Synthesis, Characterization and Antiproliferative Evaluation of Pt(II) and Pd(II) Complexes with a Thiazine-Pyridine Derivative Ligand

Chemical, pharmacological, and clinical research on anticancer coordination complexes has led to noteworthy anticancer drugs such as cisplatin, carboplatin and oxaliplatin. Although these compounds are effective chemotherapeutic agents in the treatment of different tumors, they are associated with high toxicity and numerous side effects. Several studies have shown that the range of platinum complexes with antitumor activity is not limited to structural analogs of cisplatin. Therefore, the development of convenient anticancer drugs that can be effectively used for the treatment of human tumors has become the main goal of most research groups in this field. In this sense, active platinum complexes without NH groups, transplatinum complexes, multinuclear complexes, cationic complexes, and several classes of palladium(II) complexes have emerged. Herein, the synthesis and characterization of two Pt(II) or Pd(II) complexes with PyTz (2-(2-pyridyl)iminotetrahydro-1,3-thiazine), a thiazine derivative ligand, with the formula [MCl2(PyTz)]·C2H6O (M = Pt(II) or Pd(II)) were reported. The potential anticancer ability of both complexes was evaluated in epithelial cervix carcinoma HeLa, human ovary adenocarcinoma SK-OV-3, human histiocytic lymphoma U-937, and human promyelocytic leukemia HL-60 cell lines. Interestingly, the Pt(II) complex showed great cytotoxic potential against all tumor cell lines tested, whereas the Pd(II) complex displayed slight antitumor actions.


Introduction
In the last few years, many promising advances have been achieved in the field of cancer treatment. However, the disease still widely affects humanity and remains to be the second leading cause of death after cardiovascular diseases [1]. A total of 8.8 million people died from cancer in 2015, and the number of new cases is expected to increase by approximately 70% over the next twenty years [2]. Therefore, it is necessary to keep investigating the design of novel antitumor agents and seek new approaches.

