Tricarbonylrhenium(I) complexes of phosphine-derivatized amines, amino acids and a model peptide: Structures, solution behavior and cytotoxicity

Article abstract of DOI:10.1016/S0022-328X(02)01200-7

Modified Mannich reactions of amines, amino acids and a model peptide with Ph₂PH and CH₂O gave bis(disphenylphosphinomethyl) amines(Ph₂PCH₂)₂NR [R = Ph (1), CH₂CH₂OH(2), CH₂COOCH₂Ph (3), CH₂CONHCH₂COOCH₂Ph (4). CH₂COOH (5)] and [ReBr(CO)₃(Ph₂PCH₂)₂NCH ₂]₂ (12). All new complexes have been characterized by NMR and IR spectroscopy and for 7, 9 and 10, single-crystal X-ray diffraction analyses. Electrospray mass spectrometric studies show that the rhenium-phosphine chelates are very stable especially in neutral methanolic solution. Hydrolysis of the ester and amide linkages slowly occur in acidic and basic solutions over several weeks; displacement of the bromide ligand also occurs in basic medium. Cytotoxicity testing of 7-10 and 12 showed that all the complexes are active againts specific tumor cell lines, especially MCF-7 breast cancer and HeLa-S³ suspended eturine carcinoma.

Full text of DOI:10.1016/S0022-328X(02)01200-7

Journal of Organometallic Chemistry 650 (2002) 123–132
www.elsevier.com/locate/jorganchem
Tricarbonylrhenium(I) complexes of phosphine-derivatized amines,
amino acids and a model peptide: structures, solution behavior
and cytotoxicity
Jianyong Zhang a, Jagadese J. Vittal a, William Henderson b, Jessica R. Wheaton c,
Iris H. Hall c, T.S. Andy Hor a, Yaw Kai Yan d,*
a Department of Chemistry, Faculty of Science, National Uni6ersity of Singapore, 3 Science Dri6e 3, Kent Ridge, Singapore 117543, Singapore
b Department of Chemistry, Uni6ersity of Waikato, Pri6ate Bag 3105, Hamilton, New Zealand
c Di6ision of Medicinal Chemistry, School of Pharmacy, Uni6ersity of North Carolina, Chapel Hill, NC 27599-7360, USA
d Natural Sciences, National Institute of Education, Block 7 (Science), Nanyang Technological Uni6ersity, 1 Nanyang Walk,
Singapore 637616, Singapore
Received 1 November 2001; accepted 15 January 2002
Abstract
Modified Mannich reactions of amines, amino acids and a model peptide with Ph2PH and CH2O gave bis(diphenylphosphi-
nomethyl)amines (Ph2PCH2)2NR [R=Ph (1), CH2CH2OH (2), CH2COOCH2Ph (3), CH2CONHCH2COOCH2Ph (4), CH2COOH
(5)] and (Ph2PCH2)2NCH2CH2N(CH2PPh2)2 (6). Reaction with [ReBr3(CO)3]2− under mild conditions led to [ReBr(CO)3]-
{(Ph2PCH2)2NR} [R=Ph (7), CH2CH2OH (8), CH2COOCH2Ph (9), CH2CONHCH2COOCH2Ph (10), CH2COOH (11)] and
[ReBr(CO)3(Ph2PCH2)2NCH2]2 (12). All new complexes have been characterized by NMR and IR spectroscopy and for 7, 9 and
10, single-crystal X-ray diffraction analyses. Electrospray mass spectrometric studies show that the rhenium–phosphine chelates
are very stable, especially in neutral methanolic solution. Hydrolysis of the ester and amide linkages slowly occur in acidic and
basic solutions over several weeks; displacement of the bromide ligand also occurs in basic medium. Cytotoxicity testing of 7–10
and 12 showed that all the complexes are active against specific tumor cell lines, especially MCF-7 breast cancer and HeLa-S3
suspended uterine carcinoma. © 2002 Elsevier Science B.V. All rights reserved.
Keywords: Rhenium(I); Carbonyl; Bis(diphenylphosphinomethyl)amine; Cytotoxicity; Electrospray mass spectrometry
metals, can play a major role in the design of ra-
diometal–antibody conjugates [5–7]. The direct intro-
duction of phosphino groups onto peptides via the
Mannich-type reaction of hydroxymethyl phosphines
with the free amino groups on the peptide has been
studied [7]. Such procedures, however, can potentially
alter the structure and hence biological properties of the
protein. The use of polyfunctional hydroxymethylphos-
phines such as P(CH2OH)3, for example, can poten-
tially create undesirable cross-links within the protein
structure [7], or link two separate peptides to the same
radiometal atom (reducing the overall labeling effi-
ciency). An alternative strategy is the ‘‘preformed
chelate’’ approach, whereby the radiometal is first
tightly bonded to a diphosphine chelate system, fol-
lowed by the attachment of the chelate complex unit to
the protein via an appropriate functional group on the
diphosphine.
1. Introduction
There is much current interest in the development of
radiopharmaceuticals through the radiolabeling of
monoclonal antibodies with 186/188Re [1–3]. Although
much emphasis had been placed on the development of
ligand systems for chelation to the Re(V) oxo core [2],
the design of radiopharmaceuticals based on Re(I)-tri-
carbonyl complexes has gained considerable attention
recently [4]. The advantages of this organometallic ap-
proach and the methodology for generating the
[Re(CO)3]+ synthon have also been described [4].
It has also been recognized that phosphines, by virtue
of their versatile ligating capability with transition
* Corresponding author. Tel.: +65-790-3816; fax: +65-896-9432.
E-mail address: ykyan@nie.edu.sg (Y.K. Yan).
