КООРДИНАЦИОННАЯ ХИМИЯ, 2014, том 40, № 2, с. 113-117
УДК 541.49
SYNTHESIS, CHARACTERIZATION, AND CYTOTOXICITY OF MIXED-LIGAND COMPLEXES OF PALLADIUM(II) WITH 1,10-PHENANTHROLINE AND N-CARBONYL-L-ISOLEUCINE DIANION
© 2014 J. C. Zhang*, L. W. Wang, S. Y. Liu, F. F. Zhang, J. L. Du, L.W. Li, S. X. Wang*,
S. H. Li, and G. Q. Zhou
College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Hebei University,
Baoding, 071002 P.R. China Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University,
Baoding, 071002 P.R. China *E-mail: jczhang6970@yahoo.com.cn; wsx@hbu.edu.cn Received September 25, 2012
Three novel palladium(II) complexes [Pd(Phen)(Bzile)] (I), [Pd(Phen)(p-mBzile)] (II), and [Pd(Phen)(p-NBzile)] • H2O (III), where Bzile = N-benzoyl-L-isolecine), p-MBzile = N-(p-methylbenzoyl)-L-isole-cine), p-NBzile = N-(p-nitrobenzoyl)-L-isolecine), have been synthesized and characterized by elemental analysis, ES-MS, and IR. The crystal and molecular structure of the complex II has been determined by single crystal X-ray diffraction. The cytotoxicity was tested against carcinoma cell lines: KB, BGC-823, Bel-7402 and HL-60 by MTT assay. The results indicated that these complexes exerted cytotoxicity, but none of them showed higher cytotoxicity than cisplatin. The cytotoxicity against HL-60, BGC-823, Bel-7402 and KB cell lines decreases in the sequence: p-MBzile > Bzile > p-NBzile. It suggests that the acylated groups have important impact on the cytotoxicity of complexes.
DOI: 10.7868/S0132344X14020121
INTRODUCTION
Nowadays cisplatin and its derivatives are the most widely used clinical anticancer drugs. Unfortunately, they have several major drawbacks. Common problems include cumulative toxicities of nephrotoxicity and ototoxicity [1, 2]. In addition to the serious side effects, the therapeutic efficacy is also limited by inherent or treatment-induced resistant tumor cells. These drawbacks have provided the motivation for alternative chemotherapeutic strategies.
Metals, in particularly, transition metals offer potential advantages over the more common organic-based drugs. On the basis of the structural and thermodynamic analogy between platinum(II) and palladium^) complexes, there is also much interest in the study of palladium(II) derivatives as potential anticancer drugs [3—6]. It was reported that 1,10-phenanthro-line (Phen) derivatives had the ability to participate as DNA intercalators. Amino acids are the fundamental matters of life and material base of metabolism. Introducing amino acids into the antitumor drug molecules can improve their selectivity to tumor cells, enhance their liposolubility, and remit their toxicities to normal cells. In addition, owing to higher lability of palladium versus platinum analogs, amino acid ligands, which do not dissociate easily in aqueous solution, have been used to synthesize palladium anticancer complexes. These palladium complexes with amino acid ligands
are expected to be useful for the treatment of tumors of the gastrointestinal region because of their little interaction with chloride ions compared with cisplatin [7]. Besides, less kidney toxic than cisplatin is expected because of the difficulty of replacing the tightly bound bidentate amino acids in these complexes by protein bound sulphydryl groups of kidney tubule cells [8]. So Phen and amino acid have been widely used in palladium anticancer drugs as ligands. Mital's group reported the synthesis and cytotoxicity of nine palladi-um(II) complexes of type [Pd(Phen)(AA)]+ (where AA is an anion of L-glycine (Gly), L-alanine (Ala), L-leucine (Leu), L-phenylalanine (Phe), L-tyrosine (Tyr), L-tryptophan (Try), L-valine (Val), L-proline (Pro) or L-serine (Ser)). The palladium(II) complexes are found to exhibit growth inhibition of P388 lymphocytic leukemic cells. The IC50 values for the palladium^) complexes with Gly and Val are comparable to cisplatin, whereas the other palladium(II) complexes show higher IC50 values [9].
