Synthesis, spectroscopic, thermal, and in vitro anticancer properties of some M(II) Complexes of 3-(-1-(4,6-Dimethyl-2-pyrimidinylimino)methyl-2-naphthol

Article abstract of DOI:10.1080/15533174.2011.591310

Mn(II), Co(II), Ni(II), Cu(II), and Zn(II) complexes of the Schiff base 3-(-1-(4,6-dimethyl-2-pyrimidinylimino)methyl-2-naphthol have been synthesized and characterized by infrared (IR), electronic, nuclear magnetic resonance (¹H-NMR), and mass spectroscopies, elemental and thermal analyses, and room-temperature magnetic, powder X-ray diffraction, and conductance measurements. The involvement of the azomethine N and enol O atoms in bonding resulted in an N₂O₂ chromophore around the central metal atom. The room-temperature magnetic data, IR, and electronic spectral measurements are corroborative of a 4-coordinate square planar/tetrahedral geometry for the Ni(II), Cu(II), and Zn(II) complexes, and a 6-coordinate octahedral geometry for the Mn(II) and Co(II) complexes with water occupying the fifth and sixth coordination sites. All the complexes are high spin and nonelectrolyte in dimethylformamide (DMF). The metal complexes generally have mild to very good anticancer activity in vitro against HL 60 (leukemia) and 518A2 (melanoma) carcinomas, with IC₅₀ in the range 7.67-20.67 μm, respectively. [CuL₂] has the best cytotoxic activities against both HL60 (leukemia) and melanoma (518A2) carcinomas with IC50 of 7.67 and 11.20 m, respectively, which is half as sensitive as and three times more sensitive than CDDP. Copyright Taylor &Francis Group, LLC.

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Synthesis, Spectroscopic, Thermal, and In Vitro
Anticancer Properties of Some M(II) Complexes of
3-(-1-(4,6-Dimethyl-2-pyrimidinylimino)methyl-2-
naphthol
A. A. Osowole a , R. Kempe b , R. Schobert c & K. Effenberger c
a Department of Chemistry , University of Ibadan , Ibadan, Nigeria
b Anorganische Chemie II , Universität Bayreuth , Bayreuth, Germany
c Organische Chemie I , Universität Bayreuth , Bayreuth, Germany
Published online: 11 Aug 2011.
To cite this article: A. A. Osowole , R. Kempe , R. Schobert & K. Effenberger (2011) Synthesis, Spectroscopic, Thermal,
and In Vitro Anticancer Properties of Some M(II) Complexes of 3-(-1-(4,6-Dimethyl-2-pyrimidinylimino)methyl-2-
naphthol, Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 41:7, 825-833, DOI:
10.1080/15533174.2011.591310
To link to this article: http://dx.doi.org/10.1080/15533174.2011.591310
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Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 41:825–833, 2011
Copyright ꢀ Taylor & Francis Group, LLC
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ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2011.591310
Synthesis, Spectroscopic, Thermal, and In Vitro Anticancer
Properties of Some M(II) Complexes of
3-(-1-(4,6-Dimethyl-2-pyrimidinylimino)methyl-2-naphthol
A. A. Osowole,1 R. Kempe,2 R. Schobert,3 and K. Effenberger3
1Department of Chemistry, University of Ibadan, Ibadan, Nigeria
2
¨
Anorganische Chemie II, Universitat Bayreuth, Bayreuth, Germany
3
¨
Organische Chemie I, Universitat Bayreuth, Bayreuth, Germany
carbonic anhydrase.[6] Furthermore, Schiff bases of benzyl-
monophenylhydrazone have been used extensively as biolog-
ically active complexing agents in analytical reagents.[7] In ad-
dition, Schiff bases are widely studied due to their ease of
preparation and coordination to many metal ions. The stabi-
lization of such ions in various oxidation states has enabled
the use of these metal chelates in catalytic transformations.[8–12]
There is a dearth of information in the literature on Schiff bases
derived from 2-hydroxynaphthaldehyde and various amino
(methyl)pyrimidines.[13–16] Consequently, our aim is to study the
