858 μM.

Full text of DOI:10.1021/acs.inorgchem.9b03239

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Water-Soluble Rhenium Phosphine Complexes Incorporating the
Ph2C(X) Motif (X = O−, NH−): Structural and Cytotoxicity Studies
Abdullah F. Alshamrani, Timothy J. Prior, Benjamin P. Burke, David P. Roberts, Stephen J. Archibald,
Lee J. Higham, Graeme Stasiuk,* and Carl Redshaw*
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ABSTRACT: Reaction of [ReOCl3(PPh3)2] or [ReO2I(PPh3)2]
with 2,2′-diphenylglycine (dpgH2) in refluxing ethanol afforded the
air-stable complex [ReO(dpgH)(dpg)(PPh3)] (1). Treatment of
[ReO(OEt)I2(PPh3)2] with 1,2,3-triaza-7-phosphaadamantane
(PTA) afforded the complex [ReO(OEt)I2(PTA)2] (2). Reaction
of [ReOI2(PTA)3] with dpgH2 led to the isolation of the complex
[Re(NCPh2)I2(PTA)3]·0.5EtOH (3·0.5EtOH). A similar reaction
but using [ReOX2(PTA)3] (X = Cl, Br) resulted in the analogous
halide complexes [Re(NCPh2)Cl2(PTA)3]·2EtOH (4·2EtOH) and
[Re(NCPh2)(PTA)3Br2]·1.6EtOH (5·1.6EtOH). Using benzilic
acid (2,2′-diphenylglycolic acid, benzH) with 2 afforded the complex
[ReO(benz)2(PTA)][PTAH]·EtOH (6·EtOH). The potential for
the formation of complexes using radioisotopes with relatively short
half-lives suitable for nuclear medicine applications by developing conditions for [Re(NCPh2)(dpg)I(PTA)3] (7)[ReO4]− in a 4 h
time scale was investigated. A procedure for the technetium analog of complex [Re(NCPh2)I2(PTA)3] (3) from 99mTc[TcO4]− was
then investigated. The molecular structures of 1−7 are reported; complexes 3−7 have been studied using in vitro cell assays (HeLa,
HCT116, HT-29, and HEK 293) and were found to have IC50 values in the range of 29−1858 μM.
potential method for modulating toxicity, localization, etc., in
mammalian cells.11,12 The use of amino acids has allowed for
the development of many new chelate families, particularly
where steric bulk is not a prerequisite for complex
formation.13,14 They can also act as bifunctional chelators,
i.e., can attach to targeted biomolecules and bear coordination
sites to the radionuclide that can direct the biodistribution of
the radiotracer.15−17 The use of simple carboxylic acids also
allows for optical properties of metal complexes to be probed
with a view to enhancing their bioapplication.18,19 In other
studies, we and others have found that the use of the acids
Ph2C(X)CO2H (X = OH, NH2) can impart high crystallinity
in products and be beneficial for characterization.20−23 Thus,
herein we report our initial studies on rhenium complexes
bearing ligands derived from diphenylglycine (X = NH2) and
the related pro-ligand benzilic acid (X = OH).
INTRODUCTION
■
The diagnosis and early treatment of diseases such as cancer
and heart disease have benefited greatly from the availability of
technetium-based imaging agents.1 99mTc is used as a γ-emitter
in single-photon emission computed tomography (SPECT).
Moreover, 99mTc has been used for diagnosis as an imaging
agent because of the optimal 140-keV γ-ray emission, the 6 h
half-life, lower tissue damage, and the availability of a
convenient generator.2−5 By contrast, rhenium has two
isotopes that are β-emitters, namely, 186Re and 188Re, with
half-lives (t1/2) of 90 and 17 h, respectively, making them
suitable as therapeutics in a theranostic pair with technetium.6
Given the similarities between the chemistries of these two
metals, any advances in the synthetic methodology to access
one type of metal chelate can usually be applied to the other
metal and vice versa.2,7 Currently, much research effort is
devoted to developing targeted agents, thereby ensuring any
delivered radiation is localized.3,8,9
The use of chelates with added functional groups is a
particularly promising avenue,10 and with this in mind, we have
initiated a program to investigate the use of amino acid derived
chelates bound to rhenium. We note that data concerning the
cellular uptake, toxicity, and localization of rhenium amino acid
complexes are scant.11 Moreover, the use of amino acid
derived ligation at the rhenium core has been recognized as a
Convenient entry points into high-oxidation-state rhenium
chemistry are the phosphine complexes [ReOCl3(PPh3)2] and
[ReO2I(PPh3)2]; however, it must be noted that the low
Received: November 5, 2019
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© XXXX American Chemical Society
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(d, J = 11.4 Hz, 2H, NH2). 31P NMR (CDCl3) δ: 5.3 (s). IR (KBr):
3303 (w), 3258 (w), 1584 (m), 1569 (m), 1092 (s), 998 (s), 980 (s),
955 (s), 936 (s), 908 (s) cm−1. MALDI-MS m/z: 917.21 [M + H+].
Synthesis of [ReO(dpgH)(dpg)(PPh3)] (1) from [ReO2I(PPh3)2]. As
above, but using [ReO2I(PPh3)2] (0.50 g, 0.57 mmol) and 2,2′-
diphenylglycine (0.26 g, 1.14 mmol), afforded 1 as green prisms.
Yield: 0.30 g (57%). Elemental anal. calcd for C46H38N2O5PRe: C,
60.26%; H, 4.14%; N, 3.05%. Found: C, 60.32%; H, 3.89%; N, 3.07%.
1Η ΝΜR (CDCl3) δ: 11.24 (s, 1H, NH), 6.91−7.72 (m, 21H,
HaromPPh3/CPh2), 6.66 (d, J = 11.5, 14H, HaromPPh3/CPh2), 5.92 (d,
J = 11.5, 2H, NH2). 31P NMR (CDCl3) δ: 5.3 (s). IR (KBr): 3301
(w), 3256 (w), 1584 (w), 1569 (w), 1092 (s), 998 (s), 979 (m), 955
(m), 936 (m), 908 (m) cm−1. MALDI-MS m/z: 917.21 [M + H+].