0022-328X/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(02)01200-7

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J. Zhang et al. / Journal of Organometallic Chemistry 650 (2002) 123–132
Bis(diphenylphosphinomethyl)amines are good can-
amine tricarbonylrhenium(I) complexes as well. The
possibility of having bis(diphenylphosphino-methyl)-
amine tricarbonylrhenium(I)-based radiopharmaceuti-
cals serving dual functions as both chemo- and
radiotherapeutic agents is appealing.
In this paper, we report the synthesis of tricarbonyl-
rhenium(I) complexes of representative bis(diphenyl-
phosphinomethyl)amines derived from aniline, glycine,
and glycylglycine, and the study of their in vitro stabil-
ity by electrospray mass spectrometry. Preliminary re-
sults of the cytotoxicity screening of these complexes
against 18 cancer cell lines are also presented.
didates for the preformed chelate approach. They are
readily synthesized via the Mannich reaction between
primary amines and secondary phosphines (with form-
aldehyde) [8,9] or bis(hydroxymethyl)phosphonium
salts [10], and are known to form stable chelate com-
plexes with palladium, platinum and rhodium [11,12].
In principle, any desired functional group (for protein
conjugation or for increasing water-solubility) can be
attached onto the nitrogen atom by appropriate choice
of the NH2 group-containing starting material (Scheme
1). When the functional group or molecular chain that
links the chelate unit with the biomolecule is attached
to the middle atom of the diphosphine backbone, the
steric interaction between the radiometal’s coordination
sphere with the protein is minimized. The relative sim-
plicity of the chelating system is also attractive.
2. Experimental
All reactions were performed under pure dry nitrogen
using standard Schlenk techniques. The solvents were
purified and dried by standard methods and distilled
under nitrogen prior to use. [NEt4]2[ReBr3(CO)3] was
prepared by the published procedure [15]. 1H- and
31P{1H}-NMR spectra were recorded on a Bruker ACF
300 MHz spectrometer at ca. 300 K at operating fre-
In the course of our ongoing research on rhenium(I)
carbonyl alkoxo complexes [13], we have found that the
complexes [Re2(m-OR)3(CO)6]− (R=H, Me, Et, Ph),
[Re2(m-OH)(m-OPh)2(CO)6]−,
[Re2(m-OR)2(m-dppf)-
(CO)6]
[dppf=1,1%-bis(diphenylphosphino)ferrocene;
R=H, Me, Ph] and fac-[Re(OPh)(h2-dppf)(CO)3] ex-
hibit potent cytotoxicity against a number of cancer cell
lines [14]. It is of interest, therefore, to investigate the
anti-tumour activity of bis(diphenylphosphinomethyl)-
1
quencies of 300.0 and 121.5 MHz, respectively. H and
31P chemical shifts are quoted in ppm downfield of
tetramethylsilane and external 80% H3PO4, respectively.
2-D ROESY NMR analysis was carried out on a
Bruker DRX 500 spectrometer at an operating fre-
quency of 500.23 MHz. IR spectra were taken in a KBr
disc on a Perkin–Elmer 1600 FTIR spectrophotometer.
Elemental analyses were carried out in the Microanalyt-
ical Laboratory at the National University of
Singapore.
2.1. Preparation of bis(diphenylphosphinomethyl)amines
Bis(diphenylphosphinomethyl)amines (Ph2PCH2)2NR
{R=Ph [12] (1), CH2CH2OH [10] (2), CH2COOCH2Ph
(3), CH2CONHCH2COOCH2Ph (4), CH2COOH [8]
(5)} and (Ph2PCH2)2NCH2CH2N(CH2PPh2)2 [12] (6)
were generally prepared by the procedure in Ref. [10]
with only slight modifications. 31P{1H}-NMR (CDCl3):
1 l −27.4 (s); 2 l −27.3 (s); 3 l −26.9 (s); 4 l −27.3
(s); 5 l −27.0 (s); 6 l −28.2 (s).
2.2. Preparation of bis(diphenylphosphinomethyl)amine
tricarbonylrhenium(I) bromide complexes—general
method
[NEt4]2[ReBr3(CO)3] (144 mg, 0.2 mmol) was dis-
solved in MeOH (30 ml) and an equimolar amount of
the appropriate bis(diphenylphosphinomethyl)amine
added. The solution was stirred overnight at room
temperature, after which the solvent was evaporated
under reduced pressure and the waxy residue was tritu-
rated with Et2O (20 ml) to form a crystalline solid.
Scheme 1.

J. Zhang et al. / Journal of Organometallic Chemistry 650 (2002) 123–132
125
After decantation, the product was extracted from the
[NEt4]Br with THF (30 ml) and precipitated with hex-
ane. Recrystallization of the solid from CH2Cl2–EtOH
afforded colorless crystals of the product.
21.7 (s). IR (cm−1, KBr): 2029vs, 1948vs, 1909vs
(CꢀO), 1718m(br) (CꢁO, carboxyl).
