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Inorganica Chimica Acta 363 (2010) 1140–1149
Contents lists available at ScienceDirect
Inorganica Chimica Acta
journal homepage: www.elsevier .com/locate / ica
Synthesis and structural studies of gallium(III) and indium(III) complexesof 2-acetylpyridine thiosemicarbazones
Jessica Chan, Amber L. Thompson *, Michael W. Jones *, Josephine M. PeachInorganic Chemistry Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom
a r t i c l e i n f o
Article history:Received 1 June 2009Received in revised form 30 September 2009Accepted 24 October 2009Available online 30 October 2009
Dedicated to Prof. Jonathan R. Dilworth.
Keywords:Gallium complexesIndium complexesThiosemicarbazonesCrystal structuresFluorescence
0020-1693/$ - see front matter � 2009 Elsevier B.V. Adoi:10.1016/j.ica.2009.10.020
* Corresponding authors.E-mail addresses: [email protected]
[email protected] (M.W. Jones).
a b s t r a c t
Four 2-acetylpyridine 4N-alkyl thiosemicarbazones, and their Ga(III) and In(III) complexes have been pre-pared and characterised by fluorescence, UV–Vis, IR, 1H and 13C NMR spectroscopy, mass spectrometryand X-ray crystallographic analysis. Comparison of the crystal structures gave an insight into the natureof the complexes formed, demonstrating a preference for [ML2]+ type complexes with gallium and [MLX3]species with indium. Stability studies on two candidates indicated that complex [InL3Cl2MeOH] was sta-ble to chemical degradation for prolonged periods in human serum, giving this complex potential for fur-ther biological evaluation.
� 2009 Elsevier B.V. All rights reserved.
1. Introduction for their anti-tumour activity. The pharmacological activity of
Thiosemicarbazones and their metal complexes have receivedconsiderable attention owing to their potent biological activity asantifungals [1–7], anti-virals [8] anti-malarials [9–11], and mostnotably, as anti-tumour agents [12–15]. The anti-tumour featurehas prompted the synthesis and study of numerous metal com-plexes [5,16–38], and thorough investigations of the mechanismof action, which may be as a ribonucleotide reductase inhibitor[39–43], or a topoisomerase II inhibitor [25,44,45]. We have beeninterested in the study of metal chelating ligands, for the complex-ation and distribution of radio-isotopes principally for PET andSPECT medical imaging [46–52].
While copper-64 has been of major focus due to its long half life(t1/2 = 12.7 h), the paramagnetic nature of copper(II) removes thepotential for dual fluorescence-PET in vivo imaging when com-plexed by all but the most fluorescent of ligands [53–57]. In con-trast, gallium and indium are of particular interest as bothmetals are diamagnetic and do not suffer from the excited staterelaxation through internal conversion present in copper(II) com-plexes. Judicious choice of radionuclide also allows gallium to beused as a PET or SPECT agent depending on the radio-isotope used.Several other groups, notably those of Keppler, Jalilian andBernhardt [58–63], have investigated the gallium(III) complexes,of 2-acetylpyridine N-alkyl thiosemicarbazones amongst others,
ll rights reserved.
k (A.L. Thompson), michael.
these complexes has been probed and a gallium(III) bis(2-acetyl-pyridine 4N-dimethyl thiosemicarbazonato) complex has beenfound to have potent cytotoxicity against three human cancercell-lines during in vitro tests with cytotoxicity, as measured byIC50, in the nano-molar range [58]. This complex was also foundto be strongly anti-proliferative, and several orders of magnitudemore cytotoxic than the analogous iron(III) compounds.
A further in-depth study by the same group also found that gal-lium greatly enhances the already potent activity of the thiosemi-carbazone ligands [62]. Indium-111 is additionally an Augerelectron emitter, potentially enabling its complexes to be dualimaging-therapeutic agents. Only a small number of brief reportsof indium(III) thiosemicarbazonato complexes have been reportedto date [16,64–66], with the most extensive by Abrams and co-workers who studied the gallium(III) and indium(III) complexes offour 2-acetylpyridine 4N-alkyl thiosemicarbazone derivatives [16].
Herein we present a systematic study of the indium and galliumcomplexes of four ligands together with the identification of twocompounds for biological evaluation and the results of associatedserum stability studies.
2. Experimental
2.1. Methods and equipment
All reactions involving moisture-sensitive reagents were carriedout under a nitrogen atmosphere using standard vacuum line
J. Chan et al. / Inorganica Chimica Acta 363 (2010) 1140–1149 1141
techniques and glassware that was flame dried and cooled undernitrogen before use. Solvents were dried according to the proce-dure outlined by Grubbs and co-workers [67]. Water was purifiedby an Elix� UV-10 system. All other solvents and reagents wereused as supplied (analytical or HPLC grade) without prior purifica-tion. Melting points were recorded on a Gallenkamp Hot Stageapparatus and are uncorrected. IR spectra were recorded on BrukerTensor 27 FT-IR spectrometer as a KBr disc (KBr). Selected charac-teristic peaks are reported in cm�1. NMR spectra were recorded onBruker Avance spectrometers in the deuterated solvent stated. Thefield was locked by external referencing to the relevant deuteronresonance. Chemical shifts (d) are reported in ppm and couplingconstants (J) in Hz. The thiosemicarbazones were numbered asoutlined in Fig. 1 with the pyridyl protons/carbons identified as‘Ar–H’ and ‘Ar–C’. Where necessary, to achieve distinction betweenpyridyl protons/carbons and other aromatic moieties, pyridyl pro-tons/carbons are defined as ‘Py–H’ and ‘Py–C’ and other moieties as‘Ar–H’ and ‘Ar–C’. Low-resolution mass spectra were recorded oneither a VG MassLab 20-250 or a Micromass Platform 1 spectrom-eter. Accurate mass measurements were run on either a BrukerMicroTOF internally calibrated with polyalanine, or a MicromassGCT instrument fitted with a Scientific Glass Instruments BPX5 col-umn (15 m 0.25 mm) using amyl acetate as a lock mass, by themass spectrometry department of the Chemistry Research Labora-tory, University of Oxford, UK. Ultra-Violet-Visible spectra (UV–Vis) were recorded on a Perkin–Elmer UV/VIS/NIR Lambda 2 Spec-trometer using DMSO as the solvent. Absorption maxima (kabs) ofthe major absorptions are recorded by the wavelength (nm) atwhich absorption took place. Analytical HPLC was performed ona Gilson HPLC system with UV–Vis detector (254 nm) and a re-versed phase Hamilton column. The samples used a 35-min gradi-ent method. The mobile phase solvents were MeCN and H2O.Fluorescence measurements were done on a Hitachi F-4500 Fluo-rescence Spectrophotometer using DMSO as the solvent. Singlecrystal diffraction data were collected using an Enraf-Nonius Kap-paCCD diffractometer (Mo Ka radiation (k = 0.71073 Å) at 150(2) Kwith an Oxford Cryosystems Cryostream N2 open-flow coolingdevice [68] and processed using the DENZO-SMN package [69],including inter-frame scaling (which was carried out usingSCALEPACK within DENZO-SMN). The structures were solved usingSIR92 [70] (1, 1a, 2, 5, 7, 8, 9, 10 and 13) or SHELXS [71] (6 and 110)or SuperFlip [72] (4, 11 and 12). Refinement was carried out usingfull-matrix least-squares within the CRYSTALS suite [73], on eitherF2 or F (11 only). In general, all non-hydrogen atoms were refinedwith anisotropic displacement parameters, however, for 6 the oxy-gen ellipsoids for the nitrate were decidedly prolate suggestingrotation about the axis perpendicular to the NO3 plane. Effortswere made to model the disorder, however, anisotropic refinementwas unstable so the final refinement used isotropic displacement
'5 '4
6'
N1' 2'
3'
S
R1 R2 Yield
L1 H Me 97%
L2 H Et 41%
L3 H Ph 64%
L4 Me Me 87%
N1NH 2
8'
N4
R1
7'
R2
Fig. 1. The ligands 1–4 and the numbering scheme for the 2-acetylpyridine N-alkylthiosemicarbazones.