Synthesis of [ReO(OEt)I2(PTA)2] (2). At room temperature, 1,3,5-
triaza-7-phosphaadamantane (0.51 g, 3.27 mmol) was dissolved in the
minimum volume of dichloromethane (∼30 mL), and the solution
was added to a conical flask containing a suspension of [ReO(OEt)-
I2(PPh3)2] (1.00 g, 1.09 mmol) in dichloromethane (20 mL), which
caused a color change from light khaki to yellow-orange. The reaction
mixture was stirred for 1 h, and then the volatiles were removed under
vacuum. Ethanol (5 mL) was added, and slow evaporation of the
solvent at room temperature afforded a yellow-orange solid, which
was collected and washed with EtOH (10 mL) and Et2O (10 mL).
Orange crystals of 2 suitable for X-ray crystallography were obtained
by recrystallization from CH2Cl2/EtOH. Yield: 0.81 g (92%).
Elemental anal. calcd for C14H29I2N6O2P2Re: C, 20.60%; H, 3.55%;
N, 10.30%. Found: C, 21.01%; H, 3.95%; N, 10.64%. 1Η ΝΜR
(CDCl3) δ: 4.48−4.74 (m, 2H, CH2), 4.03−4.35 (m, 12H, N−CH2−
N), 3.87 (d, J = 9.2 Hz, 12H, P-CH2), 1.58 (s, 3H, CH3). 31P NMR
(CDCl3) δ: −4.8 (s); in (D2O) δ: −2.2 (s). IR (KBr): 1281 (m),
1040 (m), 1013 (s), 969 (s), 945 (s), 902 (s) cm−1. MALDI-MS m/z:
816.95 [M + H+].
Synthesis of [Re(NCPh2)I2(PTA)3]·0.5EtOH (3·0.5EtOH). To [Re-
OI2(PTA)3] (0.50 g, 0.53 mmol) and dpgH2 (0.24 g, 1.07 mmol) was
added dry ethanol (20 mL). After the mixture was refluxed for 4 h, the
solution was filtered, and on prolonged standing (2 to 3 days) at
ambient temperature, green crystals of 3 formed. Yield: 0.40 g (68%).
Elemental anal. calcd for C64H88I4N20P6Re2·0.5EtOH: C, 34.57%; H,
4.41%; N, 12.60%. Found: C, 34.90%; H, 4.79%; N, 12.72%. 1Η ΝΜR
(C6D6) δ: 7.05−7.29 (m, 10H, HaromCPh2), 3.85−4.08 (m, 18H, N−
CH2−N), 3.66 (d, J = 41.6 Hz, 18H, P-CH2). 31P NMR (C6D6) δ:
−104.9 (t, J = 11.3 Hz), −120.9 (d, J = 12.5 Hz); in (CDCl3) δ:
−104.2 (t, J = 12.5 Hz), −118.7 (d, J = 12.5 Hz); in (D2O) δ: −107.3
(t, J = 11.3 Hz), −123.3 (d, J = 12.5 Hz). IR (KBr): 1592 (w), 1416
(m), 1313 (m), 1276 (s), 1241 (s), 1041 (m), 1015 (s), 969 (s), 946
(s) cm−1. ES-MS m/z: 1092 [M + H+].
biocompatibility, high molecular weight, and hydrophobicity of
arylphosphines renders these complexes unsuitable for medical
uses.24 The challenge, therefore, is to replace PPh3 with a more
biocompatible and hydrophilic phosphine. 1,2,3-Triaza-7-
phosphaadamantane (PTA) is a phosphine that is widely
used as a water-soluble ligand and possesses an adamantane-
like structure. Daigle et al. first prepared this phosphine in
1974, and because of its solubility and stability in water, it has
been widely used in the fields of organometallic catalysis and
coordination chemistry;25,26 others have recently published on
the coordination chemistry of PTA and outlined its medical
and catalytic chemistry.27−30 Thus, herein we have employed
PTA to produce water-soluble rhenium complexes for facile
biological evaluation. We also note that the rhenium oxo
complexes can be isolated from [3 + 2] reactions involving
diphenyl ketene.31 The dpgH2, benzH and complexes 1−7
prepared herein are shown below in Schemes 1 and 2.
Scheme 1. 2,2′-Diphenylglycine (dpgH2) and Benzilic Acid
(2,2′-Diphenylglycolic Acid, benzH)
Finally, given that the aim of this work is to develop new
technetium-based imaging agents, we have conducted the
preparation of a water-soluble dpgH2-derived rhenium
complex from (NH4)[ReO4] in 4 h and have investigated
this synthetic methodology with [99mTc]TcO4 .
−
EXPERIMENTAL SECTION
■
General Information. All manipulations were carried out under
an atmosphere of dry nitrogen using conventional Schlenk and
cannula techniques or in a conventional nitrogen-filled glovebox.
Hexane and ethanol were dried over sodium prior to use.
Dichloromethane was refluxed over calcium hydride. Diethyl ether
was dried over sodium benzophenone. All solvents were distilled and
degassed prior to use. IR spectra (nujol mulls, KBr windows) were
1
Synthesis of [Re(NCPh2)Cl2(PTA)3]·2EtOH (4·2EtOH). To [Re-
OCl2(PTA)3] (0.50 g, 0.68 mmol) and dpgH2 (0.27 g, 1.10 mmol)
was added dry ethanol (20 mL). After the mixture was refluxed for 4
h, the solution was filtered, and on prolonged standing (2 to 3 days)
at ambient temperature, green crystals of 4 formed. Yield: 0.40 g
(67%). Elemental anal. calcd for C31H46Cl2N10P3Re (sample dried in-
vacuum −2EtOH): C, 40.93%; H, 5.06%; N, 15.40%. Found: C,
recorded on a Nicolet Avatar 360 FT IR spectrometer; H NMR
spectra were recorded at room temperature on a Varian VXR 400 S
spectrometer at 400 MHz or a Gemini 300 NMR spectrometer or a
1
Bruker Advance DPX-300 spectrometer at 300 MHz. The H NMR
spectra were calibrated against the residual protio impurity of the
deuterated solvent. Elemental analyses were performed by the
elemental analysis service at the London Metropolitan University
and the Department of Chemistry and Biochemistry at the University
of Hull.
The precursors [ReOCl3(PPh3)2], [ReOBr3(PPh3)2], [ReO2I-
(PPh3)2], [ReO(OEt)I2(PPh3)2], and [ReOCl2(PTA)3] were pre-
pared by the literature methods; [ReOX2(PTA)3] (X = Br, I) was
prepared following the method used for [ReOCl2(PTA)3].24,32−34 All
other chemicals were purchased from Sigma-Aldrich.
