Synthesis and structure-activity relationships of metal-ligand complexes that potently inhibit cell migration

Article abstract of DOI:10.1016/j.bmcl.2007.11.099

We screened the National Cancer Institute Diversity Set compound collection for small molecules that affect mammalian cell migration and identified NSC 295642 as an inhibitor of cell motility with nanomolar potency. We found by LC-MS and X-ray crystallogr

Full text of DOI:10.1016/j.bmcl.2007.11.099

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 498–504
Synthesis and structure–activity relationships of metal–ligand
complexes that potently inhibit cell migration
*
´
´
Anwar B. Beshir, Sankar K. Guchhait, Jose A. Gascon and Gabriel Fenteany
Department of Chemistry, University of Connecticut, Storrs, CT 06269, USA
Received 29 September 2007; revised 23 November 2007; accepted 27 November 2007
Available online 3 December 2007
Abstract—We screened the National Cancer Institute Diversity Set compound collection for small molecules that affect mammalian
cell migration and identified NSC 295642 as an inhibitor of cell motility with nanomolar potency. We found by LC–MS and X-ray
crystallography that NSC 295642, a Cu(II) complex of the Schiff base product of condensation of S-benzyl dithiocarbazate and 2-
acetylpyridine, has a bridged dimeric Cu2Cl2(L)2 structure with distorted square pyramidal geometry. Each of the two copper atoms
is five-coordinated to one of the two tridentate chelating ligands and both bridging chlorine atoms. To define structure–activity rela-
tionships, we investigated the bioactivity of related metal–ligand complexes derived from different metal(II) atoms and different
ligands. Complexation of the NSC 295642 ligand with Zn(II) or Ni(II), delivered as metal(II) chloride salts under conditions iden-
tical to those used for preparation of the original Cu(II) complex, instead results in distorted octahedral bis-chelate structures, where
a single metal atom is six-coordinated to two ligands. The Zn(L)2 complex possesses a potency similar to that of the Cu2Cl2(L)2
complex, while the Ni(L)2 has no antimigratory activity at all. We carried out density functional theory calculations to obtain
the electronic ground state geometry of the complexes, both in vacuum and implicit water solvent. The X-ray crystal and
energy-minimized structures are very similar and exhibit a transoid orientation of the S-benzyl groups relative to the central
metal-coordinated rings for both of the bioactive Cu2Cl2(L)2 and Zn(L)2 complexes, despite their different coordination geometries.
In contrast, the biologically inactive Ni(L)2 complex adopts a cisoid conformation. Varying the ligand structure, we found that
hydrophobic S-alkylaryl groups are required for activity. Complexes with a simple S-methyl group, S-benzyl groups with polar sub-
stitutions or a carboxylated pyridine ring exhibit dramatically reduced activity. We tested the most potent metal–ligand complex in a
number of cancer cell lines and found cell-type selectivity in its effect on cell motility. Collectively, these results suggest that a two-
ligand structure with bulky nonpolar S-substituents in a transoid conformation is important for the antimigratory activity of these
metal–ligand complexes.
Ó 2008 Published by Elsevier Ltd.
Complexes of metals and organic ligands are becoming
recognized as useful probes for biological research and
as potential therapeutic agents.1 Certain metal–ligand
complexes can form structures that resemble traditional
drug-like organic molecules. In these complexes, the me-
tal serves to coordinate the organic ligand, thus poten-
tially generating an organic pharmacophore whose
structure is determined by the structure imposed upon
the ligand through chelation of the metal. A number
of biologically active metal–ligand complexes of this
kind have been identified.1
Cell migration is a basic biological process involved in
a range of normal and pathological events, including
wound healing, embryonic and tissue development,
immune function and inflammation, angiogenesis and
tumor metastasis. We screened the National Cancer
Institute (NCI) Diversity Set collection of compounds
in a cell migration assay based on the closure of
scratch wounds by Madin–Darby canine kidney
(MDCK) epithelial cell sheets in culture, a system
we have previously used to identify new agents with
antimigratory activity.2–4 Here we report that NSC
295642 (Fig. 1), a Cu(II) complex of the Schiff base
product of condensation of S-benzyl dithiocarbazate
and 2-acetylpyridine, is a potent inhibitor of cell
motility with an IC50 of 93 nM (Table 1). This com-
pound has also been reported to weakly inhibit the
dual specificity phosphatase Cdc25.5 Other complexes
of the same ligand have antifungal6 and antiamoebic
activities.7,8
Keywords: Cell migration inhibitors; Metal–ligand complexes; Struc-
ture–activity relationships.