parameters for the minor component (which refined with an occu-pancy of 8.4(4)%). Hydrogen atoms on nitrogen atoms were gener-ally visible in the difference map. Together with the otherhydrogen atoms, their positions and isotropic displacementparameters were refined using restraints prior to inclusion intothe model with riding constraints. The exception to this was struc-ture 11, for which the N–H hydrogen was not visible in the differ-ence map and was therefore added geometrically, based on thechemistry. The crystals that yielded structure 110 were of particu-larly poor quality and it was only possible to refine the light atomswith isotropic ADPs. Although the results are therefore very poor,data are included here as evidence of the second polymorph forthe benefit of other scientists potentially attempting to repeatthe work. Selected structural details for the new compounds are in-cluded in Table 1.
2.2. Experimental
2.2.1. General procedure for the synthesis of mono-thiosemicarbazonesA solution of the requisite thiosemicarbazide (1 eq), in aqueous
5% AcOH was stirred at 50 �C until a transparent solution wasformed. 2-Acetylpyridine (1 eq, 25% in aqueous 5% AcOH) was thenadded drop-wise to the mixture over 5 min under an atmosphereof nitrogen and the resultant mixture stirred for a further 4 h. Aftercooling to room temperature, the solid was collected by filtrationand washed sequentially with H2O and EtOH to give the desiredproduct.
2.2.1.1. Compound 1: 2-acetylpyridine 4N-methyl thiosemicarbazone;L1. Following the general procedure, 4N-methyl thiosemicarbazide(4.20 g, 40 mmol), 5% aqueous AcOH solution (50 mL) and 2-ace-tylpyridine (4.84 g, 40 mmol) gave L1 as a white solid. Recrystalli-sation of the solid using EtOAc gave an analytical sample of L1 as acolourless crystalline solid (8.06 g, 97%); m.p. 169–170 �C (EtOAc);{lit. [74] m.p. 167–170 �C, EtOH}; mmax (KBr) 3290 (N–H), 3241 (N–H), 1578 (C@N), 1538 (C@S), 1461, 1231, 1037, 780 cm�1; UV–Viskmax 319 nm; Fl kem 369 nm, kex 275 nm; dH (400 MHz, d6-DMSO)2.39 (3H, s, CH3C@N), 3.06 (3H, d, J 4.8 Hz, CH3NH), 7.38–7.41(1H, m, H-50), 7.82 (1H, ddd (app. dt), J 7.9, 7.9, 1.7 Hz, H-40), 8.43(1H, d, J 8.2 Hz, NHN@C, D2O exchangeable), 8.59 (1H, d, J 4.1 Hz,H-30), 8.64 (1H, d, J 4.4 Hz, H-60), 10.36 (1H, br s, NHCH3, D2Oexchangeable); dC (100 MHz, d6-DMSO) 13.0 (CH3C@N), 32.0(NHCH3), 121.6, 124.7, 137.2, 148.7, 149.7 (Ar–C), 155.6 (C@N),180.0 (C @S); m/z (ESI+) 209 ([M+H]+, 100%); HRMS (ESI+)C9H12N4NaS+ ([M+Na]+) requires 231.0678, found: 231.0675; HPLCtr = 9.3 min. Crystal structure was comparable with that reportedpreviously [1] and the crystal structure of the chloride salt (com-pound 1a) was also determined.
2.2.1.2. Compound 2: 2-acetylpyridine 4N-ethyl thiosemicarbazone;L2. Following the general procedure, 4N-ethyl-3-thiosemicarbazide(1.19 g, 10 mmol), 5% aqueous AcOH solution (40 mL) and 2-ace-tylpyridine (1.21 g, 10 mmol) gave L2 as a white solid. Recrystalli-sation from EtOAc gave an analytical sample of L2 as a colourlesscrystalline solid (915 mg, 41% yield); m.p. 142–143 �C (EtOAc);{lit. [2] m.p. 143 �C, EtOH}; mmax (KBr) 3348 (N–H), 2924 (C–H),1580 (C@N), 1532 (C@S), 1468, 1377, 1222, 825 cm�1; UV–Vis kmax
319 nm; Fl kem 352 nm, kex 281 nm; dH (400 MHz, d6-DMSO) 1.17(3H, t, J 7.2 Hz, CH3CH2), 2.39 (3H, s, CH3C@N), 3.64–3.66 (2H, m,CH2CH3), 7.40–7.43 (1H, m, H-50), 7.83 (1H, ddd, J 8.0, 8.0, 1.9 Hz,H-40), 8.41 (1H, d, J 8.0 Hz, H-30), 8.59 (1H, d, J 4.8 Hz, H-60), 8.70(1H, t, J 5.5 Hz, NHCH2, D2O exchangeable), 10.27 (1H, s, NHN@C,D2O exchangeable); dC (100 MHz, d6-DMSO) 13.0 (CH3C@N), 15.3(CH2CH3), 39.4 (CH2CH3), 121.7, 124.8, 137.2, 148.8, 149.3 (Ar–C),155.6 (C@N), 178.5 (C @S); m/z (ESI+) 223 ([M+H]+, 100%); HRMS(ESI+) C10H14N4NaS+ ([M+Na]+) requires 245.0835, found:
Tabl
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Crys
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32G
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C 18H
22C
l 4In
2N
8S 2
C1
0H
14C
l 3In
N4S
C 10H
14C
l 3In
N4S
C 15H
17C
l 2In
N4O
SC
11H
17C
l 2In
N4O
SM
olec
ula
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eigh
t24
4.75
546.