physicochemical, thermal, and anticancer properties of Mn(II),
Co(II), Ni(II), Cu(II), and Zn(II) complexes of the pyrimidinyl
Schiff base 3-(-1-(4,6-dimethyl-2-pyrimidinyl imino)methyl-2-
naphthol (derived from condensation of 2-amino-4,6-dimethyl
pyrimidine and 2-hydroxy-1-naphthaldehyde) with the hope of
finding a leading, metal(II) complex for future probable use in
drug development against melanoma and leukaemia carcino-
mas. These complexes and the ligand are new and are reported
here for the first time.[13–16]
Mn(II), Co(II), Ni(II), Cu(II), and Zn(II) complexes of
the Schiff base 3-(-1-(4,6-dimethyl-2-pyrimidinylimino)methyl-2-
naphthol have been synthesized and characterized by infrared (IR),
electronic, nuclear magnetic resonance (1H-NMR), and mass spec-
troscopies, elemental and thermal analyses, and room-temperature
magnetic, powder x-ray diffraction, and conductance measure-
ments. The involvement of the azomethine N and enol O atoms
in bonding resulted in an N2O2 chromophore around the central
metal atom. The room-temperature magnetic data, IR, and elec-
tronic spectral measurements are corroborative of a 4-coordinate
square planar/tetrahedral geometry for the Ni(II), Cu(II), and
Zn(II) complexes, and a 6-coordinate octahedral geometry for the
Mn(II) and Co(II) complexes with water occupying the fifth and
sixth coordination sites. All the complexes are high spin and non-
electrolyte in dimethylformamide (DMF). The metal complexes
generally have mild to very good anticancer activity in vitro against
HL 60 (leukemia) and 518A2 (melanoma) carcinomas, with IC50 in
the range 7.67–20.67 µm, respectively. [CuL2] has the best cytotoxic
activities against both HL60 (leukemia) and melanoma (518A2)
carcinomas with IC50 of 7.67 and 11.20 µm, respectively, which is
half as sensitive as and three times more sensitive than CDDP.
Keywords anticancer activities, cell lines, CDPP (cis-platin), thermal
analysis, Schiff base
EXPERIMENTAL
Reagents and Solvents
All the chemicals used were of reagent grade. 2-Amino-4,6-
dimethylpyrimidine and 2-hydroxy-1-naphthaldehyde (Across)
and hydrated manganese(II) nitrate, cobalt(II) nitrate, nickel(II)
nitrate, copper(II) nitrate, and zinc(II) nitrate (Aldrich) were
used as received. Solvents were dried and distilled before use.
INTRODUCTION
The biological significance of pyrimidines cannot be overem-
phasized, as they make up the basic nucleus in DNA and
RNA, which has been found to be associated with diverse bio-
activities such as anti-HIV, antimicrobial and anticancer.[1–5]
For example, (3-formyl chromone) pyrimidinyl sulfanilamides
are inhibitors of the tumor-associated, transmembrane isozyme
Preparation of Ligand
The ligand {[C10H6(OH)CH:N(C6H7N2)]}, HL, was pre-
pared by refluxing a mixture of 0.012 mol (2.00 g) of 2-amino-
4,6-dimethylpyrimidine and 0.012 mol (1.43 g) of 2-hydoxy-1-
naphthaldehyde with 6 drops of acetic acid in 60 mL ethanol
for 6 h. The yellow product, formed on cooling in ice, was fil-
tered and recrystallized from ethanol and dried in vacuo over
anhydrous calcium chloride. The yield of the resulting Schiff
base (Figure 1) was 2.25 g (70%). Nuclear magnetic resonance
Received 11 November 2010; accepted 16 February 2011.
A.A.O. thanks the Alexander von Humboldt (AvH) Foundation for
the Georg Forster Fellowship.
Address correspondence to A.A. Osowole, Department of Chem-
istry, University of Ibadan, Ibadan, Nigeria. E-mail: aderoju30@yahoo.
com
825

826
A. A. OSOWOLE ET AL.
using an enzyme-linked immunosorbent assay (ELISA) plate
reader. All experiments were carried out in quadruplicate, and
the percentage of viable cells quoted was calculated as the mean
SD with respect to the controls set to 100%. Blank tests have
shown that DMSO used in the preparation of the test compound
does not have any effect on the cancer cell lines.