*
Corresponding author. Tel.: +1 860 486 6645; fax: +1 860 486
2981; e-mail: gabriel.fenteany@uconn.edu
Present address: Department of Medicinal Chemistry, National
Institute of Pharmaceutical Education and Research, SAS Nagar,
Punjab 160062, India.
0960-894X/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2007.11.099

A. B. Beshir et al. / Bioorg. Med. Chem. Lett. 18 (2008) 498–504
499
S
N
S
N
S
N
N
N
Ni
N
N
Zn
N
S
N
Cu
N
S
S
N
N
S
S
N
N
S
Cl Cl
Cu
N
N
S
N
S
N
S
Cu2Cl2(L1)2
Zn(L1)2
Ni(L1)2
S
N
S
N
N
N
S
N
Cu
N
S
S
N
S
Cl Cl
Cu
Zn
N
S
N
N
N
N
N
S
Cu
Cl
N
S
N
S
Cu2Cl2(L2)2
Zn(L2)2
CuCl(L3)
MeO
F
S
N
S
N
N
N
S
N
Cu
Cl Cl
Cu
N
S
S
N
Cu
Cl Cl
Cu
N
S
O
S
N
N
OH
N
N
S
Cu
Cl
N
N
N
S
S
Cu2Cl2(L4)2
CuCl(L6)
Cu2Cl2(L5)2
OMe
F
Figure 1. Metal(II)–ligand complexes synthesized and tested for antimigratory activity.
Table 1. Antimigratory activity of NSC 295642 and its analogs
MICb (nM)
% of controlc
MLCd (nM)
a
IC50 (nM)
Compound
Cu2Cl2(L1)2
Zn(L1)2
93
75
50
34
56
2000
1000
1000
1000
1000
3000
500
238
NAe
58
Ni(L1)2
NA
30
NA
29
Cu2Cl2(L2)2
Zn(L2)2
CuCl(L3)
Cu2Cl2(L4)2
Cu2Cl2(L5)2
CuCl(L6)
181
NA
Tf
100
NA
T
44
NA
—
T
NA
T
NA
—
NA
500
2000
a Concentration for half-maximal inhibition of wound closure at 24-h post-wounding.
b Minimum inhibitory concentration (lowest concentration that showed statistically significant inhibition of wound closure at 24-h post-wounding,
based on unpaired two-tailed Student’s t-test with p < 0.05).
c Degree of inhibition of wound closure at 24-h post-wounding expressed as a function of percent of parallel controls at maximal subtoxic
concentrations. The smaller the value, the more bioactive the compound is.
d Minimum lethal concentration (as determined by the Trypan blue dye exclusion assay).
e No activity; not significantly different from control.
f Cytotoxic without any subtoxic antimigratory activity.
We prepared NSC 295642 and found the compound
synthesized in our laboratory to have biological activity
that was indistinguishable from the sample from NCI.
This molecule and the other complexes described below
were prepared by synthesis of the different ligands and
complexation with metal(II), delivered as CuCl2, ZnCl2
or NiCl2, as shown in Schemes 1 and 2.9–13 Although
NSC 295642 is depicted as a single-ligand structure of

500
A. B. Beshir et al. / Bioorg. Med. Chem. Lett. 18 (2008) 498–504
H
H
1. EtOH/H2O (9:1), KOH
2. CS2, 0 °C
RX
K
S
N
S
N
NH2NH2•H2O
NH2
R
NH2
EtOH/H O (9:1), 0 C
°
2
S
S
O
EtOH,
reflux
N
R
S
N
N
Cu2Cl2(L1)2: R = Bn
H
S
Cu
N
CuCl2
Cu2Cl2(L2)2: R = Naphthalen-2-ylmethyl
Cu2Cl2(L4)2: R = 4-Methoxybenzyl
Cu2Cl2(L5)2: R = 4-Fluorobenzyl
S
N
R
N
Cl Cl
Cu
EtOH, reflux
N
S
S
N
N
N
S
R
CuCl2,
EtOH,
reflux
MCl2,
EtOH,
reflux
R
S
N
R
S
N
M
N
M = Metal(II)
N
Zn(L1)2: R = Bn
S
N
N
S
N
Ni(L1)2: R = Bn
S
Cu
Cl
N
Zn(L2)2: R = Naphthalen-2-ylmethyl
N
S
R
CuCl(L3): R = CH3
Scheme 1. Synthesis of metal(II) complexes of Schiff base products of condensation of S-alkyl dithiocarbazates with 2-acetylpyridine (L1 to L5
complexes).