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4.34
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6.01
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3.49
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1142 J. Chan et al. / Inorganica Chimica Acta 363 (2010) 1140–1149
245.0831; HPLC tr = 9.4 min. Crystal structure was comparablewith that reported previously [75].
2.2.1.3. Compound 3: 2-acetylpyridine 4N-phenyl thiosemicarbazone;L3. Following the general procedure, 4N-phenyl-thiosemicarbazide(334 mg, 2 mmol), 5% aqueous AcOH solution (20 mL) and 2-ace-tylpyridine (242 mg, 2 mmol) gave L3 as a pale yellow solid.Recrystallisation of the yellow solid using EtOAc gave an analyticalsample of L3 as a crystalline yellow solid (348 mg, 64%); m.p. 178–179 �C (EtOAc); {lit. [76] m.p. 178–180 �C}; mmax (KBr) 3300 (N–H),3241 (N–H), 1580 (C@N), 1522 (C@S), 1444, 1188, 800, 689 cm�1;UV–Vis kmax 324 nm; Fl kem 391 nm, kex 357 nm; dH (400 MHz, d6-DMSO) 2.47 (3H, s, CH3C@N), 7.23 (1H, t, J 7.5 Hz, Ph–H), 7.37–7.42(3H, m, 2 Ph–H, 1 � H-50), 7.54–7.57 (2H, m, Ph–H), 8.55 (1H, d, J8.1 Hz, H-40), 8.59–8.61 (2H, m, H-30, H-60), 10.20 (1H, s, NHC@S),10.69 (1H, s, NHN@C); dC (100 MHz, d6-DMSO) 13.4 (CH3C@N),122.1 (Py–C), 125.0 (Ph–C), 126.5 (Ph–C), 127.1 (Ph–C), 129.0(Py–C), 137.3 (Ph–C), 140.0 (Py–C), 149.3 (Py–C), 150.0 (Py–C),155.4 (C@N), 178.1 (C @S); m/z (ESI+) 271 ([M+H]+, 95%); HRMS(ESI+) C14H14N4NaS+ ([M+Na]+) requires 293.0823, found:293.0823; HPLC tr = 15.3 min.
2.2.1.4. Compound 4: 2-acetylpyridine 4,4N,N-dimethyl thiosemicar-bazone; L4. Following the general procedure, 4,4N,N-dimethyl-3-thiosemicarbazide (238 mg, 2 mmol), 5% aqueous AcOH solution(20 mL) and 2-acetylpyridine (242 mg, 2 mmol) gave L4 as a yellowsolid. Recrystallisation of the crude product using EtOH gave ananalytical sample of L4 as yellow needles (386 mg, 87%); m.p.148–149 �C (EtOH); {lit. [61] m.p. 148–150 �C, EtOH}; mmax (KBr)2890 (C–H), 1581 (C@N), 1530 (C@S), 1495, 1363, 1233, 1145,781 cm�1; UV–Vis kmax 308 nm, 404 nm; Fl kem 445 nm, kex
362 nm; NMR data was shown to contain a mixture of three iso-mers; E, E0 and Z in the ratio 1:0.8:1.1 respectively, E isomer: dH
(400 MHz, CDCl3) 2.61 (3H, s, CH3), 3.38–3.44 (6H, m, N(CH3)2),7.31 (1H, dd, J 8.0, 4.8 Hz, H-50), 7.54 (1H, d, J 8.1 Hz, H-30), 7.78(1H, ddd (app. td), J 8.0, 8.0, 1.8 Hz, H-40), 8.46 (1H, br s, NH),8.72–8.74 (1H, m, H-60); E0 isomer: dH (400 MHz, CDCl3) 2.37 (3H,s, CH3), 3.38–3.44 (6H, m, N(CH3)2), 7.23–7.27 (1H, m, H-50), 7.67(1H, td, J 8.0, 1.8 Hz, H-40), 7.96 (1H, d, J 8.0 Hz, H-30), 8.57 (1H,d, J 5.1 Hz, H-60), 14.82 (1H, br s, NH); Z isomer: dH (400 MHz,CDCl3) 2.52 (3H, s, CH3), 3.38–3.44 (6H, m, N(CH3)2), 7.36–7.39(1H, m, H-50), 7.60–7.62 (1H, m, H-30), 7.92 (1H, ddd (app. td), J7.9, 1.9 Hz, H-40), 8.63 (1H, dd, J 4.9, 1.9 Hz, H-60), 15.51 (1H, br s,NH); dC (100 MHz, CDCl3) 13.8 (CH3), 18.4 (CH3), 22.6 (CH3), 58.2(N(CH3)2), 120.1, 120.7, 123.7, 124.3, 136.6, 137.3, 138.0, 140.8,146.9, 146.9, 148.7, 150.2 (Ar–C), 153.2 (C@N), 180.6 (C@S), re-ported as a mixture of isomers E, E0 and Z; m/z (ESI+) 223([M+H]+, 80%), 467 ([2M+H]+, 100); HRMS (ESI+) C10H14N4NaS+
([M+Na]+) requires 245.0825, found: 245.0831; HPLC tr = 26.8 min.Crystal structure was comparable with that reported previously[77].
2.2.2. General procedure for preparation of Ga(III) thiosemicarbazonecomplexes
A solution of Ga(NO3)3�xH2O or GaCl3 in anhyd. EtOH was addeddrop-wise to a solution of the requisite thiosemicarbazone in an-hyd. EtOH (20 mL) under an atmosphere of nitrogen with vigorousstirring over 10 min. After 1 h, the product was collected by filtra-tion, washed with anhyd. EtOH and anhyd. Et2O, and recrystallisedfrom anhyd. EtOH to give the gallium complex.