N
N
N
OH
Physical Measurements
FIG. 1. Structural formula of 3-(-1-(4,6-dimethyl-2-pyrimidinylimino)
methyl-2-naphthol.
The elemental analyses for C, H, and N were recorded on a
GmbH VarioEl analyzer. Manganese, cobalt, nickel, copper, and
zinc were determined titrimetrically.[17] The 1H-NMR spectrum
was recorded on a 300-MHz Oxford Varian NMR instrument
(1H-NMR) (ppm): δ10.8 (s, OH), δ 7.25-8.29 (m, 6H, C9H6);
6.78 (s, 1H, CHpyrimidine); 6.72 (s, 1H, CH); 2.48 (s, 6H, CH3–
CNpyrimidine).
1
in CDCl3 at 295 K. H chemical shifts were referenced to the
residual signals of the protons of CDCl3 and are quoted in parts
per million (ppm). Magnetic susceptibilities were measured on
a Johnson Matthey magnetic susceptibility balance at room tem-
perature (27◦C) and diamagnetic corrections were calculated us-
ing Pascal’s constant.[18] The reflectance spectra were recorded
on a Perkin-Elmer λ20 spectrophotometer equipped with an in-
tegrating sphere. The infrared spectra were measured as KBr
discs on a Bruker-IFS 66V spectrometer in the range 4000–400
Preparation of the Metal(II) Complexes
A solution of the metal(II) nitrates (0.54 mmol, 0.10-0.16
g) in 20 mL ethanol was added to a stirring solution of the
ligand (1.08 mmol, 0.30 g) in 30 mL ethanol at room tempera-
ture (26◦C), followed by gradual addition of triethylamine (1.08
mmol, 0.15 mL). The resulting homogeneous solution was fur-
ther stirred for 6 h at 50◦C, during which the products formed.
These were later filtered, washed with ethanol, and dried in
vacuo over anhydrous CaCl2.
cm−1 and frequencies are believed to be accurate within
2
cm−1. Thermogravimetric analyses were done in static air, using
a T6 Linseis thermal analyzer with a heating rate of 10◦C/min
in the range 30–700◦C, while electrolytic conductivities of the
compounds in DMF were determined using a Hanna HI 8828N
conductometer, and melting points (uncorrected) were done us-
ing a Stuart scientific melting point apparatus smp3. X-ray pow-
der diffraction was performed using a Panalytical Xpert Pro with
Cu-Kα radiation.
Biological Studies
Human HL-60 leukemia cells were obtained from the Ger-
man National Resource centre for Biological materials(DSMZ),
Braunschweig. Human 518A2 melanoma cells were cultured in
the Department of Oncology and Hematology, Medical Faculty
of the Martin-Luther University, Halle, Germany.
Cytotoxicity (MTT) Assay
RESULTS AND DISCUSSIONS
MTT [3(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium
bromide] was used to identify viable cells that are capable of
reducing it in their mitochondria by succinate dehydrogenase to
a violet formazan product.
The reactions of the ligand with the metal(II) nitrates (Mn,
Co, Ni, Cu, and Zn) gave colored complexes in good yields
(60–70%). All complexes isolated adopted ML2·xH2O stoi-
chiometry (Mn, Co: x = 2; Ni, Zn: x = 1) except the Cu(II)
complex, which was anhydrous. Evidence for the formation of
the ligand in pure form is from microanalyses and H-NMR.
The generalized equation for the formation of the complex is as
follows:
Cell Lines and Culture Conditions
1
HL-60 cells (0.5 × 106 cells/mL) and 518A2 cells (1.7 × 105
cells/mL) were seeded out and cultured for 24 h. Incubation (5%
CO2, 95% humidity, 37◦C) of cells following treatment with the
test compounds was continued for 24, 48, and 72 h. Blank and
solvent controls were incubated under identical conditions. Then
a 5-mg/mL stock solution of MTT in phosphate-buffered saline
(PBS) was added to a final concentration of 0.05%. After 2 h
M(NO3)2 · aH2O + 2HL → [ML2]xH2O + HNO3 + bH2O,
[1]
the precipitate of formazan crystals was redissolved in a 10% where M = Mn(II)/Cu(II) (a = 4/2, x = 2/0, b = 2) and
solution of sodium dodecyl sulfate (SDS) in dimethyl sulfoxide Co(II)/Ni(II), Zn(II) (a = 6, x = 2/1, b = 4/5).