Synthesis of [ReO(dpgH)(dpg)(PPh3)] (1). To [ReOCl3(PPh3)2]
(0.50 g, 0.60 mmol) and 2,2′-diphenylglycine (0.27 g, 1.20 mmol)
was added dry ethanol (20 mL). After the mixture was refluxed for 4
h, volatiles were removed in vacuum and the residue was extracted
into CH2Cl2 (20 mL). Addition of a layer of Et2O (20 mL) afforded,
on prolonged standing, green prisms of 1. Yield: 0.40 g (74%).
Elemental anal. calcd for C46H38N2O5PRe: C, 60.26%; H, 4.14%; N,
3.05%. Found: C, 59.93%; H, 4.00%; N 3.02%. 1Η ΝΜR (CDCl3) δ:
11.24 (s, 1H, NH), 7.13−7.51 (m, 21H, HaromPPh3/CPh2), 6.98 (d, J
= 8.2 Hz, 6H, HaromPPh3), 6.67 (d, J = 11.4 Hz, 8H, Harom CPh2), 5.92
1
40.52%; H, 4.95%; N, 15.01%. Η ΝΜR (C6D6) δ: 7.06−7.29 (m,
10H, HaromCPh2), 3.55−3.63 (m, 18H, N−CH2−N), 3.19 (d, J = 8.7
Hz, 18H, P-CH2). 31P NMR (C6D6) δ: −82.0 (t, J = 10.0 Hz), −94.9
(d, J = 10.0 Hz); in (CDCl3) δ: −81.2 (t, J = 10.0 Hz), −94.2 (d, J =
10.0 Hz); in (D2O) δ: −77.4 (t, J = 10.0 Hz), −91.6 (d, J = 7.5 Hz).
IR (KBr): 1598 (w), 1462 (s), 1315 (w), 1281 (w), 1242 (w), 1040
(w), 1015 (m), 972 (m), 947 (m) cm−1.MALDI-MS m/z: 909.20 [M
+ H+].
Synthesis of [Re(NCPh2)Br2(PTA)3]·1.6EtOH (5·1.6EtOH). To
[ReOBr2(PTA)3] (0.50 g, 0.60 mmol) and dpgH2 (0.27 g, 1.20
mmol) was added dry ethanol (20 mL). After the mixture was
refluxed for 4 h, the solution was filtered, and on prolonged standing
(2 to 3 days) at ambient temperature, green crystals of 5 formed.
Yield: 0.35 g (58%). Elemental anal. calcd for C31H46Br2N10P3Re·
0.5EtOH (sample dried in-vacuum, −1.1EtOH): C, 37.64%; H,
4.80%; N, 13.72%. Found: C, 37.83%; H, 5.18%; N, 13.26%. 1Η ΝΜR
(DMSO−D6) δ: 7.53 (t, J = 7.8 Hz, 6H, HaromCPh2), 6.94−7.11 (m,
B
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Scheme 2. Complexes 1−7 Prepared Herein
4H, HaromCPh2), 3.91−4.39 (m, 18H, N−CH2−N), 3.73 (d, J = 9.6
Hz, 18H, P-CH2). 31P NMR (DMSO−D6) δ: −87.5 (t, J = 10.0 Hz),
−103.6 (d, J = 10.0 Hz); in (CDCl3) δ: −89.4 (t, J = 10.0 Hz),
−103.3 (d, J = 10.0 Hz); in (D2O) δ: −70.8(m), −82.2 (d, J = 5 Hz).
IR (KBr): 1459 (s), 1376 (s), 1281 (m), 1277 (m), 1239 (m), 1094
(s), 1040 (m), 1011 (s), 969 (s), 945 (s) cm−1. MALDI-MS m/z:
840.68 [M − PTA].
Synthesis of [ReO(benz)2(PTA)][PTAH]·EtOH (6·EtOH). To [ReO-
(OEt)I2(PTA)2] (0.61 g, 0.74 mmol) and benzilic acid (0.34 g, 1.48
mmol) was added dry ethanol (20 mL). After the mixture was
refluxed for 4 h, the solution was allowed to cool to room
temperature, whereupon purple crystals of 6·EtOH formed. Yield:
0.50 g (68%). Elemental anal. calcd for C82H96N12O15P4Re2: C,
49.47%; H, 4.87%; N, 8.47%. Found: C, 49.35%; H, 4.60%; N, 8.65%.
1Η ΝΜR (C6D6) δ: 7.24−7.96 (m, 20H, HaromCPh4), 3.22−3.29 (m,
12H, N−CH2−N), 2.91 (d, J = 7.8 Hz, 12H, P-CH2). 31P NMR
(C6D6) δ: −90.4 (s), −94.5 (s); in (D2O) δ: −88.5 (s), −91.6 (s). IR
(KBr): 1656 (s), 1631 (s), 1025 (s), 1011 (m), 981 (w), 969 (s), 945
(s), 923 (w) cm−1. MALDI-MS m/z: 971.24 [M + H+].
under reflux for 15 min. The obtained olive-green solid was filtered off
and washed with ethanol (25 mL) and diethyl ether (25 mL), with no
further drying. This compound was then added to the solvent mixture
(1:25) (water/acetone), which was stirred in an ice bath for 30 min. A
violet compound [ReO2I(PPh3)2] precipitated which was then filtered
off and dried in vacuum. 1,3,5-Triaza-7-phosphaadamantane (2.17 g,
13.8 mmol) was dissolved in a minimum volume of dichloromethane,
and the solution was then mixed (at room temperature) with the
preprepared [ReO2I(PPh3)2] (2.00 g, 2.30 mmol) dissolved in
dichloromethane (30 mL); the color changed from dark brown to
pale brown. The reaction mixture was stirred for 40−50 min,
following which the volume of the solution was reduced in under
vacuum to remove any volatiles. Ethanol (5 mL) was then added, and
after 5 min, the remaining solvent was removed using a rotary
evaporator. The obtained product was then washed with ethanol to
give a yellow-orange solid [ReO2I(PTA)3]. Finally, [ReO2I(PTA)3]
(2.00 g, 2.44 mmol) and dpgH2 (1.11 g, 4.88 mmol) were mixed in
ethanol (20 mL). The reaction was then stirred at 100 °C under reflux
for 90 min to produce a green solution. This green solution was
filtered, and the solvent was then removed via rotary evaporation to
produce a fine green solid of complex 7. Yield: 1.80 g (62%). Green
crystals suitable for X-ray analysis were obtained by recrystallization of
the product [Re(NCPh2)(dpg)I(PTA)3] (7) in benzene. Elemental
Synthesis of [Re(NCPh2)(dpg)I(PTA)3]·2C6D6 (7·2C6D6). Ammo-
nium perrhenate (1.09 g, 4.10 mmol) and triphenylphosphine (5.00 g,
19.0 mmol) were stirred in ethanol (30 mL). Hydroiodic acid (56%, 5
mL) was then added carefully, and the brown mixture was heated
C
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D
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anal. calcd for C45H58I1N11P3Re: C, 45.34%; H, 4.86%; N, 12.93%.