O
O
O
O
NaOH, H2O
reflux
OCH3
OH
N
N
S-benzyl dithiocarbazate,
EtOH, reflux
CuCl2
O
O
H
S
N
S
N
EtOH, reflux
N
OH
N
OH
S
Cu
Cl
N
S
N
Scheme 2. Synthesis of CuCl(L6) complex.
basic formula CuCl(L1) in the NCI’s Developmental
Therapeutics Program database, both the NCI sample
and the material we prepared are dimers. The complex
has a basic formula of Cu2Cl2(L1)2 and is composed of
two five-coordinate copper atoms each chelated by one
of the tridentate ligands and bridged by the two chlorine
atoms (Fig. 1), based on LC–MS13 and X-ray
crystallography.14
ligands form a bis-chelate structure with a single six-
coordinate zinc atom, a complex with a basic formula
of Zn(L1)2, as determined by LC–MS13 and X-ray crys-
tallography.14 Since Zn(II) is diamagnetic, unlike the
paramagnetic Cu(II), we acquired 1H and 13C NMR
spectra for the Zn(L1)2 complex.13 The NMR data also
suggest a stable Zn(L1)2 structure, with diastereotopic S-
benzyl methylene protons, and are not consistent with a
mixture of dissociated single-ligand Zn(L1) complex and
free ligand; furthermore, the free ligand displays a dis-
tinct NMR profile.13 In addition, a complex of Zn(II)
with an almost identical ligand that simply lacks the
L1 methyl group (nor-L1) also has a two-ligand struc-
ture, with the same (N,N,S)2 donor set and basic coordi-
We synthesized related molecules to define structure–
activity relationships, varying both the chelated metal
and structure of the ligand (Schemes 1 and 2).9–13 Com-
plexation of the NSC 295642 ligand with Zn(II) also re-
sulted in a two-ligand complex (Fig. 1). However, the

A. B. Beshir et al. / Bioorg. Med. Chem. Lett. 18 (2008) 498–504
501
nation geometry as Zn(L1)2, and does not dissociate in
DMSO, based on conductivity measurements.15
Despite its difference in coordination geometry from the
Cu2Cl2(L1)2 complex, the Zn(L1)2 complex is nonethe-
less also highly potent as an inhibitor of cell migration,
with an IC50 of 238 nM (Table 1). Complexation of the
NSC 295642 ligand with Ni(II) also yielded a six-coordi-
nate complex with the basic formula Ni(L1)2, as revealed
by LC–MS13 and X-ray crystallography.14 In contrast to
the other NSC 295642 ligand-based complexes, how-
ever, Ni(L1)2 is completely devoid of any subtoxic activ-
ity in our wound closure experiments, although it does
become cytotoxic at P1 lM.
The bioactivity of the Cu(II)–ligand or Zn(II)–ligand
complexes appears to depend on an intact structure that
is already formed upon treatment of the cells. Treatment
with non-complexed ligand alone (5 lM), on the one
hand, or CuCl2 or ZnCl2 (or NiCl2) alone (50 lM), on
the other, has no effect on cells (data not shown). There-
fore, the bioactivity cannot be attributed to the products
of possible complete dissociation of the bioactive com-
plexes. We cannot definitively rule out, however, that
the Cu2Cl2(L1)2 and Zn(L1)2 complexes could dissociate
under the conditions of cell culture into single-ligand
complexes that might possess bioactivity, for example,
two single-ligand complexes in the case of Cu2Cl2(L1)2
and a single-ligand complex and inactive free ligand in
the case of Zn(L1)2. However, the Cu2Cl2(L1)2 and
Zn(L1)2 complexes appear stable under different analyt-
ical conditions,13,14 as does the Zn(II) complex of nor-
L1.15
We generated analogs where the original S-benzyl group
of NSC 295642 was substituted with other groups. An
S-naphthalen-2-ylmethyl group in the ligand resulted
in slightly better bioactivity for the Cu(II) and Zn(II)
complexes [Cu2Cl2(L2)2 and Zn(L2)2], with IC50 values
of 58 and 181 nM, respectively. Fig. 2a shows the pro-
gress of wound closure in MDCK cell monolayers in
the presence of the most potent of the metal–ligand
complexes tested, Cu2Cl2(L2)2. In contrast, an S-methyl
substituent yielded a complex with a single-ligand struc-
ture [CuCl(L3)] and no subtoxic activity. Ligands with
more polar substitutents, S-4-methoxybenzyl and S-4-
fluorobenzyl, also resulted in complexes, Cu2Cl2(L4)2
and Cu2Cl2(L5)2, respectively, that were devoid of sub-
toxic activity. Finally, an analog was generated with a
carboxyl group in the para position of the pyridine ring
[CuCl(L6)]. The complex has a single-ligand structure, as
with ligand L3, and has no subtoxic activity. While we
cannot rule out that single-ligand structures derived
from different ligands could also potentially be bioac-
tive, among the compounds examined, all of the bioac-
tive molecules have a two-ligand structure.