(DMSO) containing 0.6% acetic acid in the case of the HL-60
The physical and analytical data, colors, percent yields, m/z
cells. For the adherent melanoma (518A2) cells, the microplates (100%), melting points/decomposition temperatures, and room-
were swiftly turned to discard the medium prior to adding the temperature magnetic moments of the compounds are presented
solvent mixture. The microplates were gently shaken in the in Table 1. The complexes are thermally stable but decom-
dark for 30 min and left in the incubator overnight, to ensure a posed when heated and are soluble in methylene chloride, DMF,
complete dissolution of the formazan. Finally, the absorbance DMSO, and tetrahydrofuran (THF). The found and calculated
at wavelength 570 nm and 630 nm (background) was measured percentages of CHN are in good agreement with each other and

827

828
A. A. OSOWOLE ET AL.
prove the suggested molecular formula of the complexes. The the involvement of the enolic O in bonding to the metal ions.
decomposition pattern obtained from the TGA curve corrob- A new broad band, ν(OH) at 3500 cm−1, in the hydrated com-
orates the proposed formulation of the complexes. The molar plexes was assigned to coordinated water. The uncoordinated
conductances of the complexes were in the range 8–20 Ω−1 cm2 C=N and C=C stretching vibrations in the ligand were expect-
mol−1 in DMF, showing they were nonelectrolytes; a value of edly coupled and generated four bands at 1624–1531 cm−1 [7,11]
.
60–90 is expected for a 1:1 electrolyte.[19] Attempts to isolate These bands suffer bathochromic shifts to 1614–1520 cm−1 in
suitable crystals for single-crystal x-ray structural determina- the Schiff base complexes, thus confirming the involvement of
tion have not been successful till now. Thus, powder diffraction the imine N atom in coordination to metal(II) ion.[15,16] The δC–
measurements were taken.
H vibration of the ligand was observed at 979 cm−1 and suffers
bathochromic shift to 831–744 cm−1 in the complexes due to
the pseudo-aromatic nature of the chelates.[13] The bands due to
ν(M–O) and ν(M–N) were observed at 468–407 and 567–520
cm−1, respectively, in the complexes.[11,12]
1H-NMR Spectra
The ligand showed the naphthyl ring protons resonate as
a multiplet at δ 7.22–8.29 ppm (m, 6H, C10H6). The phenolic
proton was observed as a singlet at 10.8 ppm (s, 1H, OH) and the
CH signal resonates at δ 6.78 ppm (s, 1H, H=CN), while CH of Electronic Spectra and Magnetic Moments
the pyrimidine ring resonates at δ 6.72 ppm (s, 1H, CHpyrimidine).
The two methyl substituents of pyrimidine resonate as a 6H
singlet at 2.48 ppm (s, 6H, CH3).
In the ultraviolet (UV) region, the electronic spectra of all
the complexes are similar (Table 2), displaying three band max-
ima between 27.66 and 30.57, 32.19 and 39.40, and 40.63 and
42.0 kK, respectively, assigned to π–π∗ and charge transfer
transitions.[20,21]
In the Zn(II) complex spectra, the naphthyl ring protons were
deshielded and resonate as a multiplet at δ 7.30–8.60 ppm (m,
6H, C10H6). The phenolic proton was conspicuously absent, in-
dicating the involvement of OH in chelating. The HC=N proton
signal appeared at δ 7.07 ppm; the downfield shift indicates
deshielding due to coordination of the imine nitrogen atom,
while the upfield shifts of the CH of the pyrimidine and methyl
substituents of the pyrimidine to δ 6.62 and δ 2.15 ppm, respec-
tively, also corroborate coordination through the imine nitrogen
of the pyrimidine moiety.