Found: C, 45.12%; H, 5.12%; N 12.72%. 1Η ΝΜR (C6D6) δ: 7.64 (d,
J = 8.3 Hz, 4H, HaromCPh2), 6.82−7.34 (m, 6H, HaromCPh2), 3.55−
4.34 (m, 32H, CH2(PTA)), 3.17−3.40 (m, 2 H, NH2). 31P NMR
(C6D6) δ: −4.7 (s), −102.3 (s); in (CDCl3) δ: −4.8 (s), −98.2 (s); in
(D2O) δ: −2.2 (s), −95.3 (s). IR (KBr): 3409 (w), 1633 (m), 1035
(w), 1012 (s), 968 (m), 945 (m) cm−1. MALDI-MS m/z: 1191.80
[M]+, 1175.85 [M+ − NH2].
removed from the wells and 100 μL of the compound in the media
was added. Various concentrations of compounds in the range of 6.25
mM to 6.25 nM were tested. After 24 h of incubation, the contents of
the wells were removed using a multipipette, and then 180 μL of
sterilized PBS was added followed by the addition of 20 μL of MTS
reagent (Promega, U.K.). Plates were then returned to the incubator
for 4 h. Color intensity (absorbance) of the treated wells was
measured at 490 nm using a Synergy HT microplate reader. The
percentages of the cell viability of the treated cells were calculated
based on positive and negative control where they represent 100%
and 0% viable cells, respectively. IC50 values were calculated using
GraphPad Prism software.
Synthesis of [99mTc][Tc(NCPh2)I2(PTA)3]. [99mTc]TcO4− was eluted
in saline from an Ultra Technekow FM 99Mo/99mTc generator
(Curium, U.K.), and 100 μL (∼200 MBq, in saline) was added to a 2
mL glass vial containing a mixture of 900 μL of dimethylformamide
(DMF), triphenylphosphine (66.5 mg, 0.255 mmol), and hydroiodic
acid (66.5 μL, 0.883 mmol). The vial was heated at 137 °C for 30
min. After the vial was allowed to cool, a solution of 1,3,5-triaza-7-
phosphaadmantane (3.7 mg, 0.0235 mmol) in DMF (100 μL) was
added to the reaction mixture, and the mixture was stirred for 40 min
at 99 °C. Finally, a solution of 2,2′-diphenylglycine (0.17 mg, 0.00074
mmol) in DMF (10 μL) was added to the reaction mixture, and the
mixture was stirred at 137 °C for 2 h. Quality control analysis was
carried out by HPLC or radio-TLC. Radio-TLC experiments were
carried out on aluminum-backed silica TLC plates with saline as the
mobile phase. Detection was performed using a Scan-RAM Radio
RESULTS AND DISCUSSION
■
Use of 2,2′-Diphenylglycine. A convenient entry point
into much rhenium(V) oxo chemistry is the readily available
[ReOCl3(PPh3)2].38 Reaction of this complex with two
equivalents of dpgH2 in refluxing ethanol afforded, following
workup, the green complex [ReO(dpgH)(dpg)(PPh3)] (1) in
moderate-to-good yield (≤74%). The IR spectrum contained a
strong band at 955 cm−1 assigned to νRe=O along with strong
Re−P stretches at 1092 cm−1 and νN−H at 3303 cm−1. The 31
P
−
TLC detector. [99mTc]TcO4 RF = 0.967; [99mTc] [TcO2I(PPh3)2]
NMR spectrum displayed a singlet at δ 5.3 ppm for the PPh3
ligand. Single crystals suitable for an X-ray crystal structure
determination were grown by diffusing diethyl ether into a
saturated dichloromethane solution at ambient temperature.
The crystal structure of 1 is rather complex because there are
four chemically equivalent, but symmetry-independent mole-
cules in the asymmetric unit. Each of these four molecules
features the same binding of the ligands, but these molecules
have phenyl rings in different orientations which renders them
symmetry independent. Rather than describe the four related
molecules in words, the geometry about the metal for one of
these is reported and displayed in Figure 1 (the full asymmetric
RF = 0.04; and [99mTc][TcOI2(PTA)3] RF = 0.087.
HPLC Conditions. HPLC analysis was performed on an Agilent
1100 Series system equipped with a diode array UV (detection at 254
nm) and LabLogic NaI crystal gamma detectors controlled by Laura
software.
The analytical HPLC was performed on a Gemini 5 μm C18 110 Å
LC column (150 × 4.6 mm, Phenomenex) at a flow rate of 1 mL
min−1, with a mobile phase consisting of methanol with 0.1% TFA
(solvent A) and water with 0.1% TFA (solvent B). Gradient 1 [time/
min](solvent A/solvent B): [0−2](50:50), [2−17](95:5), [17−22]
(95:5), [22−26](50:50). The HPLC sample was prepared by taking
10 μL of sample dissolved in 90 μL of methanol. Semipreparative
HPLC was carried out on a Luna 5 μm C18(2) 100 Å LC column
(250 × 10 mm; Phenomenex) and a Pursuit 200 Å C18 10 × 250
mm, 10 μm, HPLC column (Agilent) at a flow rate of 5 mL min−1,
with a mobile phase consisting of methanol with 0.1% TFA (solvent
A) and water with 0.1% TFA (solvent B). Semipreparative gradient
[time/min](solvent A/solvent B): [0−2](95:5), [2−22](95:5−
50:50), [0−2](95:5), [2−22](95:5−50:50). Prior to the HPLC
purification, the reaction mixtures were passed through C-18
−
cartridges to trap unreacted [99mTc]TcO4 .
X-ray Crystallography. X-ray diffraction data from single crystals
of 3·0.5EtOH and 6·EtOH were collected at the EPSRC
crystallography service in Southampton, U.K. For the other samples,
full sets of X-ray diffraction intensity data were collected in series of
ω-scans using a Stoe IPDS2 image plate diffractometer operating with
Mo Kα radiation at 150(2) K. A multiscan method was applied for the
absorption corrections of the collected data.35
The structures were solved using dual-space methods within
SHELXT and full-matrix least-squares refinement was carried out
within SHELXL-2018 via the WinGX program interface.36,37 All non-
hydrogen positions were located in the direct and difference Fourier
maps and refined using anisotropic displacement parameters. Crystal
structure data for the compounds reported here are summarized in
Table 1.