Figure 2. Progress of wound closure in different cell monolayers as a
function of concentration of Cu2Cl2(L2)2. Cell lines: (a) MDCK
epithelial cells; (b) T47D human breast carcinoma cells; (c) BT20
human breast carcinoma cells; (d) HCT116 human colorectal carci-
noma cells.
cell monolayers. MDCK cells are clearly the most sensi-
tive of the cell lines to the Cu2Cl2(L2)2 (Fig. 2a). The
compound displays antimigratory activity in T47D cells
(Fig. 2b), less in BT20 cells (Fig. 2c), and very little in
HCT116 cells (Fig. 2d). The compound thus appears
selective for certain cell lines.
Since Cu2Cl2(L2)2 was the most potent inhibitor of cell
migration (Table 1), we evaluated its biological activity
in a number of cancer cell lines as well, specifically hu-
man breast carcinoma (T47D and BT20) and human
colorectal carcinoma (HCT116) cell lines. We employed
scratch-wound assays similar to that used with MDCK
Finally, we sought to understand why NSC 295642
[Cu2Cl2(L1)2] and the corresponding Zn(II) complex
[Zn(L1)2] were bioactive, while the corresponding Ni(II)

502
A. B. Beshir et al. / Bioorg. Med. Chem. Lett. 18 (2008) 498–504
complex [Ni(L1)2] was not. We therefore compared the
X-ray crystal structures of these three complexes.14
The bioactive Cu2Cl2(L1)2 possesses a distorted square
pyramidal coordination geometry, while both the bioac-
tive Zn(L1)2 complex and inactive Ni(L1)2 complex have
distorted octahedral coordination geometries (Fig. 3).
Figure 3. X-ray crystal and energy-minimized structures of metal(II)–ligand complexes. X-ray crystal structures are shown, on the left, as thermal
ellipsoid plots (at 50% probability level) and, on the right, as capped stick models superimposed over wire models of structures derived from DFT
energy-minimization calculations for Cu2Cl2(L1)2, Zn(L1)2, and Ni(L1)2 complexes.

A. B. Beshir et al. / Bioorg. Med. Chem. Lett. 18 (2008) 498–504
503
Clearly, differences in coordination geometry cannot ex-
plain the differences in bioactivity between the
complexes.
References and notes
1. Meggers, E. Curr. Opin. Chem. Biol. 2007, 11, 287.
2. Mc Henry, K. T.; Ankala, S. V.; Ghosh, A. K.; Fenteany,
G. ChemBioChem 2002, 11, 1105.
3. Zhu, S.; Mc Henry, K. T.; Lane, W. S.; Fenteany, G.
Chem. Biol. 2005, 12, 981.
4. Kahsai, A. W.; Zhu, S.; Wardrop, D. J.; Lane, W. S.;
Fenteany, G. Chem. Biol. 2006, 13, 973.
5. Vogt, A.; Cooley, K. A.; Brisson, M.; Tarpley, M. G.;
Wipf, P.; Lazo, J. S. Chem. Biol. 2003, 10, 733.
6. Hossain, M. E.; Alam, M. N.; Ali, M. A.; Nazimuddin,
M.; Smith, F. E.; Hynes, R. C. Polyhedron 1995, 15, 973.