The Mn(II) complex showed three weak bands expectedly at
12.00, 16.50, and 19.00 kK, respectively, typical of 6-coordinate
octahedral geometry, and are assigned to the forbidden transi-
4
4
4
tions 6A1g → T1g, 6A1g → T2g (G), and 6A1g → Eg(G). The
effective magnetic moments of Mn(II) complexes are expected
to be close to the spin-only value of 5.90 B.M. since the ground
6
term is A1g and as such there is no orbital contribution. Con-
sequently, a moment of 5.71 B.M. observed for this complex
indicates that it is high spin and complementary of octahedral
geometry.[22]
Infrared Spectra
The relevant infrared data are presented in Table 2. The as-
The Co(II) complex exhibited three bands at 11.21, 16.03,
4
signments of the infrared bands were made by comparing the and 21.00 kK, assigned to 4T1g(F) → T2g(F), (ν1), 4T1g(F) →
spectra of the compounds with reported literature on similar 4A2g(F), (ν2), and T1g(F) → T1g(P), (ν3), transitions of an
systems.[13–16] This νOH band of the ligand was seen at 3440 octahedral geometry.[5,7] The observed moment of 4.82 B.M is
cm−1. The disappearance of this band in the complexes indicates also corroborative of an octahedral geometry, since moment in
4
4
TABLE 2
Infrared and electronic (kK) spectral data of the complexes
Compound
[HL]
νOH ν(C=N) + ν(C=C) νPh/C–O δC–H ν(M–N) ν(M–O) d-d Transitions C.T/ π-π∗ transitions
3440s 1624s
1591s
1611s
1531s
1579s
1430s
1360s
979s
—
—
—
33.20, 35.00, 40.00
[Mn(L)2(H2O)2] 3500b 1615s
1214s 829s 795s 567m 437m 12.00, 16.50, 19.00 30.57, 33.20, 41.70
1523s
[Co(L)2(H2O)2] 3500b 1614s
1523s
1165s
553m
410s
1578s 1247m 829s 752s 552s
1139m
1602s 1214m
452m 11.21, 16.03, 21.00 28.68, 35.21, 42.0
539m 420m
551m 463m 14.50, 17.20
539m 407m
[Ni(L)2 ]H2O
3500b 1614s
1583s
831s
750m
28.36, 32.20, 39.40
29.06, 32.19, 40.63
27.66, 32.45, 41.67
1520s
1167s
[Cu(L)2]
—
1615s
1579s
1600s 1283m 830s 750s 552m 458m 17.21, 23.04
1522s 1186m
1603s 1285m
1524s 1166m
520m 430m
550m 468m
530m 424m
[Zn(L)2]H2O
3500b 1616s
1580s
831s
744s
—
Key: b = broad, s = strong, m = medium, 1kK = 1000 cm−1
.

SYNTHESIS, SPECTROSCOPIC, AND ANTICANCER PROPERTIES
829
The observance of two bands at 17.20 and 23.04 kK in
the Cu(II) complex indicates square planar geometry with the
bands assigned as 2B1g → A1g and 2B1g → E1g transitions. A
moment of 1.9–2.2 B.M. is usually observed for mononuclear
copper(II) complexes, regardless of stereochemistry, expectedly
higher than the spin-only moment due to orbital contribution and
spin-orbit coupling.[21] [CuL2] has a moment of 2.21 B.M. and
is consequently mononuclear.
The Zn(II) complex showed only the CT transitions from
M → L, as no d-d transition is expected. The bands at 27.66,
32.45, and 41.67 kK are assigned as π–π∗ and charge transfer
transitions, respectively. An observed moment of 0.32 B.M.
for this complex confirms that it is essentially diamagnetic and
complimentary of tetrahedral geometry.[24]
2
2
N
N
O
N
N
N
N
H2O
M
O
FIG. 2. Proposed geometry for the metal(II) complexes (M=Ni, Zn).