Cytotoxicity. MTS assay was used to calculate the percentage of
viable cells in the culture media. This assay depends on the
transformation of a tetrazolium salt into formazan in viable cells by
mitochondrial dehydrogenase enzyme activity. There is a positive
correlation between the amount of formazan and the number of viable
cells in the culture media. HeLa, HCT116, HT-29, and HEK 293 cells
were seeded in 96 flat-bottomed microliter tissue culture plates with
20 000 cells per well in 200 μL media of McCoy’s and Dulbecco’s
Modified Eagle’s Medium (DMEM). In order to attach the cells to
the well base in the microliter plates, the plates were incubated
overnight in a 5% CO2 incubator at 37 °C. After 24 h, the media was
Figure 1. Molecular structure of one metal ion in [ReO(dpgH)-
(dpg)(PPh3)] (1). Selected bond lengths (Å) and angles (deg):
Re(1)−O(1) 1.705(4), Re(1)−O(5) 2.064(4), Re(1)−O(7)
2.025(3), Re(1)−N(1) 2.250(5), Re(1)−N(2) 1.889(5), Re(1)−
P(1) 2.4487(13); O(5)−Re(1)−N(1) 73.85(15), O(1)−Re(1)−
O(7) 104.88(15), N(2)−Re(1)−O(7) 80.47(16), O(5)−Re(1)−
P(1) 88.69(10).
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Figure 2. Molecular structure of [ReO(OEt)I2(PTA)2] (2). Selected bond lengths (Å) and angles (deg): Re(1)−O(1) 1.706(5), Re(1)−O(3)
1.906(5), Re(1)−I(1) 2.8117(5), Re(1)−I(2) 2.7450(5), Re(1)−P(1) 2.4673(17), Re(1)−P(2) 2.4523(17); O(1)−Re(1)−O(3) 172.6(2),
P(2)−Re(1)−P(1) 176.27(6), O(1)−Re(1)−I(2) 95.59(16), C(31)−O(3)−Re(1) 146.9(4), O(3)−C(31)−C(32) 111.9(6). Re(2)−O(2)
1.705(5), Re(2)−O(4) 1.906(5), Re(2)−I(3) 2.7519(5), Re(2)−I(4) 2.8080(5), Re(2)−P(3) 2.4555(17), Re(2)−P(4) 2.4631(17); O(2)−
Re(2)−O(4) 174.3(2), P(3)−Re(2)−P(4) 176.24(6), O(2)−Re(2)−I(3) 94.42(15), C(33)−O(4)−Re(2) 152.0(4), O(4)−C(33)−C(34)
111.2(5).
unit and full details of bond lengths about each metal center
are in the SI.) The metal ion adopts a distorted octahedral
geometry where the main distortion occurs as a result of
binding through COO− and NH− of the two diphenylglycine-
derived ligands. One of these (dpgH) is only deprotonated at
the acid, but is bound through the NH2 (Re(1)−N(1)
2.250(5) Å). The second is twice-deprotonated, i.e., dpg, once
at the carboxylic acid and once at the amine, and it binds
through COO− and NH−. Accordingly, the two Re−N bond
lengths are very different (Re(1)−N(2) 1.889(5) Å).
It proved possible to obtain 1 by use of a similar reaction but
employing [ReO2I(PPh3)2] as the rhenium source.
With a view to conducting biological assays, we decided to
employ the water soluble phosphine 1,2,3-triaza-7-phosphaa-
damantane (PTA). Treatment of [ReO(OEt)I2(PPh3)2] with
three equivalents of PTA in dichloromethane/ethanol
afforded, after workup, the complex [ReO(OEt)I2(PTA)2]
(2) in high yield. The IR spectrum was dominated by the
signals of νRe=O at 945 and 902 cm−1 for ν(O−CH2). Also, the IR
spectrum contained strong bands of coordinated PTA ligand at
969 and 1013 cm−1. The 1H NMR spectrum exhibited
methylene protons for PTA between 4.03 and 4.74 ppm, while
there were no signals displayed for the aromatic groups related
to a PPh3 ligand. The 31P NMR spectrum showed a singlet at
−4.8 ppm, suggesting the presence of two equivalent PTA
ligands.
adopts a distorted octahedral geometry with one bulky PTA
ligand trans to the one other PTA. An ethoxide ligand is
positioned trans to the oxo group.
The two independent complexes in the asymmetric unit are
related by pseudo-translational symmetry. Upon warming of
the crystal, the structure simplifies and the pseudo-translation
becomes a strict symmetry element. The structure at 298 K
crystallizes in the space group C2/c with a single Re complex in
the asymmetric unit (Z = 4) (Figure S3). There is small-scale
disorder of the position of the ethoxide alkyl chain in this
structure, which suggests that the presence of two independent
complexes at low temperature is a result of ordering of the
alkyl chains.
The reaction of [ReOI2(PTA)3] with two equivalents of
dpgH2 in ethanol afforded, after workup, the complex
[Re(NCPh2)(PTA)3I2]0.5EtOH (3·0.5EtOH). The infrared
spectrum of 3 exhibited the signals of PTA ligands at 946, 969,
and 1015 cm−1, together with a weak band for νN=C at 1592
cm−1. Also, in the IR spectrum, symmetric νP−CH2 was found at
1313 cm−1, while νN−CH2 and νN−C−N were observed at 1276
and 1241 cm−1, respectively. The 1H NMR spectrum displayed
signals for methylene protons of PTA between 3.66 and 4.08
ppm as well as aromatics between 7.05 and 7.29 ppm. The 31
P
NMR spectrum (C6D6) exhibited (similar shifts were noted in
CDCl3, see the Experimental Section) a triplet and doublet at δ
−104.9 and −120.9 ppm; these shifts (and those of 4 and 5)
are somewhat downfield of those reported for the complex
[ReNCl2(PTA)3] (−78.2 and −74.5 ppm in CDCl3).24 This
data is consistent with the presence of two equivalent and one
other PTA ligands. In order to assess the stability of complex 3,
a sample of 3 was dissolved in D2O and monitored by 31P
NMR spectroscopy. The spectrum showed the peak of one
PTA at −107.3 ppm and two PTA ligands trans to each other
at −123.3 ppm. The two signals look similar to the triplet-
Single crystals suitable for a structure determination were
grown via diffusion of dichloromethane/ethanol at ambient
temperature. Structure determination for the crystal at 150 K
was routine, and this demonstrated that 2 crystallized with two
chemically identical molecules in the asymmetric unit (Z = 2)
in space group P21/n.