2.2.2.1. Compound 5: [GaL12]NO3. Following the general procedure,
Ga(NO3)3�xH2O (127 mg, 0.5 mmol) in EtOH (10 mL) and L1
(104 mg, 0.5 mmol) in EtOH (10 mL) gave 5 as a crude yellow solid.Recrystallisation of the solid using EtOH gave 5 as yellow crystals(87 mg, 72%); m.p. >250 �C (EtOH); mmax (KBr) 3222 (N–H), 2980
J. Chan et al. / Inorganica Chimica Acta 363 (2010) 1140–1149 1143
(C–H), 1603 (C@N), 1458, 1292, 1238, 831, 628 cm�1; UV–Vis kmax
299 nm, 398 nm; Fl kem 505 nm, kex 417 nm; dH (400 MHz, d6-DMSO) 2.85 (3H, s, CH3C@N), 2.98 (3H, d, J 4.1 Hz, NHCH3), 7.62(1H, br s, H-50), 7.93–7.95 (1H, m, H-40), 8.24–8.27 (2H, m, H-30,H-60), 8.67 (1H, br s, NHCH3); dC (100 MHz, d6-DMSO) 14.4(CH3C@N), 29.3 (NHCH3), 124.0, 127.2, 142.3, 145.1, 145.5 (Ar–C),147.7 (C@N), 178.8 (N–S); m/z (ESI+) 485 ([M+H]+, 100%); HRMS(ESI+) C18H22GaN8S2
+ ([M]+) requires 485.0626, found 485.0649.
2.2.2.2. Compound 6: [GaL22]NO3. Following the general procedure,
Ga(NO3)3�xH2O (256 mg, 1 mmol) in EtOH (10 mL) and L2 (222mg, 1 mmol) in EtOH (20 mL) gave 6 as a crude yellow solid.Recrystallisation of the solid using EtOH gave 6 as yellow crystals(215 mg, 84%); m.p. >250 �C (EtOH); mmax (KBr) 3231 (N–H), 2960(C–H), 1603 (C@N), 1523, 1379, 1258, 1080, 779 cm�1; UV–Vis kmax
300 nm, 405 nm; Fl kem 487 nm, kex 423 nm; dH (400 MHz,d6-DMSO) 1.15–1.21 (3H, m, CH2CH3), 2.82 (3H, s, CH3C@N),3.43–3.47 (2H, m, CH2CH3), 7.60–7.62 (1H, m, H-50), 7.92–7.97(1H, m, H-40), 8.23–8.25 (1H, m, H-30), 8.29–8.34 (1H, m, H-60),10.29 (1H, br s, NHCH2CH3); dC (100 MHz, d6-DMSO) 13.3(CH3C@N), 14.6 (CH2CH3), 37.3 (CH2CH3), 121.0, 124.2, 127.2,136.8, 146.1 (Ar–C), 148.2 (C@N), 177.6 (C–S); m/z (ESI+) 511([M+H]+, 100%); HRMS (ESI+) C20H26GaN8S2
+ ([M]+) requires511.0961, found: 511.0972.
2.2.2.3. Compound 7: [GaL32]NO3. Following the general procedure,
Ga(NO3)3�xH2O (257 mg, 1 mmol) in EtOH (10 mL) and L3
(270 mg, 1 mmol) in EtOH (20 mL) to give 7 as a crude yellow solid.Recrystallisation of the crude product using EtOH gave 7 as yellowcrystals (365 mg, 60%); m.p. 220–221 �C (EtOH); mmax (KBr) 3397(N–H), 3249 (N–H), 3074 (C–H), 1634, 1599 (C@N), 1314, 1235,1023, 763, 588 cm�1; UV–Vis kmax 409 nm, 264 nm; Fl kem
559 nm, kex 448 nm; dH (400 MHz, d6-DMSO) 2.94 (3H, s, CH3C@N),7.10 (1H, t, J 7.3 Hz, Ar–H), 7.38 (2H, t, J 8.0 Hz, Ar–H), 7.67–7.69(1H, m, H-50), 7.79 (2H, d, J 8.1 Hz, Ar–H), 8.10 (1H, d, J 5.3 Hz, H-30), 8.28–8.32 (1H, m, H-40), 8.36–8.38 (1H, m, H-60), 10.26 (1H, s,NHPh); dC (100 MHz, d6-DMSO) 15.2 (CH3C@N), 121.4, 123.5,124.8, 127.9, 128.7, 139.6, 142.6, 144.7, 144.7 (Ar–C), 151.2(C@N), 171.6 (C–S); m/z (ESI+) 607 ([M+H]+, 98%); HRMS (ESI+)C28H26GaN8S2
+ ([M]+) requires 607.0952, found: 607.0972.
2.2.2.4. Compounds 8 and 9: [GaL42]GaCl4 and [GaL4Cl2]. Following
the general procedure, GaCl3 (176 mg, 1 mmol) in EtOH (10 mL)and L4 (222 mg, 1 mmol) in EtOH (20 mL) gave a crude yellowsolid. Recrystallisation of the crude product using EtOH gave 8and 9, in a 1:2 ratio respectively, as yellow crystals (174 mg,68% combined yield); m.p. >250 �C (EtOH); mmax (KBr) 2900 (C–H), 1602 (C@N), 1520, 1392, 1295, 1247, 1157, 901 cm�1; UV–Vis kmax 259 nm, 306 nm, 407 nm; Fl kem 487 nm, kex 412 nm.NMR spectra showed a mixture of complexes 8 and 9 in the ratioof 1:2, respectively: dH (400 MHz, d6-DMSO) 2.60 (3H, s, CH3),2.84 (3H, s, CH3), 3.36 (6H, br s, N(CH3)2), 7.59 (1H, ddd (app.td), J 5.6, 5.6, 4.0 Hz, Ar–H), 7.84 (1H, ddd, J 7.6, 5.6, 1.0 Hz,Ar–H), 7.93 (1H, d, J 5.6 Hz, Ar–H), 8.12 (1H, d, J 8.0 Hz, Ar–H),8.22–8.26 (2H, m, 2 Ar–H), 8.34 (1H, ddd (app. td), J 8.0, 8.0,1.6 Hz, Ar–H), 8.93 (1H, d, J 4.0 Hz, Ar–H), reported as a mixtureof complexes 8 and 9; dC (100 MHz, d6-DMSO) 13.3 (CH3), 14.3(CH3), 30.7 (N(CH3)2), 38.1 (N(CH3)2), 123.2, 123.9, 126.1, 127.0,142.2, 142.4, 142.7, 144.2, 145.3 (Ar–C), 145.8 (C@N), 146.6(C@N), 175.1 (C–S), 175.3 (C–S), reported as a mixture of bisand mono complexes; m/z (ESI+) 511 ([M+H]+, 100%); HRMS(ESI+) C20H26GaN8S2
+ ([M+H]+) requires 511.0963, found:511.0972. Crystal structures comparable with those reported pre-viously [58,62].