7. Bharti, N.; Maurya, M. R.; Naqvi, F.; Azam, A. Bioorg.
Med. Chem. Lett. 2000, 10, 2243.
8. Neelam, B.; Mannar, M.; Fehmida, N.; Alok, B.; Sudha,
B.; Amir, A. Eur. J. Med. Chem 2000, 35, 481.
9. Das, M.; Livingstone, S. E. Inorg. Chim. Acta 1976, 19, 5.
10. Ali, M. A.; Tarafder, M. T. H. J. Inorg. Nucl. Chem. 1977,
39, 1785.
The Cu2Cl2(L1)2 and Zn(L1)2 complexes do, however,
share a common conformational feature. Both these
bioactive complexes exhibit a transoid orientation of
the sulfides with respect to the central metal-coordinated
rings; note the S–C bonds of the two S-benzyl groups
relative to the S–C bonds of the coordinated rings
(Fig. 3a and b). The Zn(II) complex of nor-L1 also
adopts a transoid conformation.15 The S-benzyl groups
of the Cu2Cl2(L1)2 and Zn(L1)2 complexes point in
opposite directions, despite the difference in metal stoi-
chiometry and coordination geometry. In contrast, the
biologically inactive Ni(L1)2 complex possesses a cisoid
orientation of the sulfides relative to the Ni(II)-coordi-
nated rings, with the S-benzyl groups in closer proximity
to one another (Fig. 3c).
11. Hossain, M. E.; Begum, J.; Alam, M. N.; Nazimuddin,
M.; Ali, M. A. Transition Met. Chem. 1993, 18, 497.
12. Mikel, C.; Potvin, P. G. Polyhedron 2002, 21, 49.
13. A mixture of each prepared S-alkyl dithiocarbazate and 2-
acetylpyridine (or 2-acetylisonicotinic acid in the case of
synthesis of L6) in a 1:1 molar ratio in absolute ethanol
was boiled for 2 h.9–11 Precipitates of the Schiff bases were
deposited from the mixture upon cooling in ice. The
precipitates were filtered off, washed with ice-cold ethanol,
and dried in vacuo (yield = 50–80%). L6 was prepared by
hydrolysis of the methyl ester of methyl 2-acetylisonico-
tinate,12 followed by reaction with S-benzyl dithiocarbaz-
ate as above. To prepare each metal(II) complex, an
equimolar mixture of Schiff base ligand and CuCl2, ZnCl2
or NiCl2 in absolute ethanol was heated at 60 °C (oil-bath
temperature) for 10 min. Precipitates of each complex
formed upon cooling to room temperature. The precipi-
tates were filtered off, washed with ice-cold ethanol,
crystallized in acetonitrile, and dried in vacuo
(yield = 40–54%). NMR spectra were acquired for all free
ligands, as well as the Zn(L1)2 and Ni(L1)2 complexes.
(Note: The four pyridyl protons appeared duplicated by
1H NMR for the free ligands L1, L2, and L3 in CDCl3,
possibly as a consequence of thione–thiol tautomerism;
more directly consistent with this possibility, we observed
broadened and weakened NH proton signal, although we
were unable to clearly identify SH proton resonance.) LC-
ESIMS was performed in methanol.
Energy minimization via density functional theory
(DFT) calculations,16,17 both in vacuum and implicit
water solvent, resulted in structures that were substan-
tially similar to the X-ray crystal structures (Fig. 3).
The DFT calculations thus suggest that the conforma-
tions the complexes assume as crystals are likely to be
close to the lowest-energy conformations they would
adopt in solution. We calculated that the transoid con-
formation of Cu2Cl2(L1)2, for example, would be
7.6 kcal/mol more stable than the cisoid conformation.
Interestingly, there is an even stronger preference in sil-
ico for a transoid conformation when the S-benzyl
groups of Cu2Cl2(L1)2 are replaced with O-benzyl
groups, with transoid favored over cisoid by 12.3 kcal/
mol.
The data presented here imply that the pharmacophore
of NSC 295642 and related metal–ligand complexes is
at least in part formed by hydrophobic S-alkylaryl
groups that adopt a transoid orientation relative to
the central metal-coordinating rings, which affects the
way the hydrophobic moieties project from the core
structures. It is possible that each hydrophobic group
fits into a hydrophobic pocket on a target protein when
the groups are projected far enough away from one an-
other, as in the transoid Cu2Cl2(L1)2 and Zn(L1)2 com-
plexes. In contrast, the two S-benzyl groups in the
cisoid Ni(L1)2 complex are closer together, and so steric
hindrance may prevent a target protein from binding
either group.