Because the coordination behavior of N-carbonyl-amino acids show some similarities to that of the O-terminal end of peptides and proteins, great attention has been paid to the coordination properties of these ligands. The deprotonated Pt(II)/Pd(II) complexes, in which N-acetylglycine acts as an N,O-chelating ligand, are obtained in [10]. Several palladi-
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um(II) complexes with deprotonated sulfonamides nitrogen have been synthesized in [11]. Four new mixed-ligand complexes of palladium(II) with N-benzoyl-a-amino acid dianion and ethyldiamine, 2,2'-bipyridine (Bipy) or Phen were synthesized [12]. Until now, the cytotoxicity of mixed-ligand complexes of palladium(II) with N-carbonyl amino acid dianion and diamine has not been reported. In the present work, we present the synthesis, characterization and cytotoxicity of three mixed-ligand palladium(II) complexes with N-carbonyl-L-isoleucine dianion and Phen for the first time.
Synthesis of complexes I—III. N-carbonyl-L-iso-lecine and [Pd(Phen)Cl2] were prepared by the reported methods [13, 14]. Reaction of [Pd(Phen)Cl2] with two equivalents of N-carbonyl-L-isolecine produced the title complexes (I—III) [11]. Complex II (15 mg, 0.028 mmol) was dissolved in 3 mL mixture CH3OH— CHCl3 (V/V = 2 : 1). After several days, yellow crystals suitable for X-ray studies were obtained by the slow evaporation. The synthetic routines of complexes I— III are given below:
Step 1:
EXPERIMENTAL
Materials and methods. Benzoyl chloride, ^-meth-ylbenzoyl chloride, ^-nitrobenzoyl chloride and K2PdCl4 were of chemical grade, Phen and L-isole-cine (Ile) were of analytical grade. RPMI-1640 medium, trypsin and fetal bovine serum were purchased from Gibco. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphe-nyl tetrazolium bromide], SRB (sulforhodamine B), benzyl penicillin and streptomycin were from Sigma. Four different human carcinoma cell lines: HL-60 (immature granulocyte leukemia), Bel-7402 (liver carcinoma), BGC-823 (gastro carcinoma) and KB (nasopharyngeal carcinoma) were obtained from American Type Culture Collection.
Elemental analysis was determined on an Elementar Vario EL III elemental analyzer. The IR spectra were recorded using KBr pellets and a PerkinElmer Model-683 spectrophotometer. The mass spectra were measured by LC-MS apparatus Agilent 1200-6310. X-ray single crystal structure was performed on a Bruker SMART APEX II CCD diffractometer. The OD was measured on a microplate spectrophotometer (Bio-Rad Model 680, USA).
K2PdCl4 +
N
N
EtOH : H2O = 1 : 1
2h "
1,10-phenanthroline
Nv ,Cl Pd
n' nci
Pd(Phen)Cl2
Step 2:
R
R
+
C=O I
Cl
HO "O
carbonyl agent L-isolecine N-carbonyl-L-isolecine
Step 3:
R
N
N
R rS
✓Cl V C=O
i + s 1 HN.
Cl Y
Pd(Phen)Cl2
MeOH : H2O = 1 :1
2h "
HO O
N-carbonyl-L-isolecine
N N.
Pd / \
N O
O
I. n = 0, R = H
II. n = 0, R = CH
III. n = 1, R = NO
3
• nH2O
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SYNTHESIS, CHARACTERIZATION, AND CYTOTOXICITY OF MIXED-LIGAND
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IR for BzileH2, ^-MBzileH2, ^-NBzileH2 (KBr; v, cm-1): 3352, 3356, 3348 v(NH-amide), 1639, 1630, 1642 v(amide I), 1536, 1543, 1545 v(amide II), 1726, 1724, 1711 v(OCO)as, 1208, 1206, 1346 v(OCO)s, respectively.