2.2.3. General procedure for preparation of In(III) thiosemicarbazonecomplexes 10–13
InCl3 (1 mol equiv.) in MeOH was added to a stirred suspensionof thiosemicarbazone (1 mol equiv.) in MeOH at room tempera-ture. The resultant mixture was heated at 70 �C for 0.5 h, cooledto room temperature and then placed in a fridge. Overnight, theIn(III) complexes were deposited as yellow crystals suitable forX-ray crystallographic analysis.
2.2.3.1. Compound 10. [InL12Cl2]2 InCl3 (55 mg, 0.25 mmol) in
MeOH (50 mL) and L1 (52 mg, 0.25 mmol) in MeOH (25 mL) weretreated by the general procedure to afford 10 as yellow crystals(23 mg, 22%); m.p. >250 �C (MeOH); mmax (KBr) 3262 (N–H), 3153(O–H), 2702, 2054, 1558 (C@N), 1494, 1224, 749 cm�1; UV–Viskmax 317 nm; Fl kem 380 nm, kex 350 nm; dH (400 MHz, d6-DMSO)2.40 (3H, s, CH3C@N), 2.88 (3H, s, CH3OH of recrystallisation),3.06 (3H, s, NHCH3), 3.53 (1H, br s, CH3OH of recrystallisation),8.41–8.42 (1H, m, H-50), 8.67–8.69 (1H, m, H-30), 8.72–8.74 (1H,m, H-40), 9.14–9.16 (1H, m, H-60), 10.67 (1H, s, NHCH3); dC
(100 MHz, d6-DMSO) 12.4 (CH3C@N), 45.0 (CH3OH), 29.4 (NHCH3),122.5, 124.9, 128.3, 131.1, 134.0 (Ar–C), 145.84 (C@N), 178.6 (C–S);m/z (ESI+) 529 ([M]+, 75%); HRMS (ESI+) C18H22InN8S2
+ ([M]+) re-quires 529.0436, found: 529.0442.
2.2.4. Compound 11[InL2Cl3] InCl3 (55 mg, 0.25 mmol) in MeOH (50 mL) and L2
(56 mg, 0.25 mmol) in MeOH (25 mL) were treated by the generalprocedure to afford 11 as yellow crystals (31 mg, 28%); m.p.>250 �C (MeOH); mmax (KBr) 3282 (N–H), 3211 (O–H), 3065 (C–H), 2977 (C–H), 1573 (C@N), 1332, 1094, 776 cm�1; UV–Vis kmax
318 nm; Fl kem 490 nm, kex 400 nm; dH (400 MHz, d6-DMSO) 1.16(3H, t, J 7.1 Hz, CH2CH3), 2.55 (3H, s, CH3C@N), 3.16 (3H, s, CH3OHof recrystallisation), 3.45 (1H, br s, CH3OH of recrystallisation),3.62–3.64 (2H, m, CH2CH3), 7.45–7.50 (1H, m, H-50), 7.92–7.95(1H, m, H-40), 8.40–8.44 (1H, m, H-30), 8.61–8.63 (1H, m, H-60),10.34 (1H, s, NHCH2CH3); dC (100 MHz, d6-DMSO) 14.8 (CH3C@N),45.0 (CH3OH), 121.9, 124.7, 132.1, 138.8, 148.3 (Ar–C), 154.1(C@N), 178.4 (C–S); m/z (ESI+) 557 ([M]+, 100%); HRMS (ESI+)C20H26InN8S2
+ ([M]+) requires 557.0758, found: 557.0755.
2.2.4.1. Compound 12. [InL3Cl2�MeOH] InCl3 (55 mg, 0.25 mmol) inMeOH (50 mL) and L3 (68 mg, 0.25 mmol) in MeOH (25 mL) weretreated by the general procedure to afford 12 as yellow crystals(34 mg, 28%); m.p. >250 �C (MeOH); mmax (KBr) 3358 (N–H), 3333(O–H), 3069 (C–H), 1594 (C@N), 1458, 1315, 1250, 782 cm�1;UV–Vis kmax 264 nm, 322 nm, 399 nm; Fl kem 520 nm, kex
444 nm; dH (400 MHz, d6-DMSO) 2.67 (3H, s, CH3C@N), 3.17 (3H,d, J 5.0 Hz, CH3OH of recrystallisation), 4.13 (1H, q, J 5.0 Hz, CH3OHof recrystallisation), 7.04 (1H, t, J 7.3 Hz, Ar–H), 7.34 (2H, dd (app t),J 7.6 Hz, Ar–H), 7.79 (2H, d, J 7.6 Hz, Ar–H), 7.88 (1H, dd, J 7.8,5.0 Hz, H-50), 8.22 (1H, d, J 7.8 Hz, H-30), 8.33 (1H, ddd (app. td), J7.8, 7.8, 1.5 Hz, H-40), 8.78 (1H, d, J 4.3 Hz, H-60), 10.01 (1H, s,NH); dC (100 MHz, d6-DMSO) 15.4 (CH3C@N), 48.6 (CH3OH),121.0, 122.9, 124.7, 126.8, 128.6, 140.1, 142.0, 145.9, 146.7, 147.1(Ar–C), 170.4 (N–S); m/z (ESI+) 653 ([M]+, 100%); HRMS (ESI+)C28H26InN8S2
+ ([M]+) requires 653.0749, found: 653.0755.