1
L1 ligand. H NMR (400 MHz, CDCl3) d 9.97 (br s, 1H,
NH), 8.76 (dd, J = 1.6 Hz, 4.0 Hz, 1H, Py-H), 8.62 (d,
J = 5.2 Hz, 1H, Py-H), 8.18 (d, J = 8.8 Hz, 1H, Py-H),
7.90 (dt, J = 1.6 Hz, 8.0 Hz, 1H, Py-H), 7.75 (t, J = 7.6 Hz,
1H, Py-H), 7.59 (d, J = 8.4 Hz, 1H, Py-H), 7.26–7.44 (m,
7H, Ph-H and Py-H), 4.55 (s, 2H, CH2), 2.42 (d,
J = 9.5 Hz, 3H, CH3). 13C NMR (100 MHz CDCl3) d
200.05, 199.36, 153.80, 147.99, 137.83, 137.38, 135.74,
129.50 (2C), 129.46, 129.21, 128.67 (2C), 128.54, 127.61,
127.31, 124.47, 124.07, 121.42, 39.68, 38.92, 22.11, 11.43.
Zn(L1)2 complex. 1H NMR (400 MHz, CDCl3) d 7.90–7.92
(m, 1H, Py-H), 7.80 (dt, J = 1.6 Hz, 6.3 Hz, 1H, Py-H),
7.68–7.69 (d, J = 6.4 Hz, 1H, Py-H), 7.42–7.44 (m, 2H, Ph-
Acknowledgments
This work was supported by grants from the National
Institutes of Health (R01GM077622) and the American
Cancer Society (RSG-02-250-01-DDC) to G.F. We
thank the NCI for providing its Diversity Set collection
of compounds and an additional sample of NSC
295642, D.J. Wink for technical assistance and C.
H
and Py-H), 7.21–7.31 (m, 4H, Ph-H), 4.58 (d,
J = 10.7 Hz, 1H, CH2), 4.47 (d, J = 10.7 Hz, 1H, CH2),
2.72 (s, 3H, CH3). 13C NMR(100 MHz, CDCl3) d 191.50,
152.84, 149.52, 147.07, 138.70, 137.98, 129.17 (2C), 128.29
(2C), 126.77, 125.55, 122.30, 36.72, 14.34.
1
Ni(L1)2 complex. H NMR (400 MHz, CDCl3) d 8.66 (d,
Bruckner and S.C. Burdette for critical reading of the
¨
manuscript.
J = 5.6 Hz, 1H, Py-H) 7.88–7.92 (m, 2H, Py-H), 7.29–7.42
(m, 6H, Ph-H and Py-H), 4.36 (s, 2H, CH2), 2.30 (s, 3H, CH3).

504
A. B. Beshir et al. / Bioorg. Med. Chem. Lett. 18 (2008) 498–504
ESIMS for L1 complexes. Cu2Cl2(L1)2: calcd 760.9
14. Crystallographic data for Cu2Cl2(L1)2, Zn(L1)2, and
Ni(L1)2 have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication
numbers CCDC-660437, -660438, and -660439, respec-
tively. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/cgi-bin/catreq.cgi, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
15. Tarafder, M. T. H.; Kasbollah, A.; Crouse, K. A.; Ali, A.
M.; Yamin, B. M.; Fun, H.-K. Polyhedron 2001, 20, 2363.
16. Starting from the coordinates of the X-ray crystal struc-
tures, DFT calculations were performed using the Becke-
3–Lee–Yang–Parr hybrid density functional to predict the
ground electronic state geometry. We employed the basis
set LANL2DZ for the transition metals, which includes
electron core potential, and 6-31G(d) for the rest of the
atoms. Energy minimization for each of the three com-
pounds was carried out in both vacuum and in the
presence of implicit water solvent. The program Gaussian
0317 was used for all DFT calculations.
[MÀCl]+, found 760.7. Zn(L1)2: calcd 687.0 [M+Na]+;
found: 686.8. Ni(L1)2: calcd 681.0 [M+Na]+; found: 680.9.