2.2.6. [ReBr(CO)3(Ph2PCH2)2NCH2]2 (12)
[NEt4]2[ReBr3(CO)3] (144 mg, 0.2 mmol) was dis-
solved in MeOH (30 ml) and the bis(diphenylphosphi-
nomethyl)amine 6 (85 mg, 0.1 mmol) added. The
solution was stirred overnight at room temperature,
and the solvent evaporated under reduced pressure
giving a waxy residue. The residue was separated,
washed with THF and then with EtOH–H2O, giving 12
2.2.1. [ReBr(CO)3{(Ph2PCH2)2NPh}] (7)
The bis(diphenylphosphinomethyl)amine 1 (98 mg,
0.2 mmol) gave complex 7 (120 mg, 72%). Found for
C35H29BrNO3P2Re: C, 50.2; H, 3.5; N, 1.6. Calc.: C,
1
50.1; H, 3.5; N, 1.7%. H-NMR (CDCl3): l 7.74–7.28
(m, 20H, P-Ph), 7.10 (t, 2H, N-Ph), 6.95 (t, 1H, N-Ph),
6.26 (d, 2H, N-Ph), 4.75 (m, 2H, CH2P), 4.14 (m, 2H,
CH2P). 31P{1H}-NMR (CDCl3): l −21.1 (s). IR
(cm−1, KBr): 2031vs, 1950vs, 1901vs (CꢀO).
as
a colorless solid (97 mg, 63%). Found for
C60H52Br2N2O6P4Re2: C, 46.5; H, 3.3; N, 1.8. Calc.: C,
46.4; H, 3.4; N, 1.8%. 31P{1H}-NMR (CDCl3): l −
20.7 (s). IR (cm−1, KBr): 2035vs, 1953vs, 1945vs(sh),
1925vs, 1907vs (CꢀO).
2.2.2. [ReBr(CO)3{(Ph2PCH2)2NCH2CH2OH}] (8)
The bis(diphenylphosphinomethyl)amine 2 (92 mg,
0.2 mmol) gave complex 8 (83 mg, 51%). Found for
C31H29BrNO4P2Re: C, 46.0; H, 3.7; N, 1.8. Calc.: C,
2.3. Electrospray mass spectrometry
ESMS spectra were recorded in the positive-ion
mode (unless otherwise stated) using a VG Platform II
instrument employing nitrogen as both the drying and
nebulizing gas. The spectra were typically obtained with
an average of 10–12 scans. A range of cone voltages,
from 20–100 V were typically applied on each sample
to investigate the fragmentation behavior. The analyte
solution (ca. 0.1 mM) was delivered to the mass spec-
trometer source using a Spectra System P1000 HPLC
pump, at a flow rate of 0.01 ml min−1. Spectra were
recorded in neutral, acidic and basic MeOH solutions,
as well as in MeCN–H2O solutions. Acidic solutions
were prepared by dilution of five drops of 50% formic
acid to 2 ml with methanol. Two drops of this solution
were added to the rhenium complex solutions, and the
mixture allowed to stand for several weeks. Basic solu-
tions were prepared by adding three drops of NH3
solution (2 M) to the rhenium complex solution, and
the mixture allowed to age over 1 month. Assignment
of major ions was aided by a comparison of the exper-
imental and calculated isotope distribution patterns, the
latter obtained using the ISOTOPE program [16].
1
46.1; H, 3.6; N, 1.7%. H-NMR (CDCl3): l 7.68–7.26
(m, 20H, Ph), 4.31 (m, 2H, CH2P), 3.73 (m, 2H, CH2P),
3.18 (t, 2H, CH2O), 2.71 (br s, 2H, CH2N). 31P{1H}-
NMR (CDCl3): l −19.6 (s). IR (cm−1, KBr): 2031vs,
1944vs, 1899vs (CꢀO).
2.2.3. [ReBr(CO)3{(Ph2PCH2)2NCH2COOCH2Ph}] (9)
The bis(diphenylphosphinomethyl)amine 3 (110 mg,
0.2 mmol) gave complex 9 (118 mg, 65%). Found for
C38H33BrNO5P2Re: C, 50.0; H, 3.7; N, 1.6. Calc.: C,
1
50.0; H, 3.6; N, 1.5%. H-NMR (CDCl3): l 7.66–7.26
(m, 25H, C6H5), 5.10 (s, 2H, OCH2Ph), 4.63 (m, 2H,
CH2P), 3.50 (m, 2H, CH2P), 3.31 (s, 2H, NCH2C).
31P{1H}-NMR (CDCl3): l −21.7 (s). IR (cm−1, KBr):
2031vs, 1952vs, 1896vs (CꢀO), 1734m (CꢁO, ester
linkage).
2.2.4. [ReBr(CO)3{(Ph2PCH2)2NCH2CONHCH2-
COOCH2Ph}] (10)
The bis(diphenylphosphinomethyl)amine 4 (124 mg,
0.2 mmol) gave complex 10 (134 mg, 69%). Found for
C40H36BrN2O6P2Re: C, 49.6; H, 3.8; N, 2.9. Calc.: C,
49.6; H, 3.8; N, 2.9%. 1H-NMR (CDCl3): 7.44–7.25 (m,
25H, Ph), 5.50 (m, 1H, NH), 5.13 (s, 2H, OCH2Ph),
4.37 (m, 2H, CH2P), 3.42 (m, 2H, CH2P), 3.32 (m, 4H,
NCH2C). 31P{1H}-NMR (CDCl3): l −18.1 (s). IR
(cm−1, KBr): 2032vs, 1954vs, 1904vs (CꢀO), 1735m,
1673m (CꢁO, ester and amide linkages).
2.4. X-ray crystallography
Colorless crystals of 7 suitable for X-ray diffraction
analysis were obtained from
a CH2Cl2–CHCl3–
C2H5OH solution at −20 °C and colorless crystals of 9
and 10 were obtained from a CH2Cl2–C2H5OH solu-
tion at −20 °C. All the crystals take the form of
rectangular blocks. Data collection was carried out on
a Siemens SMART CCD diffractometer using Mo–Ka
2.2.5. [ReBr(CO)3{(Ph2PCH2)2NCH2COOH}] (11)
The bis(diphenylphosphinomethyl)amine 5 (94 mg,
0.2 mmol) gave complex 11 (87 mg, 53%). Found for
C31H27BrNO5P2Re: C, 45.5; H, 3.3; N, 1.7. Calc.: C,
,
radiation (u 0.71073 A). The data were corrected for
absorption effects using the SADABS program [17].