2.2.4.2. Compound 13. [InL4Cl2�MeOH] InCl3 (55 mg, 0.25 mmol) inMeOH (50 mL) and L4 (56 mg, 0.25 mmol) in MeOH (25 mL) weretreated by the general procedure to afford 13 as yellow crystals(30 mg, 28%); m.p. >250 �C (MeOH); mmax (KBr) 3454 (O–H), 2930(C–H), 2360, 1599 (C@N), 1556, 1384, 1171, 774 cm�1; UV–Viskmax 261 nm, 304 nm, 403 nm; Fl kem 497 nm, kex 438 nm; dH
(400 MHz, d6-DMSO) 2.58 (3H, s, CH3C@N), 3.18 (3H, d, J 5.0 Hz,
N
NNH
NSR2
R1
N
NN
NSR2
R1N
NN
N SR1
R2
Ga
N
NNH
NSEt
H
InClCl
Cl
N
NN
NSR2
R1
InClCl
N
NN
NSMe
H
InClCl
N
NN
N SMe
H
In
Cl
Cl
N
NN
NSMe
Me
GaClCl
R1 = H, R2 = Me (5) X = NO3R1 = H, R2 = Et (6) X = NO3R1 = H, R2 = Ph (7) X = NO3R1 = R2 = Me (8) X = GaCl4
a or b c
9
10
11R1 = H, R2 = Ph (12)R1 = R2 = Me (13)
R1 = H, R2 = Me (1)R1 = H, R2 = Et (2)R1 = H, R2 = Ph (3)R1 = R2 = Me (4)
X
OMeH
Scheme 1. Reagents/conditions: (a) Ga(NO3)3�xH2O, anhyd. EtOH, room temp., 1 h; (b) GaCl3, anhyd. EtOH, room temp., 1 h; (c) (i) InCl3, MeOH, 70 �C, 0.5 h; (ii) 4 �C, 18 h.
1144 J. Chan et al. / Inorganica Chimica Acta 363 (2010) 1140–1149
CH3OH), 3.31 (6H, s, N(CH3)2), 4.13 (1H, q, J 5.0 Hz, OH), 7.80 (1H,ddd, J 7.6, 5.0, 1.0 Hz, H-50), 8.09 (1H, d, J 7.9 Hz, H-30), 8.27 (1H,ddd (app. td), J 7.8, 7.8, 1.0 Hz, H-40), 8.72 (1H, dd, J 5.2, 0.8 Hz,H-60); dC (100 MHz, d6-DMSO) 13.6 (CH3C@N), 41.3 (N(CH3)2),48.6 (CH3OH), 123.8, 125.8, 141.8 (Ar–C), 142.8 (C@N), 146.4,146.7 (Ar–C), 174.3 (C–S); m/z (ESI+) 557 ([M]+, 100%); HRMS(ESI+) C20H26InN8S2
+ ([M]+) requires 557.0756, found: 557.0755.
Table 2Fluorescence data for the compounds in this study.
Compound kex (nm) kem (nm) Compound kex (nm) kem (nm)
1 362 369 7 448 5592 281 352 8/9 412 4873 357 391 10 350 3804 362 445 11 400 4905 417 505 12 444 5206 423 487 13 438 497
Fig. 2. UV–Vis measurements over 4 h for (a) [Ga(L3)2]NO3 7 t = 0, 5, 10, 15, 20, 25, 30, 60240 min; as 0.034 mM in 3.2% DMSO/human serum at 37 �C.
3. Results and discussion
3.1. Synthesis
The one-step synthesis of the mono-thiosemicarbazones hasbeen reported several times previously, and proceeds by the reac-tion of 2-acetylpyridine and substituted N-alkyl-3-thiosemicarbaz-ides in the presence of acetic acid in aqueous media. The crystalstructures of the ligands have also been reported in the recent lit-erature (Fig. 1) [1,62,75,78].
The 2-acetylpyridine 4N-alkyl thiosemicarbazones were reactedwith Ga(III)NO3�xH2O, Ga(III)Cl3 or In(III)Cl3 to afford the respectivecomplexes 5–13 in low to moderate yields (Scheme 1). The yieldsfor the complexes were found to be considerably better for the gal-lium complexes (60–84%) than the indium complexes (22–28%).
Of these, [GaL42GaCl4], 8, and [GaL4Cl2], 9, have been reported
previously, and the crystal structures determined by X-ray crystal-lographic analysis [58,62]. The gallium compounds, with only oneexception (9), were found to form distorted pseudo-octahedral
, 90, 120, 180, 240 min; (b) [InL3Cl2MeOH] 12 t = 0, 5, 10, 15, 30, 45, 60, 90, 120, 180,
J. Chan et al. / Inorganica Chimica Acta 363 (2010) 1140–1149 1145
complexes with the two tri-dentate meridional ligands lying inperpendicular planes. L4 was unusual in this respect in that itformed both the [ML2]+ and 1:1 MLX2 structures. The 1:1 MLX2
structure was in a neutral trigonal-bipyramidal coordinationgeometry, with the two chlorides projecting out of the thiosemi-carbonazato ligand plane. This might seem slightly surprising, asthe reaction was conducted under the same conditions as Kepplerand co-workers, and we found both the 1:1 and the 1:2 (M:L) com-plexes formed concomitantly in our hands with both structuressolved by X-ray crystallography. However, Keppler and co-workerssuggest that in the presence of the tetrachlorogallate(III) salt [62],there is an equilibrium between the 1:1 and 1:2 (M:L) species,which was circumvented in their later paper, where an unreactivePF6
� counterion was used. In this respect, the fact that the gallium
(a)
(c) (
(e)
Fig. 3. The different types of complex. (a) Complex 5, an example of mononuclear, [ML2]+;10, dinuclear [MLX2]2 and (d) and (e) complexes 11 and 13, two examples of mononucl
formed [ML2]+ complexes with a nitrate counterion is less remark-able. Careful examination of the original NMR data reported byKeppler and co-workers for the 1:2 (M:L) complex also appearsto indicate the presence of both species, and are in agreement withthe NMR data that were obtained in our study.
For the In(III) complexes, the structures all formed 1:1 metal toligand complexes in a pseudo-octahedral configuration. At firstglance, the unusual species in the compounds discussed herein isthe complex formed with L1, compound 10, which formed a chlo-ride bridged dimer in contrast to the monomeric InLX3 speciesformed by with L2, L3 and L4 (where X is a monodentate ligand,either chloride or methanol). However, on closer inspection it isapparent that the more remarkable complex is formed by L2, withan ethyl substituent (compound 11), which remains protonated,
(b)
d)
(b) complex 9, the only example of mononuclear, [MLX2] reported here; (c) complexear [MLX3] species (where X = Cl and/or MeOH).
Table 3Selected bond lengths for the uncomplexed ligands and their gallium and indium complexes; \SNN is depicted in Scheme 2 for clarity.