The molecular structure is shown in Figure 2, with bond
lengths and angles given in the caption. Each rhenium center
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doublet pattern of 3 in C6D6 (−104.9 and −120.9 ppm).
Complex 3 was isolated as single crystals from EtOH, and the
crystal structure was determined by X-ray diffraction. The
molecular structure is shown in Figure 3 (for an alternative
view see Figure S4), with selected bond lengths and angles
given in the caption. The rhenium center adopts a distorted
octahedral geometry in which the phosphine Re(1)−P(1)
binds trans to the Re(1)−P(3). The distortion occurs as a
result of the bulky nature of all the ligands present.
In accordance with the structure of 3, the Re(1)−P(1) and
Re(1)−P(3) bonds found in the trans positions each display
longer distances of 2.3929(12) and 2.4004(12) Å. The Re(1)−
I(2) bond lengthening of 2.8652(4) Å can be ascribed to trans
influence exerted by the Re(1)−N(10) that itself has a bond
length of 1.817(4) Å. We have noted the loss of CO2 from
dpgH2 during complexation in previous studies,39,40 while a
search of the CSD for MNCPh2 or MNCHPh2 type motifs
revealed 19 hits.39,41,42
A similar reaction but using [ReOCl2(PTA)3] and
[ReOBr2(PTA)3] also resulted after workup in the isolation
of a green complex of formula [Re(NCPh2)(PTA)3Cl2]·
2EtOH (4·2EtOH) and [Re(NCPh2)(PTA)3Br2]·1.6EtOH
(5·1.6EtOH), respectively. However, a single-crystal X-ray
diffraction study revealed that although the geometry at the
metal is essentially the same as in 3, there are different
amounts of solvent present. The molecular structures for
complexes 4·2EtOH and 5·1.6EtOH are shown in Figure 4
(for alternative views see Figures S5 and S6), with selected
bond lengths and angles given in the caption.
Use of Benzilic Acid. The reaction of [ReO(OEt)-
I2(PTA)2] (2) with two equivalents of benzilic acid in ethanol
afforded, after workup, the complex [ReO(benz)2(PTA)]-
[PTAH]·EtOH (6·EtOH). The infrared spectrum of 6
exhibited bands for the PTA ligand at 1025 cm−1, together
Figure 3. Molecular structure of 3·0.5EtOH (unbound ethanol not
shown). Selected bond lengths (Å) and angles (deg): Re(1)−I(1)
2.7939(4), Re(1)−I(2) 2.8652(4), Re(1)−P(1) 2.3929(12), Re(1)−
P(2) 2.3911(11), Re(1)−P(3) 2.4004(12), N(10)−Re(1) 1.817(4),
N(10)−C(19) 1.279(6); I(1)−Re(1)−I(2) 82.391(11), P(2)−
Re(1)−P(1) 94.14(4), Re(1)−N(10)−C(19) 179.3(3).
1
with νRe=O stretching at 945 cm−1. The H NMR spectrum
displayed signals for the methylene protons of PTA between
2.91 and 3.29 ppm as well as aromatics between 7.24 and 7.96
ppm. The 31P NMR spectrum showed two singlet peaks for
two PTA ligands at −90.4 and −94.5 ppm. The stability of 6
was examined in D2O via 31P NMR spectroscopy, which
Figure 4. Molecular structures of 4·2EtOH and 5·1.6EtOH. Selected bond lengths (Å) and angles (deg): For 4·2EtOH: Re(1)−Cl(1) 2.4517(7),
Re(1)−Cl(2) 2.4608(8), Re(1)−P(1) 2.4095(8), Re(1)−P(2) 2.4009(7), Re(1)−P(3) 2.4310(8), Re(1)−N(10) 1.804(2), N(10)−C(19)
1.300(3); Cl(1)−Re(1)−Cl(2) 85.79(3), P(2)−Re(1)−P(1) 92.46(3), Re(1)−N(10)−C(19) 177.5(2). For 5: Re(1)−Br(1) 2.5960(9), Re(1)−
Br(2) 2.6499(9), Re(1)−P(1) 2.3875(19), Re(1)−P(2) 2.387(2), Re(1)−P(3) 2.3923(19), Re(1)−N(10) 1.801(6), N(10)−C(19) 1.307(9);
Br(1)−Re(1)−Br(2) 82.88(3), P(2)−Re(1)−P(1) 95.69(7), Re(1)−N(10)−C(19) 177.4(5).
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revealed two singlets at −88.5 and −91.6 ppm, similar to the
signals observed for complex 6 in C6D6 albeit with slightly
downfield shifts. The complex is completely soluble in benzene
and less soluble in water. For example, in 5 mL of D2O, when
100 mg of 6 was dissolved, after filtration, the remaining
undissolved solid weighed 40 mg, i.e., 60 wt % uptake.
Scheme 3. One-Pot 4 h Preparation of 3 and 7 from
Perrhenate
Complex 6 was isolated as single crystals from EtOH and
examined by X-ray diffraction. The molecular structure is
shown in Figure 5 (for an alternative view see Figure S7), with
The IR spectrum of 7 exhibited signals associated with PTA
ligands in the range of 1012 and 1035 cm−1, together with
1
νRe−O stretching at 945 cm−1 and νNH2 at 3409 cm−1. The H
NMR spectrum displayed signals for the methylene protons of
PTA between 3.55 and 4.34 ppm as well as aromatics between
6.82 and 7.64 ppm. Complex 7 was isolated as single crystals
from benzene-d6 and was examined by X-ray diffraction. The
molecular structure is shown in Figure 6 (for an alternative
view see Figure S8), with selected bond lengths and angles
given in the caption. The rhenium center adopts a distorted
octahedral geometry in which the phosphine Re(1)−P(1)
binds trans to the Re(1)−P(3). One of the dpg ligands has lost
CO2 and binds to the rhenium via the nitrogen atom, in a
similar fashion to that observed in 3. The second
diphenylglycine-derived ligand is deprotonated at the carbox-
ylic acid and binds in a monodentate fashion through a single
oxygen atom of the carboxylate. Similar to the structure 3, the
Re(1)−P(1) and Re(1)−P(3) bond in a trans fashion and
display long distances at 2.3932(18) and 2.4017(18) Å,
respectively. The Re(1)−I(1) bond lengthening of 2.8101(5)
Å can be ascribed to the trans influence exerted by Re(1)−
P(2) that itself has a bond length 2.3980(16) Å. The Re(1)−
O(1) bond lengthening of 2.158(5) Å can also be ascribed to
the trans influence exerted by Re(1)−N(10) which has a bond
length of 1.801(5) Å.