Crystal and refinement data are summarized in Table 1.
The structures of the three complexes were solved by
direct methods and difference Fourier maps. Full-ma-
trix least-squares refinements (on F2) were carried out
1
45.3; H, 3.3; N, 1.7%. H-NMR (CDCl3): l 7.71–7.29
(m, 20H, Ph), 4.62 (m, 2H, CH2P), 3.47 (m, 2H, CH2P),
3.32 (s, 2H, NCH2C). 31P{1H}-NMR (CDCl3): l −

126
J. Zhang et al. / Journal of Organometallic Chemistry 650 (2002) 123–132
Table 1
Crystallographic data
7·CHCl3
9
10
Empirical formula
Formula weight
Space group
C36H30BrC13NO3P2Re
959.01
C38H33BrNO5P2Re
911.70
Pbca
Orthorhombic
16.4076(3)
17.3407(4)
25.0776(5)
90
90
90
7135.1(3)
8
C40H36BrN2O6P2Re
968.76
(
(
P1
P1
Crystal system
Triclinic
11.6694(5)
12.4671(6)
14.8036(7)
113.358(1)
98.992(1)
105.582(1)
1818.5(2)
2
Triclinic
9.9690(1)
12.4920(2)
16.1088(2)
102.511(1)
96.301(1)
94.926(1)
1934.14(4)
2
,
a (A)
,
b (A)
,
c (A)
h(o)
i (o)
k (o)
3
,
V (A )
Z
Temperature (K)
293(2)
223(2)
223(2)
Crystal dimensions (mm)
0.18×0.10×0.08
4.785
49.4
0.26×0.24×0.06
4.660
58.6
0.26×0.14×0.10
4.305
58.6
v(Mo–Ka) (mm−1
Max. 2q (°)
)
Number of reflections collected
9064
42 627
12 688
Number of unique reflections (Rint
Completeness of data to 2qmax (%)
Max/min transmission
)
5965 (0.0318)
95.9
0.7299, 0.5436
425
0.0511
0.1111
9017 (0.0433)
92.5
0.6040, 0.3850
433
0.0332
0.0547
9000 (0.0168)
85.2
0.7045, 0.5100
469
0.0288
0.0643
Number of parameters
a
R1
b
wR2
a R1=SꢀꢀFoꢀ−ꢀFcꢀꢀ/SꢀFoꢀ.
b wR2=[S[w(Fo2−Fc2)2]/S[w(F2o)2]]1/2
.
with anisotropic thermal parameters for all non-hydro-
gen atoms, using all of the unique data. All hydrogen
atoms were introduced in calculated positions and
refined using the riding model. Computations were
carried out using the SHELXTL software package [18].
Selected geometric parameters of the complexes are
given in Table 2.
3. Results and discussion
3.1. Syntheses
The Mannich reactions of aniline, ethanolamine,
H2NCH2COOCH2Ph, H2NCH2CONHCH2COOCH2-
Ph, H2NCH2COOH and ethylene diamine gave bis-
(diphenylphosphinomethyl)amines 1–6, respectively.
The reaction involving the benzyl-protected glycine
tended to be cleaner than the reaction involving glycine
itself. Reactions of [NEt4]2[ReBr3(CO)3] and these bis-
(diphenylphosphinomethyl)amines gave the rhenium
complexes 7–12, respectively (Scheme 1). Complexes
7–10 are soluble in CH2Cl2 and CHCl3, and slightly
soluble in H2O, MeOH and EtOH. Complex 11 has
higher solubility in H2O due to its carboxylic acid
group, which can potentially also be functionalized for
attachment to antibodies. Unexpectedly complex 12 is
virtually insoluble in all these solvents.
2.5. Cytotoxicity tests
Complexes 7–10 and 12 were tested for cytotoxic
activity by homogenizing the compounds as a 1 mg
ml−1 solution in 0.05% Tween 80–H2O. These solu-
tions were sterilized by passing them through an
acrodisc (0.45 mm). The cell lines investigated (Table 4)
were maintained by literature techniques [19]. The NCI
protocol was used to assess the cytotoxicity of the test
compounds and standard drugs in each cell line [19].
The number of cells was determined by the trypan blue
exclusion technique [19] and the percent inhibition of
growth for each concentration of compound was calcu-
lated and averaged (N=4). The percent inhibition was
plotted against the log of the concentration of com-
pound and the ED50 value (concentration of compound
in mg ml−1 inhibiting 50% of cell growth) estimated.
Solid tumor cytotoxicity was determined using crystal
violet–MeOH and read at 580 nm (Molecular Devices)
[20]. An ED50 value of less than 4 mg ml−1 was required
for significant activity for inhibition of cell growth [19].
3.2. Crystal structures
In order to confirm the formation and geometry of
the rhenium diphosphine complexes, X-ray structure
determinations were carried out on 7, 9 and 10 (Figs.
1–3). Rhenium preferentially bonds to the phosphorus
atoms of these bis(diphenylphosphinomethyl)amines as
expected. The nitrogen atoms are uncoordinated and
the six-membered chelate rings adopt chair conforma-

J. Zhang et al. / Journal of Organometallic Chemistry 650 (2002) 123–132
127
tions with the nitrogen and rhenium atoms out of the
plane formed by the C2P2 unit. This is unlike the reported
palladium, platinum and rhodium complexes of bis(-
diphenylphosphinomethyl)amines, in which the chelate
rings adopt a flattened chair conformation with only the
nitrogen atom substantially out of the plane formed by
the C2P2M (M=Pd, Pt or Rh) [11,12] unit. The nitrogen
atoms of compounds 7, 9 and 10 are progressively more
pyramidal [average CꢂNꢂC angles: 116.0(7)° for 7,
112.7(3)° for 9, and 109.6(2)° for 10]; this is most likely
a reflection of the decreasing steric hindrance at the
nitrogen atom. The carbonyl groups are in the expected
facial arrangement within the distorted octahedral coor-
dination sphere of each of compounds 7, 9 and 10. The
Table 2
,
Selected bond lengths (A) and bond angles (°) for 7, 9 and 10 with
estimated standard deviations in parentheses
7
9
10
Fig. 1. Crystal structure of [ReBr(CO)3{(Ph2PCH2)2NPh}] 7 with
40% probability thermal ellipsoids. Hydrogen atoms on phenyl rings
are omitted for clarity.