M–S M–N M–N(py) C–S C–N N–N \SNN
L1 – 1 1.684(2) 1.368(2) 1.373(2)L2 – 2 1.6852(14) 1.3625(17) 1.3736(15)L3 –3 [78] 1.677(2) 1.358(2) 1.376(2)L4 – 4 1.7128(15) 1.3553(19) 1.3517(17) 102.05(5)L5 [81,82] 1.691(2) 1.362(3) 1.375(3)
1.697(2) 1.358(3) 1.380(3)1.686(2) 1.360(3) 1.368(3)1.692(3) 1.360(3) 1.371(3)
Ga L1 – 5 [81,82] 2.3496(7) 2.063(2) 2.151(2) 1.740(3) 1.331(4) 1.371(3) 105.68(9)2.3427(7) 2.065(2) 2.090(2) 1.746(3) 1.335(4) 1.374(3) 104.34(9)
L2 – 6 2.3702(9) 2.046(3) 2.124(3) 1.733(3) 1.341(4) 1.360(4) 105.40(11)2.3545(10) 2.041(3) 2.119(3) 1.747(4) 1.335(5) 1.360(4) 105.38(12)
L3 – 7 2.3742(6) 2.0390(19) 2.1334(19) 1.748(2) 1.318(3) 1.374(3) 106.63(8)2.3736(6) 2.0452(19) 2.125(2) 1.748(2) 1.325(3) 1.376(3) 106.21(8)
L4 – 8 2.3720(9) 2.030(3) 2.135(3) 1.745(3) 1.330(4) 1.372(4) 106.45(11)2.3555(9) 2.043(3) 2.113(3) 1.744(3) 1.342(4) 1.359(4) 105.40(10)
L4 – 9 2.3279(8) 2.054(2) 2.104(2) 1.750(3) 1.335(4) 1.360(3) 104.55(9)L5 – [MLX2] [60] 2.3407(7) 2.0452(17) 2.0979(18) 1.730(2) 1.320(3) 1.368(2) 105.97L5 – [ML2]+ [59] 2.3458(8) 2.0509(17) 2.1276(18) 1.734(2) 1.330(3) 1.369(3) 105.49
2.3649(7) 2.0523(17) 2.1094(18) 1.736(2) 1.323(3) 1.365(2) 106.06In L1 – 10 2.480(2) 2.218(6) 2.271(6) 1.758(7) 1.333(9) 1.368(8) 108.4(2)
L2 – 110 2.597(5) 2.372(10) 2.245(6) 1.667(14) 1.353(15) 1.349(15) 109.5(4)L3 – 12 2.4789(12) 2.241(4) 2.274(4) 1.758(5) 1.318(6) 1.378(5) 108.44(15)L4 – 13 2.4743(6) 2.2405(18) 2.2547(19) 1.755(2) 1.339(3) 1.360(3) 107.58(8)L5 – [MLX3] [16] 2.483(3) 2.233(7) 2.269(6) 1.744(7) 1.33(1) 1.375(9) 107.01L5 [MLX3] [65] 2.4617(9) 2.251(2) 2.252(2) 1.749(3) 1.326(4) 1.373(3) 107.55L5 [ML2]+ [16] 2.519(1) 2.230(4) 2.283(4) 1.745(5) 1.313(6) 1.381(5) 110.35
2.502(1) 2.250(4) 2.297(4) 1.749(5) 1.312(6) 1.369(5) 109.49
Fig. 4. Overlay of the ligand L1 (broken lines) and L4 showing the different conformations.
1146 J. Chan et al. / Inorganica Chimica Acta 363 (2010) 1140–1149
and hence coordinates three charge-balancing chlorides, instead oftwo chlorides and a methanol (as seen for complexes 12 and 13).This difference is due to the presence of the electron donating phe-nyl groups or dimethyl on L3 and L4. For L4, the inductive electronicdonation of the second alkyl substituent greatly enhances the elec-tron donation into the thiosemicarbazone moiety by the NMe2
group and hence facilitating deprotonation of the ligand duringcomplex formation.
Another point worthy of note was a more pronounced upfieldshift of the C@S resonance in the 13C NMR spectra for the com-plexes of ligands L3 and L4 (increase of 5.3–7.7 ppm), where thephenyl or two methyl groups provided further shielding than forthe methyl or ethyl derivatives. The origin of this is likely to bethe ability of the nitrogen centre to easily quatenize, in the two lat-ter ligands. Other changes in the 13C NMR spectra are the pro-nounced upfield shifts for the NMe2 signals in L4, which are at d58.2 in the free ligand, but shift upfield to d 30.7 and 38.1 ppmin the gallium complexes and d 41.3 ppm in the indium complex.
The presence of coordinated methanol in compounds 12 and 13in solution, is also lent support by the presence of a doublet (J5.0 Hz) at d 3.18 ppm (c.f. singlet at d 3.50) in the 1H NMR spectraand a resonance at d 48.6 ppm (c.f. d 45.0 ppm) in the 13C NMRspectra.
As we were hoping to use fluorescence techniques to measurethe extra- and intracellular distribution of the materials, the com-pounds were surveyed for their fluorescence behaviour. The resultsfor these are summarised in Table 2. All of the gallium and indiumcomplexes were found to be highly fluorescent which opened upthe possibility of multi-modal imaging, a current area of researchin our laboratory. The long wavelength in the fluorescence spectraof the gallium (559 nm) and indium (520 nm) complexes of thephenyl derivative L3 meant that these two compounds were theobvious candidates for biological evaluation. Consequently, stabil-ity tests were conducted using UV–Vis spectroscopy, in human ser-um using established protocols [79] to establish the potential forin vivo measurements of the complexes. Stability studies on both
J. Chan et al. / Inorganica Chimica Acta 363 (2010) 1140–1149 1147
complexes [Ga(L3)2]NO3, 7, and [InL3Cl2MeOH], 12, in human ser-um, are outlined in Fig. 2.
It is quite clear that [Ga(L3)2]NO3, 7, is unstable in human ser-um, owing to the rapid degradation of the complex over even a rel-atively short time scale (<20 min). However, for the indiumcomplex 12, the stability studies show that despite what is proba-bly the initial loss of coordinated of MeOH in DMSO solution, itonly gradually degrades over the measured time period in humanserum. The indium complex 12, as can be seen from Fig. 2b, indi-cated that even after 4 h approximately 67% of the complex re-mained intact. The chromophores for the degradation productswere not observed in the measured spectral window and did notmatch the UV–Visible spectrum of the free ligand (L3) in humanserum. Combined with the favourable fluorescence excitation andemission wavelength, the indium complex 12 appears to be con-siderably more stable than the corresponding gallium(III) complex.This confirms the potential of this species for multi-modal imagingthrough in vitro and in vivo studies, with the indium-111 radio-la-belled complex.