Figure 5. Molecular structure of 6·EtOH. The dashed line indicates a
hydrogen bond. Selected bond lengths (Å) and angles (deg): Re(1)−
O(1) 2.0697(14), Re(1)−O(3) 1.9624(14), Re(1)−O(4)
2.1238(14), Re(1)−O(6) 1.9677(14), Re(1)−O(7) 1.7009(15),
Re(1)−P(1) 2.3904(5); O(7)-Re(1)-O(1) 97.28(6), O(3)-Re(1)-
O(1) 81.02(6), O(6)-Re(1)-O(4) 75.49(6), O(7)-Re(1)-P(1)
89.32(5).
selected bond lengths and angles given in the caption. The
rhenium center adopts a distorted octahedral geometry in
which the phosphine (Re(1)−P(1) = 2.3904 (5) Å) binds
trans to the oxygen of an acid group. The main distortion
occurs as a result of the chelate binding of the two
deprotonated benzilic acid derived ligands. A protonated
PTA forms a hydrogen bond with one of the CO benzilic
groups. The ReO bond distance at 1.7009(15) Å is typical.43
The Re(1)−O(1) bond lengthening of 2.1238(14) Å can be
ascribed to the trans influence exerted by the Re(1)−P(1).
Potential to Form a Technetium-99m Analogue
Compound. In order that the systems herein could be
investigated and developed as radiopharmaceuticals, it is
necessary (given the 6 h half-life of 99mTc, used for SPECT
imaging) that the product preparation can be conducted from
perrhenate in about 4 h. We have chosen perrhenate as the
starting material, given the usual source of 99mTc generated
from clinical grade generators in hospital radiopharmacies is
pertechnetate.5 With this in mind, the product [Re(NCPh)-
(dpg)I(PTA)3] (7) was obtained in 4 h by preparing
[ReO2I(PPh3)2] (from (NH4)[ReO4]) and then exchanging
the PPh3 ligands with PTA to afford ReO2I(PTA)3; then, the
ReO2I(PTA)3 was reacted with two equivalents of dpgH2 in
ethanol to afford, after workup, a mixture comprising 85% of
complex 7 and 15% of complex 3 (as evidenced by NMR
spectroscopy), see Scheme 3.
The geometrical parameters associated with the MNCPh2
motif for 3, 4, 5, and 7 are compared in Figure S9. This motif
has been called azavinylidene or alkyleneamide,41 and it is clear
there is double bond character associated with the R−N bond.
Given the linearity observed here for the Re−N−C angles
(>177°), we favor the description put forward by Pombeiro et
al.,41 whereby thus linkage acts as a three electron donor, i.e.,
as
Re 3 N = CPh2
̅
This then, in terms of electron counting, gives an 18 electron
count for the complexes 3, 4, 5, and 7.
Cell Viability Studies. The complexes 3, 4, 5, 6, and 7
were tested for cytotoxicity against cancerous cell lines (HeLa,
HCT116, and HT-29) to show that they are nontoxic at
concentrations used for imaging. The IC50 values were
determined using the cell viability assay, MTS. All compounds
in this study are nontoxic in the concentration range used in
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trend of I > Br > Cl, which correlates to the size of the halogen
and a more labile atom under aqueous environment. The bond
distance between the Re metal and the halogen increases with
toxicity from 2.86 Å (Re−I), 2.64 Å (Re−Br), and 2.46 Å
(Re−Cl), suggesting that the mechanism of action is direct
binding of a protein or DNA to the metal center, in a similar
manner to that of cisplatin. The IC50 values observed here are
slightly higher than that of cisplatin for the cancer cell lines
(Table 2).44,45 The addition of the two benzilic acid or
diphenylglycine ligands in 6 and 7 with regards to HeLa cells
must allow for access to mechanism of resistance in this cell
line. Although the mechanism of action has not been explored,
it is clear that the change in structure of either amino acid
ligands or halogen has an effect on the IC50 value. To check the
biostability of compound 3 and 7, a 10 μL sample of
compound (6.25 mM) was diluted in 100 μL of biological
media (DEME) and monitored by 31P NMR spectroscopy
over a period of 5 days; the spectral form does not change
across the study (Figures S32−S35). This suggests that the
coordination of the water-soluble phosphine ligand (PTA)
remains on the metal center and that these are not removed as
part of the mechanism of action within the cells. This also
suggest that the complexes have a good stability under
biological conditions.
Synthesis of Novel Technetium-99m Phosphadaman-
tane Precursor. An attempt was made to translate these
protocols to produce technetium-99m analogues of the
rhenium complexes. Multistep protocols, such as this, are
challenging to translate to radiochemistry where the amounts
of the metal ion isotope precursor are limited and the
concentrations are low (due to accessible amounts of the
radioisotope and radiation protection issues). After several
attempts and development of an optimized protocol to
produce [99mTc][TcO2I(PPh3)2] and, subsequently, [99mTc]-
[TcOI2(PTA)3] from the commercial radioisotope generator
supplying [99mTc]pertechnetate, the reaction with diphenyl-
glycine was attempted. Despite the use of various different
conditions (including varying temperature, dpgH2 concen-
tration, and time of reaction), the target compound [99mTc]-
[Tc(NCPh2)I2(PTA)3] could not be accessed. Further method
development is required to produce the technetium analogues
from these precursors in an applicable time scale for
radiopharmaceutical synthesis.
Figure 6. Molecular structure of 7·2C6D6. Benzene molecules within
the crystal structure are not shown. Selected bond lengths (Å) and
angles (deg): Re(1)−O(1) 2.158(5), Re(1)−N(10) 1.801(5),
Re(1)−P(1) 2.3932(18), Re(1)−P(2) 2.3980(16), Re(1)−P(3)
2.4017(18), Re(1)−I(1) 2.8101(5), N(10)−C(19) 1.305(8);
Re(1)−N(10)−C(19) 177.8(5), N(10)−Re(1)−O(1) 173.3(2),
N(10)−Re(1)−P(1) 89.17(16), O(1)−Re(1)−P(1) 84.32(15),
N(10)−Re(1)−P(2) 96.65(16).