Bond lengths
Re(1)ꢂC(1)
Re(1)ꢂC(2)
Re(1)ꢂC(3)
Re(1)ꢂP(2)
Re(1)ꢂP(1)
Re(1)ꢂBr(1)
P(1)ꢂC(4)
1.900(11)
1.941(11)
1.942(12)
2.461(2)
2.468(2)
2.6460(10)
1.853(8)
1.893(3)
1.964(4)
1.969(3)
2.4669(8)
2.4848(8)
2.6604(4)
1.853(3)
1.851(3)
1.474(4)
1.476(4)
1.898(4)
1.951(4)
1.949(4)
2.4561(8)
2.4690(9)
2.6537(4)
1.856(3)
1.849(3)
1.478(4)
1.471(4)
P(2)ꢂC(5)
1.852(8)
N(1)ꢂC(4)
N(1)ꢂC(5)
N(1)ꢂC(1E)
N(1)ꢂC(6)
1.464(10)
1.452(10)
1.416(10)
1.462(4)
1.485(4)
Bond angles
C(1)ꢂRe(1)ꢂC(2)
C(1)ꢂRe(1)ꢂC(3)
C(2)ꢂRe(1)ꢂC(3)
C(1)ꢂRe(1)ꢂP(2)
C(2)ꢂRe(1)ꢂP(2)
C(3)ꢂRe(1)ꢂP(2)
C(l)ꢂRe(1)ꢂP(1)
C(2)ꢂRe(1)ꢂP(1)
C(3)ꢂRe(1)ꢂP(1)
P(2)ꢂRe(1)ꢂP(1)
C(1)ꢂRe(1)ꢂBr(1)
C(2)ꢂRe(1)ꢂBr(1)
C(3)ꢂRe(1)ꢂBr(1)
P(2)ꢂRe(1)ꢂBr(1)
P(1)ꢂRe(1)ꢂBr(1)
C(4)ꢂP(1)ꢂRe(1)
C(5)ꢂP(2)ꢂRe(l)
C(1E)ꢂN(1)ꢂC(5)
C(1E)ꢂN(1)ꢂC(4)
C(6)ꢂN(1)ꢂC(4)
C(6)ꢂN(1)ꢂC(5)
C(5)ꢂN(1)ꢂC(4)
N(1)ꢂC(4)ꢂP(1)
N(1)ꢂC(5)ꢂP(2)
89.5(4)
90.3(4)
89.3(4)
95.3(3)
91.2(3)
174.4(3)
95.1(3)
175.3(3)
91.4(3)
87.66(7)
175.7(3)
86.6(3)
91.6(3)
82.83(6)
98.73(6)
115.2(3)
112.6(3)
116.0(7)
118.8(7)
88.40(14)
89.95(14)
89.86(15)
94.56(10)
90. 19(11)
175.49(11)
97.31(10)
173.14(11)
93.92(10)
85.60(3)
176.16(10)
87.76(11)
89.97(11)
85.52(2)
86.52(2)
114.06(11)
113.35(11)
89.25(16)
88.98(15)
89.18(18)
93.68(10)
91.03(13)
177.33(11)
96.20(12)
174.44(11)
92.04(13)
87.50(3)
177.74(11)
91.29(11)
88.83(l1)
88.51(2)
83.31(2)
114.41(11)
116.19(11)
Fig. 2. Crystal structure of [ReBr(CO)3{(Ph2PCH2)2NCH2-
COOCH2Ph}] 9 with 50% probability thermal ellipsoids. Hydrogen
atoms are omitted for clarity.
111.2(3)
111.8(2)
115.2(3)
113.9(2)
113.7(2)
109.0(2)
107.4(2)
112.3(2)
112.4(2)
117.6(2)
113.3(7)
112.8(5)
112.5(5)
ReꢂBr, ReꢂCO and ReꢂP distances found for these
structures are typical for analogous rhenium(I) tricar-
bonyl complexes [21].

128
J. Zhang et al. / Journal of Organometallic Chemistry 650 (2002) 123–132
3.3. NMR spectroscopy
increasing cone voltage. The presence or absence of Br
in an ion can be readily ascertained from the isotope
pattern of the ion, due to the distinctive isotopic signa-
ture of bromine. At low cone voltages (e.g. 20 V)
spectra are dominated by the [M+H]+ ions (e.g. for 8
at m/z 808). For complex 7, protonation can only be at
the nitrogen atom, since the CO ligands are not ex-
pected to show any basicity, but for 8, 9 and 10, there
are additional oxygen atoms which are also available
for protonation. Aggregate ions of the type [2M+H]+
were observed in some cases. Complex 10 showed a
strong [2M+H]+ ion (m/z 1940), presumably due to
the ready ability of this species to engage in hydrogen
bonding. Further increasing the cone voltage (to 80 V
or higher) results in loss of CO ligands, e.g. for 9, where
ions [M−Br−CO]+ (m/z 804) and [M−Br−2CO]+
(m/z 776) ions were observed at 100 V.