For C25H23N3O3Pd (I, M = 519.89)
anal. calcd., %: C, 57.76; N, 8.08; H, 4.46.
Found, %: C, 57.76; N, 8.16; H, 4.36.
ES-MS (m/z): 542.89 [M + Na]+.
IR (KBr; v, cm-1): 1535 v(amide I), 1642 v(OCO)as,
1394 v(OCO)s, 547 v(Pd-N), 469 v(Pd-O).
1H NMR (600 MHz; CDCl3; 8, ppm): 0.84-0.78 (m., 3H, CH3), 1.20 (t., J = 5.26 Hz, 3H, CH3), 1.48 (d., J = 6.81 Hz, 2H, CH2), 2.17 (s., 1H, CH), 4.00-3.97 (m., 1H, CH), 7.33-8.60 (13H, Ar-H).
For C26H25N3O3Pd (II, M = 533.91)
anal. calcd., %: C, 58.49; N, 7.87; H, 4.72.
Found, %: C, 58.35; N, 7.83; H, 4.70.
ES-MS (m/z): 556.89 [M + Na]+.
IR (KBr; v, cm-1): 1545 v(Amide I), 1636 v(OCO)as,
1384 v(OCO)s, 552 v(Pd-N), 479 v(Pd-O).
1H NMR (600 MHz; CDCl3; 8, ppm): 0.82 (q., J = = 7.38, 6.98 Hz, 3H, CH3), 1.25 (d., J = 7.06 Hz, 3H, CH3), 1.46 (d., J = 6.75 Hz, 2H, CH2), 2.35 (s., 3H, Ar-CH3), 3.74-3.69 (m., 1H, CH), 4.01-3.98 (m., 1H, CH), 7.30-8.63 (12H, Ar-H).
For C25H22N4O5Pd (III, M = 564.89)
anal. calcd., %: C, 53.16; N, 9.92; H, 3.93.
Found,%: C, 51.51; N, 9.67; H, 4.04.
ES-MS (m/z): 565.89 [M + H]+.
IR (KBr; v, cm-1): 3420 v(water), 1554 v(amide I), 1638 v(OCO)as, 1382 v(OCO)s, 562 v(Pd-N), 474 v(Pd-O).
X-ray crystallography. The data collection of the complex II was performed on a Bruker SMART APEX II CCD diffractometer equipped with a graphite monochromatized Mo^a radiation (^ = 0.71073 A) at 296(2) K. The program SAINT was used for integration of the diffraction profiles [15]. Multiscan absorption corrections were applied using the SADABS program. The structures were solved by the direct method using the SHELXS-97 program. Refinements on F2 were performed using SHELXL-97 by the full-matrix least-squares method with anisotropic thermal parameters for all non-hydrogen atoms [16]. The hydrogen atoms were located from different Fourier maps. Supplementary material for structure II has deposited with the Cambridge Crystallographic Data Centre
(no. 771187; deposit@ccdc.cam.ac.uk or http:// www.ccdc.cam.ac.uk).
In vitro cytotoxicity study. The complexes were dissolved in DMSO at a concentration of 5 mmol/L as stock solutions and diluted in culture medium at concentrations of 1.0, 10, 100, and 500 ^mol/L as working-solution. To avoid DMSO toxicity, the concentration of DMSO was less than 0.1% (V/V) in all experiments.
The cells harvested from exponential phase were seeded equivalently into a 96-well plate, and then the complexes were added to the wells to achieve final concentrations. Control wells were prepared by addition of culture medium. Wells containing culture medium without cells were used as blanks. All experiments were performed in quintuplícate. The MTT assay was performed
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