SPECT medical imaging (nM−pM) with IC50 values in the
range of 29.87−1858 μM. MTS graphs for treatment of HeLa,
HCT116, HT-29, and HEK 293 cells with compounds 3, 4, 5,
6, and 7 are shown in the Supporting Information, Figures
S10−S31. Table 2 summarizes the IC50 values of the
complexes synthesized.
The analogues compounds 3, 4, and 5 show enhanced
toxicity in HeLa cells in comparison to that of compounds 6
and 7, although in colon cancer cell lines (HCT116 and HT-
29) compounds 6 and 7 show the higher toxicity (Table 2).
When compounds 3, 6, and 7 were studied in a noncancerous
cell line, there was a dramatic decrease in toxicity to the high
micro−millimolar (μM−mM) range, suggesting a preference
for antitumor toxicity. The most potent compounds in colon
cancer cell lines (3, 6, and 7) appear to be derived from the
iodo starting materials. When looking close at the change of
halogen with respect to IC50 values, we observed the following
CONCLUSION
■
In conclusion, we have used the precursors [ReOCl3(PPh3)2]
and [ReO2I(PPh3)2] to access a number of new water-soluble
phosphine complexes of rhenium via reaction with 1,2,3-triaza-
7-phosphaadamantane (PTA) and the acids diphenylglycine or
benzilic acid. Seven complexes have been successfully
synthesized and fully characterized, and in a number of cases
Table 2. IC50 (μM) Values of Re Complexes Synthesized Herein and of Cisplatin44−46
complex
HeLa IC50 (μM)
HCT116 IC50 (μM)
HT-29 IC50 (μM)
HEK 293 IC50 (μM)
3
4
5
6
47.17 1.207
86.62 1.032
71.72 1.415
123.60 0.6227
140.10 1.045
5.45 0.4444
40.69 2.584
84.47 1.876
37.12 2.358
29.87 2.312
42.92 2.117
8.2 0.1445
49.57 5.833
88.22 2.491
72.04 1.745
37.29 1.699
34.38 3.073
2.7 0.8645
574.7 0.836
−
−
662.1 1.062
1858 1.377
109 1246
7
cisplatin
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(e.g., 3 and 7), the acid-derived ligand has lost CO2 during
complexation.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.inorgchem.9b03239
Complexes 3, 4, 5, 6, and 7 have been screened for their
antiproliferative activity against various cancer cell lines in
order to show a nontoxic behavior at injected doses for SPECT
medical imaging. Preliminary studies to form a technetium-
99m analogue show that the [99mTc][TcOI2(PTA)3] complex
was successfully synthesized; however, the final dpgH2 complex
with 99mTc remains elusive, under the reaction conditions
attempted in this study. Further development of routes to the
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Saudi Cultural Bureau for its sponsorship (of
A.F.A.). C.R. thanks the Whitelaw Frater Cancer Trust for
funding. The EPSRC Mass Spectrometry Service Center at
Swansea University and the EPSRC National Crystallographic
Service at Southampton are thanked for data collection.
[
99mTc][TcdpgH2] complexes is required to allow future
potential applications in SPECT imaging to be explored. It is a
significant advance to have synthesized these novel compounds
with the rhenium analogues in a procedure that can be carried
out on an appropriate time scale for transfer to radio-
pharmaceutical production.
REFERENCES
■
(1) (a) Johannsen, B.; Spies, H. Technetium (V) chemistry as
relevant to nuclear medicine. In Technetium and Rhenium Their
Chemistry and Its Applications. Top. Curr. Chem. 1996, 176, 77−121.
(b) Volkert, W. A.; Jurisson, S. Technetium-99m chelates as
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(2) Abram, U.; Alberto, R. Technetium and rhenium: coordination
chemistry and nuclear medical applications. J. Braz. Chem. Soc. 2006,
17, 1486−1500.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.inorgchem.9b03239.
■
sı
Crystallography information, including alternative views
of 1−7; cell viability studies, including MTS graphs for
complexes against HeLa cells and 31P NMR spectra of
the complexes; and information on the hot studies,
including experimental preparation and characterization
analyses (PDF)
(3) Coogan, M. P.; Doyle, R. P.; Valliant, J. F.; Babich, J. W.;
Zubieta, J. Single amino acid chelate complexes of the M(CO)3+2 core
for correlating fluorescence and radioimaging studies (M= 99mTc or
Re). J. Labelled Compd. Radiopharm. 2014, 57, 255−261.
(4) Jurisson, S.; Berning, D.; Jia, W.; Ma, D. Coordination
compounds in nuclear medicine. Chem. Rev. 1993, 93, 1137−1156.
(5) Bartholoma, M. D.; Louie, A. S.; Valliant, J. F.; Zubieta, J.
Technetium and gallium derived radiopharmaceuticals: comparing
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molecular imaging era. Chem. Rev. 2010, 110, 2903−2920.
Accession Codes
CCDC 1556454, 1583688, and 1894781−1894787 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
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uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
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AUTHOR INFORMATION
Corresponding Authors
■
̈
Graeme Stasiuk − Department of Biomedical Sciences,
University of Hull, Hull HU6 7RX, U.K.; orcid.org/0000-
0002-0076-2246; Email: g.stasiuk@hull.ac.uk
Carl Redshaw − Department of Chemistry & Biochemistry,
University of Hull, Hull HU6 7RX, U.K.; orcid.org/0000-
0002-2090-1688; Email: C.Redshaw@hull.ac.uk
Authors
Abdullah F. Alshamrani − Department of Chemistry &
Biochemistry and Department of Biomedical Sciences, University
of Hull, Hull HU6 7RX, U.K.
Timothy J. Prior − Department of Chemistry & Biochemistry,
University of Hull, Hull HU6 7RX, U.K.; orcid.org/0000-
0002-7705-2701
Benjamin P. Burke − Positron Emission Tomography Research
Centre, University of Hull, Hull HU6 7RX, U.K.
David P. Roberts − Positron Emission Tomography Research
Centre, University of Hull, Hull HU6 7RX, U.K.
Stephen J. Archibald − Department of Biomedical Sciences and
Positron Emission Tomography Research Centre, University of
Hull, Hull HU6 7RX, U.K.; orcid.org/0000-0001-7581-
8817
Lee J. Higham − School of Natural & Environmental Sciences,
Newcastle University, Newcastle upon Tyne NE1 7RU, U.K.
J
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