Mass Spectroscopy and Thermal Studies
the range 4.7–5.2 B.M is usually observed for octahedral Co(II)
compounds. [20]
The mass spectra of ligand and the complexes showed peaks
attributed to the molecular ions for m/z: 277 [L]+; 607 [MnL2-
The reflectance spectra of the Ni(II) complex showed ab- 2H] +; 611 [CoL2-2H] +; 610 [NiL2-3H] +; 616 [CuL2-2H] +;
3
sorption bands at 14.50 and 17.20 kK assigned to T1(F) → 616 [ZnL2-3H] +; the m/z ratio of the isotope with 100% in-
3
3
3T2, (ν2), and T1(F) → A2, (ν3), transitions, in a tetrahedral tensity is presented in Table 1, while the decomposition stages,
environment.[13,14] Generally, square planar Ni(II) complexes temperature ranges, percentage losses in mass, and assignment
are usually diamagnetic, while tetrahedral and octahedral com- of decomposition moieties are presented in Table 3.
plexes are paramagnetic with moments in the range 3.20–4.10
and 2.90–3.30 B.M., respectively. This complex gave a moment steps. The first was at 30–80◦C, with evolution of HCN and
of 3.41 B.M. and hence is tetrahedral (Figure 2).[23]
corresponding mass losses (obs. = 9.22%, calc. = 9.75%). This
The thermal degradation of the ligand HL occurred in three
TABLE 3
Thermal data for the complexes
TG weight loss(%)
Temperature
Compound
range(◦C)
30–80
Calc.
Found
Asssignment
HCN
C9H9N2
C7H5O
C4H4N2 + 2H2O
C25H24O2N4
MnO (residue)
C4H4N4 + 2H2O
C26H24O2N2
CoO (residue)
HCN
C10H10N4 + H2O
C23H17O2N
NiO (residue)
HCN
HL (C17H15N3O)
9.75
52.35
37.90
18.03
64.04
9.22
51.67
40.03
17.65
62.88
[MnL2(H2O)2]
(MnC34H32N6O4)
200–360
360–700
[CoL2(H2O)2]
(CoC34H32N6O4)
200–370
370–700
22.26
61.23
22.03
61.26
[NiL2] H2O
(NiC34H30N6O3)
150–270
270-390
390–700
4.29
32.46
53.93
4.54
32.71
55.90
[CuL2]
(CuC34H28N6O2)
200-260
260–360
360–700
4.38
21.27
62.02
3.86
20.56
62.40
C8H7N2
C24H20O2N3
CuO (residue)
C8H8N4 + H2O
C24H20O2N2
ZnO (residue)
[ZnL2] H2O
(ZnC34H30N6O3)
190–410
410–700
28.03
57.96
27.00
58.29

830
A. A. OSOWOLE ET AL.
was followed by the loss of the organic fraction C9H9N2 (obs.
= 51.67%, calc. = 52.35%), and the final stage equals the loss
of the organic moiety C7H5O (mass losses obs. = 40.03%, calc.
= 37.90%).
The Mn(II) complex decomposed in two stages. The stage
one was between 200 and 360◦C, which indicated the loss of
the organic moiety C4H4N2 and two molecules of water (mass
losses obs. = 17.65%, calc. = 18.03% ). The second stage was
from 360 to 700◦C, assigned to the loss of the organic moiety
C25H24O2N4 (mass losses obs. = 62.88%, calc. = 64.04%),
leaving behind MnO residue.
The decomposition of the Co(II) complex occurred simi-
larly in two steps. The first step occurred within 200–370◦C,
corresponding to the loss of the organic moiety C4H4N2
and two molecules of water (mass losses obs. = 22.03%,
calc. = 22.26%). The successive decomposition occurred
within 370–700◦C and equals the loss of the organic moiety
C26H24O2N2 (mass losses obs. = 61.26%, calc. = 61.23%),
leaving CoO as the final product.
FIG. 3. The powder diffraction of the M(II) complexes.