The 31P{1H}-NMR spectrum of each rhenium com-
plex consists of a single sharp resonance, indicating the
formation of a single isomer with a plane of symmetry.
1
The H-NMR spectra show a characteristic pattern for
the methylene protons of the chelate ring. There are
two distinct environments for the four protons, due
both to the equatorial/axial distinction in the chair
conformation, and to the position of the bromide lig-
and. The 1H-1H ROESY spectrum of complex 7 is
shown in Fig. 4 as a representative spectrum. The signal
at 4.14 ppm is assigned to the equatorial protons
because these protons are nearer to the ortho protons of
the N-bonded phenyl ring (Fig. 1), and hence are
expected to have stronger interaction with the latter
(cross-peak B is stronger than cross-peak C).
In some cases several drops of pyridine were added
to the analyte solutions, both to increase the solubility
of the complexes (which in some cases were of low
solubility) and to investigate whether the neutral pyri-
dine ligand could replace the bromide ligand, leading to
charged [M−Br+pyridine]+ ions, as has been ob-
served for a wide range of other transition metal halide
complexes [22]. However, no pyridine-containing ions
were observed.
The glycine complex 11, containing a carboxylic acid
group, gave the expected intense [M−H]− ion (m/z
820) as the base peak at low cone voltages. No Re-con-
taining ions were observed in positive-ion mode. On
increasing the cone voltage, fragmentation of the parent
ion occurs, via loss of up to two CO ligands, decar-
boxylation of the CO−2 group, and fragmentation of the
phosphine ligand, giving a coordinated Ph2P group in
[Ph2PRe(CO)3Br]−. This ion also undergoes loss of one,
two or three CO ligands, giving the series of
[Ph2PRe(CO)nBr]−ions (n=0–3). Ultimately, at a very
high cone voltage of 160 V, the [P(C6H4)ReBr]−ion
(m/z 373) is observed, which can be distinguished from
the isobaric Ph2PReH by its isotope pattern. This spe-
cies presumably contains a cyclometallated C6H4P moi-
ety, with a four-membered ReꢂPꢂCꢂC ring. Finally, the
negative-ion spectrum of complex 8 was recorded, but
no ions (expected to be formed by deprotonation of the
OH group) were observed.
3.4. Electrospray (ES) mass spectrometric
characterization
Positive-ion ES spectra of the rhenium bis-
(diphenylphosphinomethyl)amine complexes 7–10 and
12 were recorded in both methanol and acetonitrile–
water solutions; ions observed in methanol solution are
given in Table 3. Generally, spectra recorded in
methanol were of better quality, probably due to im-
proved solubility in this solvent. Complex 12, however,
did not give useful spectra, presumably due to its very
poor solubility. At cone voltages of 50–60 V complexes
7, 8, 9 and 10 give both [M+H]+ and [M−Br]+ ions,
with the relative intensity of the former decreasing with
3.5. Stability studies
The stability of the rhenium–phosphine complexes,
in neutral, acidic and basic methanol solutions has also
been qualitatively surveyed by ES mass spectrometry,
by recording spectra of solutions aged for several
weeks. In neutral solutions, spectra of complexes 7, 8,
and 9 were generally similar to those of fresh solutions,
giving [M+H]+ and [M−Br]+ ions. Comparison of
the aged solution of 8 with a fresh solution indicated
Fig. 3. Crystal structure of [ReBr(CO)3{(Ph2PCH2)2NCH2-
CONHCH2COOCH2Ph}] 10 with 50% probability thermal ellipsoids.
Hydrogen atoms are omitted for clarity.

J. Zhang et al. / Journal of Organometallic Chemistry 650 (2002) 123–132
129
Fig. 4. Two-dimensional 1H ROESY-NMR spectrum of complex 7 in CDCl3 at 300.0 K. Selected NOE contacts: A, equatorial-CH2···axial-CH2;
B, equatorial-CH2···o-NꢂC6H5; C, axial-CH2··· o-NꢂC6H5.
Table 3
ESMS data for the rhenium bis(diphenylphosphinomethyl)amine complexes in methanol
Complex
Cone voltage (V) Fragment assignment [m/z, relative intensity (%)]
7
20
50
[M+H]+ (m/z 840, 100%), [M−Br]+ (m/z 760, 55%)
[M+H]+ (m/z 840, 52%), [M−Br]+ (m/z 760, 100%)
8
20
50
20
50
20
50
[M+H]+ (m/z 808, 100%), [M−Br]+ (m/z 728, 5%), [2M+H]+ (m/z 1615/1617, 5%)
[M+H]+ (m/z 808, 100%), [M−Br]+ (m/z 728, 53%), [2M+H]+ (m/z 1615/1617, 3%)
[M+H]+ (m/z 912, 100%), [M−Br]+ (m/z 832, 12%), [2M+H]+ (m/z 1823/1825, 10%)
[M+H]+ (m/z 912, 100%), [M−Br]+ (m/z 832, 90%)
9
10
11 a
[M+H]+ (m/z 969, 100%), [M−Br]+ (m/z 889, 5%), [2M+H]+ (m/z 1937/1939, 10%)
[M+H]+ (m/z 969, 100%), [M−Br]+ (m/z 889, 73%), [2M+H]+ (m/z 1937/1939, 18%)
[M−H]− (m/z 820, 100%), [2M−H]− (m/z 1641, 5%)
20
160 b
[PC6H4ReBr]− (m/z 373, 100%), [Ph2PReBr]− (m/z 451, 18%), [Ph2PReBr(CO)]− (m/z 479, 19%),
[Ph2PReBr(CO)2]− (m/z 507, 21%), [Ph2PReBr(CO)3]− (m/z 535, 20%), [M−H−2CO]− (m/z 764, 17%),
[M−H−CO]− (m/z 792, 16%), [M−H]− (m/z 820, 70%), [2M−H]− (m/z 1641, 50%)
[M+H]+ (m/z 1554, trace), [M−Br]+ (m/z 1473, trace), plus several unidentified ions
12
50
a Recorded in negative ion mode.
b Ions with relative intensity \10% only.