3.2. X-ray structural studies
As described above, the complexes present four principal types(Fig. 3). These can be described as mononuclear, [ML2]+ (as shownby all four ligands with gallium); mononuclear, [MLX2] (as shownonly by L4 with gallium); mononuclear, [MLX3] (as shown only
Fig. 5. The gallium complex of L4 (shown with a broken line) is overlayed with the indiuthe gallium metal is closer to the centre of the ligand (though slightly out of the plane
Scheme 2. Schematic depiction of the \SNN is shown in bold.
by L2, L3 and L4 with indium), and dinuclear, [MLX2]2 (as shownonly by L1 with indium). The first of these categories, which isthe dominant species for the gallium complexes, exhibits pseudoC2-symmetry relating the two cis sulphur atoms with the centralgallium in a pseudo-octahedral environment (Fig. 3a).
This is in marked contrast to the indium complexes which neverformed complexes with a 1:2 (M:L) ratio in our hands. This effect isdue to the increased size of the indium (which has a covalent ra-dius of 1.63 Å compared to 1.22 Å for gallium) [80] and can clearlybe seen in the M–L bond lengths which are systematically ca. 0.10–0.15 Å longer for the indium complexes (Table 3). Three of the fouruncoordinated ligands adopt the E(anti anti) conformation in thecrystal structure, which needs a conformational rearrangement inorder to bind to a metal. However, in contrast, the crystal structureof L4 presents a pro-binding conformation (E(syn syn; Fig. 4), givingan \SNN angle of 102.05(5)� (Scheme 2). In addition, the inductiveeffects of the N,N-dimethyl species also promote p-delocalisationof the terminal nitrogen lone pair resulting in a shortened ipso-car-bon bond and lengthening of the carbon sulphur bond by 0.03 Å forthe uncoordinated L4.
Study of the \SNN angle, demonstrates that it increases byapproximately 3� on forming a complex with gallium and 6� oncomplexing indium. These structural differences demonstratehow the thiosemicarbazone ligands can more easily ‘‘enclose” thesmaller gallium ions leading to a relatively undistorted octahedralgeometry for the [ML2]+ type structure (Fig. 5). In contrast, theanalogous [InL2]+ complex are less favoured, with complexes withone tri-dentate ligand preferred and the coordination sphere com-pleted by three monodentate ligands. This trend is not only seen inthe complexes presented here, but can also be seen in the literaturefor the unsubstituted hydrazide (R1 = R2 = H, L5) for which two gal-lium and three indium structures have been reported[59,60,64,65]. The gallium complexes are of the type [ML2]+ and[MLX2] shown here, with two of the indium complexes of the form[MLX3] (where X3 = Cl2MeOH and Cl2EtOH). Despite the definitepreference indium has for [MLX3] shown in our results, the[ML2]+ complex of L5 has also been reported [16], however this
m complex showing how the S^N^N angle is increased for the indium complex, anddue to the lower coordination number).
1148 J. Chan et al. / Inorganica Chimica Acta 363 (2010) 1140–1149
unusual [ML2]+ indium structure can be seen to have noticeablylonger M–L distances and a larger \SNN angle.
Examination of the dinuclear structure, complex 10, initiallysuggested that it could be considered to be a special case of[MLX3] where the two monodentate ligands are coordinate to asecond metal. However, in complex 10 (which occupies a positionon an inversion centre), the bridging In–Cl distances are highlyasymmetric leading to one short bridging chloride bond(2.4299(17) Å) and one longer one (2.9652(19) Å). This suggeststhat this dimeric species is related to the [MLX2] species seen inthe gallium complexes, with the covalent radius for indium leadingto a requirement for a higher coordination number which is satis-fied by dimerisation in this case, and coordination of methanol forCompounds 12 and 13.
In addition to the change in the \SNN angle on complexation,the complexes discussed here also exhibit changes to the bondlengths within the ligand. These are similar to those reported pre-viously for iron complexes [63] and show a marked lengthening ofthe C–S bond coupled with a shortening of the C–N bond consistentwith the change in conjugation associated with deprotonation andligand binding. In contrast, compound 11 (where the ligand re-mains protonated) retains bond lengths similar to those seen inthe unreacted ligand.1
4. Conclusions
In summary, four 2-acetylpyridine 4N-alkyl thiosemicarbazonesderivatives and their Ga(III) and In(III) complexes have been pre-pared and characterised in the solution and solid states. Compari-son of the crystal structures gave an insight into the nature of thecomplexes formed, demonstrating a preference for [ML2]+ for thegallium complexes and [MLX3] for the indium species. The mostlikely reason the indium complexes with a 2:1 ligand to metal ratiowere disfavoured was thought to be due to the increased covalentradius for indium over gallium, a feature that was supported bysystematically longer bond lengths in the indium complexes. Theelectronic contribution of the N-alkyl subtitutents was also foundto alter the binding, NMR characteristics and fluorescence profilesof the compounds studied. The presence of either the electrondonating phenyl system or N,N-dimethyl groups promoted theconjugation pathways through the thiosemicarbazone backbone,leading to bond shortening and enhanced fluorescence for theresulting complexes. Preliminary investigation of the solution stateand serum stability of two of the complexes, 7 and 12, indicatedthat the indium complex [InL3Cl2MeOH] 12 was much more stablethan the analogous gallium complex, and its potential as a multi-modal imaging agent will be the subject of further investigations.
Acknowledgements
The authors wish to thank Mrs. Maria Marshall for assistancewith the HPLC and Dr. Simon Bayly for helpful discussions.
Appendix A. Supplementary material
CCDC 754741–754754 contains the supplementary crystallo-graphic data for this paper. These data can be obtained free ofcharge from The Cambridge Crystallographic Data Centre viawww.ccdc.cam.ac.uk/data_request/cif.. Supplementary data asso-ciated with this article can be found, in the online version, atdoi:10.1016/j.ica.2009.10.020.
1 Although data are not presented in the table (due to unreliability caused by thepoor quality of the data), results for the structure of compound 110 are in keepingwith those reported here for compound 11.
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