The TGA curve of the Ni(II) complex revealed a three-step
decomposition. The first was the loss of HCN (obs. = 4.54%,
◦
calc. = 4.30%) at 150–270 C. The second was from 270 to 360–700◦C, corresponding to the loss of the organic moiety
390◦C, due to the loss of the organic moiety C10H10N4 and a C24H20O2N3 (obs. = 62.40%, calc. = 62.02%). The remaining
mole of water (obs. = 32.71%, calc. = 32.46%), and the final fraction was copper(II) oxide.
stage was within 390–700◦C, corresponding to the loss of the
The Zn(II) complex decomposed in two stages. The first
organic moiety C23H17NO2 (obs. = 55.90%, calc. = 53.93%). was between 190 and 410◦C, which indicated the loss of the
The remaining fraction was NiO residue.
organic moiety C8H8N4 and a mole of water (mass losses obs.
Cu(II) complex decomposed in three ways. The first was the = 27.00%, calc. = 28.03%). The second stage was from 410 to
loss of HCN (weight loss obs. = 3.86%, calc. = 4.38%) at 700◦C, assigned to the loss of the organic moiety C24H20O2N2
200–260◦C. The second was from 260 to 360◦C, which cor- (mass loss obs. = 58.29%, calc. = 57.96%), leaving behind the
responds to the loss of the organic moiety C8H7N2 (mass loss ZnO residue. Thus, the decomposition pattern corroborates the
obs. = 20.56%, calc. = 21.27%), and the final stage is within proposed formulation of the complexes.
TABLE 4
X-ray powder diffraction of the metal(II) complexes
[Mn(L)2(H2O)2]
2θ
[Co(L)2(H2O)2]
2θ
[Ni(L)2(H2O)2]
2θ
[Cu(L)2]
[Zn(L)2] H2O n
2θ
n
I
d
n
I
d
n
I
d
n
I
2θ
d
n
I
d
1 100 38.61 2.33 1 100 46.56 1.95 1 100 42.04 2.15 1 100 55.16 1.67 1 100 51.61
1.77
1.96
2.10
2.34
2.61
2.91
3.27
3.64
4.81
5.73
2
3
4
5
6
7
8
9
42 35.73 2.51
38 27.80 3.21
50 25.50 3.49
33 20.60 4.31
25 18.97 4.68
33 15.18 5.84
27 12.39 7.15
29 10.89 8.13
2
3
4
5
6
7
8
9
33 34.91 2.57
25 28.88 3.09
21 27.28 3.27
14 25.76 3.46
12 24.07 3.70
14 20.02 4.44
14 17.91 4.95
12 14.64 6.05
2
3
4
5
6
7
8
9
25 32.05 2.79
17 28.55 3.13
17 26.58 3.35
17 23.69 3.76
23 22.13 4.02
19 18.91 4.69
21 15.93 5.56
23 11.94 7.41
2
3
4
5
6
7
8
9
25 44.34 2.04
67 38.50 2.34
33 31.48 2.84
15 28.66 3.12
23 25.79 3.46
29 24.82 3.59
17 22.74 3.91
15 17.66 5.02
2
3
4
5
6
7
8
9
38 46.30
38 43.12
50 38.53
31 34.36
22 30.66
38 27.26
28 24.47
19 18.41
10
8
9.26 9.55 10 14 10.93 8.10 10 23 9.48 9.33 10 17 10.81 8.19 10 18 15.48
11 15 7.25 12.20 11 10 9.17 9.64 11 25 5.54 15.97 11 83 4.17 21.22 11 26 7.32 12.09
12 67 7.01 12.61 12 25 6.82 12.96 12 33 2.15 41.10 12 33 2.14 41.22 12 26 6.86 12.90

SYNTHESIS, SPECTROSCOPIC, AND ANTICANCER PROPERTIES
831
TABLE 5
IC50 values of the ligand and its complexes against melanonoma (518A2) and leukemia (HL60) cells
IC50 [µM], melanoma cells (518A2)
IC50 [µM], leukemia cells (HL60)
Complexes
24 h
48 h
72 h
24 h
48 h
72 h
CDDP
35
—
—
3.5
—
—
H2L
79.33 6.02
19.00 6.04
16.75 3.27
14.50 4.03
11.20 4.46
17.67 3.68
43.60 5.54
8.10 1.76
13.25 3.34
14.50 2.29
14.67 2.62
10.70 2.52
47.00 7.28
25.33 4.50
17.17 7.15
15.33 3.09
32.00 2.00
23.33 6.65
35.67 5.44
16.33 3.30
12.17 5.14
20.67 2.87
7.67 2.49
13.17 6.06
63.33 10.62
28.00 9.09
20.67 8.01
22.67 9.46
15.67 5.26
22.67 4.71
46.50 18.50
35.00 7.00
39.50 2.50
27.00 6.16
28.00 3.00
12.07 3.65
[Mn(L)2(H2O)2]
[Co(L)2(H2O)2]
[Ni(L)2]H2O
[Cu(L)2]
[Zn(L)2] H2O
Key: <5 µm = super active; 5–10 µm = strongly active; 11–19 µm = moderately active; 20–30 µm = weakly active; >30 µm = resistant.