130
J. Zhang et al. / Journal of Organometallic Chemistry 650 (2002) 123–132
that the aged solution had a higher intensity [M−Br]+
ion, together with additional low intensity ions [M−
Br+NH3]+ and [M−Br+MeOH]+. For complex 10,
the expected [M+H]+ and [M−Br]+ ions were ob-
served, together with a weak ion at m/z 879, assigned to
[ReBr(CO)3{(Ph2PCH2)2NCH2C(O)NHCH2CO2H}+
H]+, formed by hydrolysis of the terminal benzyl group
in 10. These observations suggest that the complexes
are generally stable in neutral methanol, and that ES
mass spectrometry can be used to identify degradation
products.
In aged acidic solutions (prepared by addition of a
small quantity of formic acid to the Re complex solu-
tions), complexes 7, 8 and 9 again yielded similar
spectra to the neutral solutions, indicating that the
complexes are quite stable in dilute acid solutions. The
ion [PhN{CH2P(O)Ph2}2+H]+ (m/z 522) was observed
for 7, which was not seen in fresh solutions, nor in the
aged neutral solution. For complex 10 considerable
reaction appeared to have occurred, with one ion at
m/z 760 assigned to [Re(CO)3(MeOH){(Ph2PCH2)2-
NCH2CO2H}]+ and the corresponding unsolvated ion
at m/z 729. This seems to suggest that the C(O)NH
linkage of 10 is susceptible to acid hydrolysis but the
C(O)O linkage of 9 is less so. This observation may
have implications on the choice of linker chains be-
tween the metal complex moiety and the antibody in
the radiopharmaceutical conjugate. Ideally, the linker
chain must be sufficiently stable to allow the conjugate
to survive the journey to the target tumor site, but must
be metabolized eventually to facilitate the clearance of
radioactivity from non-target tissue [23].
In aged basic solutions (formed by addition of dilute
NH3 solution) reactivity was much greater, and more
hydrolysis was observed. For 7, the diphosphine diox-
ide ion at m/z 522 was more intense, a weak [M+H]+
ion was seen, together with major ions [M−Br+
NH3]+ and [M−Br+MeOH]+; complex 8 behaved
similarly. For 9 considerable solvolysis occurred, with
the base peak at m/z 759 assigned to [Re(CO)3(MeOH)-
{(Ph2PCH2)2NCH2CO2H}]+, plus other unidentified
ions of similar masses. The ion at m/z 759 is formed by
loss of the bromide ion (and coordination of methanol)
together with hydrolysis of the ester linkage. Solvolysis
of 10 appeared to be even more severe, with no [M+
H]+ ion remaining. The base peak at m/z 831 is
assigned to [Re(CO)3(NH3){(Ph2PCH2)2NCH2C(O)-
NHCH2C(O)NH2}+NH3]+, with a hydrogen-bonded
NH3 molecule. Other major ions observed include
[Re(CO)3{(Ph2PCH2)2NCH2C(O)NHCH2CO2H}]+ (m/
z 798), [Re(CO)3(NH3){(Ph2PCH2)2NCH2CO2Me}+
NH3]+ (m/z 805), and [Re(CO)3(H2O){(Ph2PCH2)2-
NCH2C(O)NHCH2CO2H}]+ (m/z 816). Since all these
ions retain the amide linkage, it appears that the amide
linkage is robust under mildly basic conditions.
These preliminary studies suggest that the rhenium–
bis(diphenylphosphinomethyl)amine complexes possess
significant stability in neutral and mildly acidic solu-
tions, but substantial degradation occurs in basic solu-
tion. It must be emphasized, however, that the
diphosphine–rhenium chelate unit remains largely in-
tact in all the above studies, i.e. any degradation ob-
served does not cleave the diphosphine from the
rhenium atom. This is significant because one of the
most important criteria for choosing a ligand system
for the conjugation of radionuclides to antibodies for
radioimmunotherapy is the stability of the conjugate.
The solvolysis in basic medium may also represent a
possible pathway for the interaction of the [ReBr(CO)3]
moiety with blood proteins.
3.6. Cytotoxicity
Complexes 7–10 and 12 generally showed potent
cytotoxicity in the suspended murine and human
leukemias and lymphoma, as well as the HeLa sus-
pended uterine carcinoma cells (Table 4). The com-
pounds were however much more selective in inhibiting
the growth of tumors derived from human solid
cancers.
The pattern of cytotoxic activity shown by complexes
7–10 and 12 shows some similarities to that of the
rhenium alkoxo complexes [Re2(m-OR)3(CO)6]− (R=
H, Me, Et, Ph), [Re2(m-OH)(m-OPh)2(CO)6]−, [Re2-
(m-OR)2(m-dppf)(CO)6] [dppf=1,1%-bis(diphenylphos-
phino)ferrocene; R=H, Me, Ph] and fac-[Re(OPh)(h2-
dppf)(CO)3] [14]. For example, all of these rhenium
complexes show activity against L1210 mouse
leukemia, P388 mouse lymphocytic leukemia, HuT-78
Lymphoma and HeLa-S3 suspended uterine carcinoma
cells, and all are inactive against KB nasopharynx cells.