1
L2 ligand. H NMR (400 MHz, CDCl3) d 9.94 (br s, 1H,
NH), 8.75 (d, J = 4.0 Hz, 1H, Py-H), 8.56 (d, J = 4.0 Hz,
1H, Py-H), 8.11 (d, J = 8.0 Hz, 1H, naphthyl-H), 7.75–7.89
(m, 6H, naphthyl-H and Py-H), 7.63 (dt, J = 1.8 Hz, 6.2 Hz,
1H, Py-H), 7.25–7.57 (m, 5H, naphthyl-H and Py-H), 4.72
(s, 2H, CH2), 2.42 (d, J = 20 Hz, 3H, CH3).
ESIMS for L2 complexes. Cu2Cl2(L2)2: calcd 860.9
[MÀCl]+; found: 860.9. Zn(L2)2: calcd 765.1 [M+H]+;
found: 764.9.
1
L3 ligand. H NMR (400 MHz, CDCl3) d 10.04 (br s, 1H,
NH), 8.70 (dt, J = 1.6 Hz, 4.8 Hz, 1H, Py-H), 8.57 (dt,
J = 1.6 Hz, 4.8 Hz, 1H, Py-H), 8.16 (d, J = 8.0 Hz, 1H, Py-
H), 7.90 (t, J = 8.0 Hz, 1H, Py-H), 7.69 (dd, J = 1.6 Hz, 8.0
Hz, 1H, Py-H), 7.57 (d, J = 8.0 Hz, 1H, Py-H), 7.33–7.36
(m, 1H, Py-H), 7.26–7.29 (m, 1H, Py-H), 2.64 (d,
J = 10.6 Hz, 3H, CH3), 2.42 (d, J = 6.5 Hz, 3H, CH3).
ESIMS for L3 complex. CuCl(L3): calcd 608.8 [M]+; found:
608.8.
L4 ligand. 1H NMR (400 MHz, DMSO-d6) d 12.58 (s, 1H,
NH), 8.62 (d, J = 4.1 Hz, 1H, Py-H), 8.01 (d, J = 8.1 Hz,
1H, Py-H), 7.85 (dt, J = 1.8 Hz, 6.0 Hz, 1H, Py-H), 7.44 (dt,
J = 1.1 Hz, 4.8 Hz, 1H, Py-H), 7.35 (d, J = 8.7 Hz, 2H, Ph-
H), 6.90 (d, J = 8.7 Hz, 2H, Ph-H), 4.44 (d, 2H, CH2), 3.75
(s, 3H, OCH3), 3.32 (s, 3H, CH3).
17. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G.
E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, Jr., J.
A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.;
Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.;
Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda,
R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Bakken,V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.;
Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz,
J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challa-
combe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong,
M. W.; Gonzalez, C.; and Pople, J.A. Gaussian 03,
Revision B.05; Gaussian, Inc.: Wallingford CT, 2004.
ESIMS for L4 complex. Cu2Cl2(L4)2: calcd 820.9 [MÀCl]À;
found: 820.8.
L5 ligand. 1H NMR (400 MHz, DMSO-d6) d 12.66 (s, 1H,
NH), 8.62 (d, J = 4.88 Hz, 1H, Py-H), 8.03 (d, J = 6.64 Hz,
1H, Py-H), 7.88 (dt, J = 4.6 Hz, 10.9 Hz, 1H, Py-H), 7.45–
7.50 (m, 3H, Ph-Hand Py-H), 7.14–7.19 (m, 2H, Ph-H), 4.50
(s, 2H, CH2), 2.33 (s, 3H, CH3).
ESIMS for L5 complex. Cu2Cl2(L5)2: calcd 796.8 [MÀCl]À;
found: 796.9.
L6 ligand. 1H NMR (400 MHz, acetone-d6) d 10.64 (s, 1H,
COOH), 8.79 (d, J = 8.0 Hz, 1H, Py-H), 8.66 (s, 1H, NH),
7.90 (dd, J = 1.2 Hz, 3.53 Hz, 1H, Py-H), 7.46 (d,
J = 7.7 Hz, 2H, Ph-H), 7.26–7.34 (m, 4H, Ph-H and Py-
H), 4.54 (s, 2H, CH2), 2.62 (s, 3H, CH3).
ESIMS for L6 complex. CuCl(L6): calcd 440.9 [M]À; found:
440.8.