CDDP = cis-platin. — = Not determined.
the experiment, though its resistance reduced by 45 and 41%,
respectively, after exposure for the next 48 and 72 h. Further-
more, on exposing these cell lines to the metal complexes, it
was observed that all the metal complexes were moderately
active—i.e., they overcame the CDDP resistance, being twice
as sensitive as CDDP with IC50 in the range 14.50–19.00 µm.
Notably, [CuL2] was three times more sensitive than CCDP
with IC50 of 11.20 µm. Further exposure of the cell lines to the
metal complexes at 48 h showed increased sensitivity of about
twice that at 24 h in all cases, with exceptions of [CuL2] with
reduced sensitivity and [NiL2]H2O with constant activity. Pro-
longed exposure till 72 h showed that all the complexes have
become weakly active with [CuL2] losing its activity, being re-
sistant with IC50 of 32.0 µm, close to that of CDDP (35.0 µm).
X-Ray Powder Diffraction
X-ray patterns of the complexes were recorded over 2θ =
0–45◦ range. The principal interspace lines (d) and their intensi-
ties are shown in Figure 3 and presented in Table 4. The complex
[ZnL2]H2O has the highest crystallinity. Each complex has spe-
cific d values, which can be used for its characterization.[25]
Biological Studies
The growth-inhibitory effects of the ligand and its com-
plexes on the cis-platin (CDDP)-resistant 518A2 (melanoma)
and CDDP-sensitive HL60 (leukemia) cell lines are presented
in Table 5.
The ligand HL (79.33 µm) was more resistant than CDDP
(35.0 µm) against melanoma cells throughout the duration of
90
80
70
60
50
40
30
20
10
0
24 h
48 h
72 h
Complexes
FIG. 4. The inhibitory effect of the ligand and complexes against melanoma cells (color figure available online).

832
A. A. OSOWOLE ET AL.
70
CONCLUSION
65
60
55
50
45
40
35
30
25
20
15
10
5
The ligand 3-(-1-(4,6-dimethyl-2-pyrimidinylimino)methyl-
2-naphthol coordinates to Mn(II), Co(II), Ni(II), Cu(II), Mn(II),
and Zn(II) ions using the N2O2 chromophore. The Mn(II) and
Co(II) complexes are octahedral, with coordinated water oc-
cupying the fifth and sixth coordination sites, the Ni(II) and
Zn(II) complexes assume tetrahedral geometry (Figure 2), and
the Cu(II) complex is anhydrous and square planer as corrobo-
rated by IR, electronic, elemental, TGA, and room-temperature
magnetic measurements. All the complexes are high spin and
nonelectrolyte in DMF. The ligand was resistant to both HL
60 (leukemia) and 518A2 (melanoma) carcinomas, while its
metal complexes exhibited mild to very good anticancer activ-
ities against both cell lines, with IC50 in the range 7.67–20.67
and 11.20–19.00 µm, respectively, proving that coordination en-
hances anticancer activities. Notably, [CuL2] has the best cyto-
toxic activities against HL60 (leukemia) and melanoma (518A2)
carcinomas with IC50 of 7.67 and 11.20 µm, respectively, which
was half as sensitive as and three times more sensitive than
CDDP.
24 h
48 h
72 h
0
Complexes
FIG. 5. The inhibitory effect of the ligand and complexes against leukemia
cells (color figure available online).
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