However, complexes 7–10 and 12 (average ED50 for
MCF-7=2.37 mg ml−1) show much higher activity
against MCF-7 breast cancer cells than the rhenium
alkoxo complexes (average ED50 for MCF-7=9.96 mg
ml−1) [14]. It is noteworthy that compounds 7–10 and
12 show no activity against non-cancerous human
fibroblast cells (Table 4). This is an important property
for any chemotherapeutic agent since harmful side-ef-
fects of the treatment will be minimized.
Whilst it would be premature to draw any definite
conclusions on the molecular mechanism responsible
for the activity of compounds 7–10 and 12, it seems
probable that complexes 7–10 and 12 would bind to
DNA bases or side-chains of amino acid residues in
peptides and proteins after displacement of the bromide
ligands; the feasibility of this process is illustrated by
the ESMS studies in basic medium discussed earlier.
The stable (as shown by ESMS) [Re(CO)3(diphos-
phine)] moiety most probably remains intact, with the

J. Zhang et al. / Journal of Organometallic Chemistry 650 (2002) 123–132
131
Table 4
Cytotoxicity of complexes 7–10 and 12, expressed as ED50 values (mg ml−1
a
)
Tumor cell line
7
8
9
10
12
Standards b
6-MP
Ara-C
Suspension cultured cells
L1210 mouse leukemia
P388 mouse lymphocytic leukemia
HL-60 human leukemia
T molt3 human T cell leukemia
T molt4 human T cell leukemia
HuT-78 lymphoma
2.36
2.72
3.42
3.27
4.52
2.60
2.10
2.69
1.72
2.91
3.33
4.70
4.36
2.96
3.28
2.32
1.92
2.30
2.14
5.17
4.32
2.55
3.30
2.68
2.80
2.90
2.02
2.05
3.06
6.16
2.70
3.87
1.45
2.43
2.04
3.35
1.62
2.67
1.68
3.03
2.12
2.07
0.79
4.00
2.67
2.36
2.50
2.54
2.13
3.61
3.37
3.01
3.64
3.53
5.21
2.85
THP-1 acute monocytic leukemia
HeLa-S3 suspended uterine
Solid tumor cultures
KB nasopharynx
Lung 549
6.88
8.02
7.71
3.52
8.99
5.45
4.59
6.11
3.90
4.76
4.88
4.02
3.39
2.01
6.49
10.69
5.32
4.18
7.30
5.07
4.34
8.51
8.92
2.37
9.05
3.95
5.86
3.45
5.06
4.02
6.45
3.24
3.72
2.42
6.67
4.55
7.72
13.3
8.61
4.49
5.49
6.82
7.39
1.53
7.78
5.65
5.00
2.87
4.95
3.74
11.04
4.71
6.64
8.84
4.46
1.15
9.13
6.86
-
2.84
5.62
5.39
12.45
1.88
2.54
0.86
10.53
–
Ovary 1-A9
Breast MCF-7 effusion
Glioma UM 86
Ileum HCT-8
Osteosarcoma HSO
Melanoma SK2
Prostate PL
Liver Hepe-2
–
–
Non-cancerous human cells
RMPI 1788 fibroblast
6.78
7.02
7.60
6.86
9.31
–
–
a ED50 values refer to the concentration of the compound inhibiting 50% of cell growth. A value of less than 4 mg ml−1 is required for significant
activity for inhibition of cell growth [19].
b 6-MP=6-mercaptopurine, Ara-C=Cytosine b-
D-arabinofuranoside.
OH, NH and CꢁO groups on the diphosphine ligands
of complexes 8, 9 and 10 contributing further to the
binding with biomolecules via hydrogen bonding. It is
worth mentioning that the related complexes [Re2(m-
OH)3(CO)6]−, [Re2(m-OH)(m-OPh)2(CO)6]−, [Re2(m-
OMe)2(m-dppf)(CO)6] and [Re2(m-OPh)2(m-dppf)(CO)6]
have been shown to interfere with nucleic acid
metabolism at multiple enzyme sites in L1210 lymphoid
leukemia cells, and cause DNA strand scission after 60
min incubation [14].
amine-containing biomolecules with radioactive tricar-
bonylrhenium(I) fragments for radioimmunotherapy.
Complexes 7–10 and 12 also show cytotoxic activity
against several murine and human cancer cell lines,
suggesting that bis(diphenylphosphinomethyl)amine
rhenium(I) complexes with 186Re or 188Re radionuclides
can potentially have dual functions, as both chemo-
and radiotherapeutic agents, in cancer therapy.
5. Supplementary material
4. Conclusions
Crystallographic data for the structural analyses have
been deposited with the Cambridge Crystallographic
Data Centre, CCDC nos. 173096 for 7, 173097 for 9,
and 173098 for 10. Copies of this information may be
obtained free of charge from The Director, CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (Fax: +44-
1223-336033; e-mail: deposit@ccdc.cam.ac.uk or www:
http://www.ccdc.cam.ac.uk).
Bis(diphenylphosphinomethyl)amines are excellent
chelating ligands to tricarbonylrhenium(I) fragments.
Complex 11 has a free carboxyl group offering a poten-
tially reactive site for functionalization and coupling to
antibodies. Deprotection of complexes 9 and 10 by
removal of the benzyl group by hydrogenation would
also yield free carboxyl groups for protein conjugation.
ESMS studies show that the rhenium–phosphine
chelate unit is very stable, especially in neutral solution
(similar pH to blood serum). These bis(diphenylphos-
phinomethyl)amine rhenium(I) complexes thus provide
an ideal model for the labeling of antibodies or other
Acknowledgements
We acknowledge the support by the National Uni-
versity of Singapore (NUS) (RP 143-000-013-112) and

132
J. Zhang et al. / Journal of Organometallic Chemistry 650 (2002) 123–132
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advice in some syntheses. J.Z. thanks NUS for a re-
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