Crystal Structures
The X-ray study revealed that the PyTz·HCl crystals are made up of triclinic unit cells, each containing two chloride ions, two PyTzH + cations and four water molecules of crystallization. It could be therefore formulated as PyTz·HCl·2H2O. A diagram of the molecular structure and the atom numbering system used is shown in Figure 1a. Selected bond lengths, angles and hydrogen-bond parameters are listed in Table 1.  (1) x, −y−1, +z−1 3.162(1) 173.5(1) O(1W)-H(1W)···Cl (1) −x+1, −y + 1, −z + 1 3.209(1) 171.8 (2) In the electronic density map obtained in the resolution of the crystalline structure, it was possible to verify that the atoms of the organic cation were involved in a static disorder and, consequently, they were modeled using two sets of positions, for which a normal numbering system was used for the atoms of one of the arrangements and the letter A was added to those of the other (Figure 1b). However, it was not possible to model all the atoms of arrangement A because some of them almost matched in space with some atoms of the pyridine ring and, in addition, this led to an invalid model in which the pyridine   (9)   In the electronic density map obtained in the resolution of the crystalline structure, it was possible to verify that the atoms of the organic cation were involved in a static disorder and, consequently, they were modeled using two sets of positions, for which a normal numbering system was used for the atoms of one of the arrangements and the letter A was added to those of the other (Figure 1b). However, it was not possible to model all the atoms of arrangement A because some of them almost matched in space with some atoms of the pyridine ring and, in addition, this led to an invalid model in which the pyridine was not flat. In this sense, the occupancy of the two alternative orientations was restricted to the unit by calculating the occupancy factors, which were found to be 0.82(1) for the numbered orientation and 0.18(1) for the orientation named as A.
For this compound, as can be observed in Table 1 [7]. It can also be observed that the length C(1)-S(1) [1.744(2) Å] is smaller than the length C(4)-S(1) [1.806(2) Å] and it is between C=S (1.61 Å) and C-S (1.82 Å) [26]. On the other hand, bond angles in which the N(1), C(1), N(2) Pharmaceuticals 2021, 14, 395 4 of 13 and S(1) atoms are involved showed that the hybridization adopted for the first three is sp 2 , while sulfur uses~p orbitals to build the σ structure. Moreover, all these atoms are coplanar. This information indicates the presence of an extended multiple bond around the C(1) atom. These remarks, together with the presence of a hydrogen atom linked to N(1), support the fact that the predominant tautomeric form is the iminotetrahydro-1,3-thiazine form instead of the amino-5,6-dihydro-4H-1,3-thiazine form, for which a shorter exocyclic C-N bond length and a significantly longer endocyclic C-N distance would be expected.
Interestingly, as can be seen in Figure 2a, the crystal is stabilized by an intermolecular hydrogen bond system in which each chloride ion behaves like a hydrogen acceptor, N(2) atom as a hydrogen donator and water behaves in both ways.
to the unit by calculating the occupancy factors, which were found to be 0.82(1) for the numbered orientation and 0.18(1) for the orientation named as A.
For this compound, as can be observed in Table 1, the endocyclic bond C(1)-N(1) length [1.302(2) Å] is similar to the one of the exocyclic bond C(1)-N(2) [1.355(2) Å], both being between C=N [1.26 Å] and C-N [1.47 Å] [7]. It can also be observed that the length C(1)-S(1) [1.744(2) Å] is smaller than the length C(4)-S(1) [1.806(2) Å] and it is between C=S (1.61 Å) and C-S (1.82 Å) [26]. On the other hand, bond angles in which the N(1), C(1), N(2) and S(1) atoms are involved showed that the hybridization adopted for the first three is ~sp 2 , while sulfur uses ~p orbitals to build the σ structure. Moreover, all these atoms are coplanar. This information indicates the presence of an extended multiple bond around the C(1) atom. These remarks, together with the presence of a hydrogen atom linked to N(1), support the fact that the predominant tautomeric form is the iminotetrahydro-1,3thiazine form instead of the amino-5,6-dihydro-4H-1,3-thiazine form, for which a shorter exocyclic C-N bond length and a significantly longer endocyclic C-N distance would be expected.
Interestingly, as can be seen in Figure 2a, the crystal is stabilized by an intermolecular hydrogen bond system in which each chloride ion behaves like a hydrogen acceptor, N(2) atom as a hydrogen donator and water behaves in both ways. In particular, the chloride ions and the water molecules create {[(H2O)5Cl3] 3− }n tapes, whose structural parameters are summarized in Figure S1. In these tapes, the planar [(H2O)2Cl2] 2− units are linked by two water molecules, creating staircase-like architectures running parallel to the a axis ( Figure 2b). Alternatively, they can be described as a periodic repetition of fused four-membered rings (2 H2O and 2 Cl − ) and six-membered rings (4 H2O and 2 Cl − ) in the tape, which can be considered to come from the T4(2)6(2) water assembly with two H2O molecules from the hexagonal ring substituted by two chloride ions. The four-membered ring is planar but, in the (H2O)4Cl2 ring, two of the water molecules are found at 1.003 Å away from the best least-squared plane, adopting a chair configuration ( Figure 2b). Furthermore, the water molecules that link the planar [(H2O)2Cl2] 2− units are hydrogen bonded to an NH fragment of an organic cation PyTzH + , these cations filling in the spaces formed between two chains ( Figure 2c).
The crystal structures of metal complexes are made up of monomeric [MCl2(PyTz)] molecules ( Figure 3) and ethanol solvate molecules, therefore the compounds can be formulated as [PtCl2(PyTz)]·C2H6O (PtPyTz) and [PdCl2(PyTz)]·C2H6O (PdPyTz). As can be seen, PtPyTz and PdPyTz have the same coordination mode, with the metal center located in a slightly distorted square-planar coordination geometry (dihedral angles between planes Cl(1)-M-Cl (2) and N(1)-M-N(3) are 2.6° in PtPyTz and 3.6° in PdPyTz). This metal center is surrounded by one PyTz molecule, which behaves as a chelated bidentate ligand coordinated by one pyridinic nitrogen and one thiazinic nitrogen, thus forming a six- In particular, the chloride ions and the water molecules create {[(H 2 O) 5 Cl 3 ] 3− } n tapes, whose structural parameters are summarized in Figure S1. In these tapes, the planar [(H 2 O) 2 Cl 2 ] 2− units are linked by two water molecules, creating staircase-like architectures running parallel to the a axis ( Figure 2b). Alternatively, they can be described as a periodic repetition of fused four-membered rings (2 H 2 O and 2 Cl − ) and six-membered rings (4 H 2 O and 2 Cl − ) in the tape, which can be considered to come from the T4(2)6(2) water assembly with two H 2 O molecules from the hexagonal ring substituted by two chloride ions. The four-membered ring is planar but, in the (H 2 O) 4 Cl 2 ring, two of the water molecules are found at 1.003 Å away from the best least-squared plane, adopting a chair configuration ( Figure 2b). Furthermore, the water molecules that link the planar [(H 2 O) 2 Cl 2 ] 2− units are hydrogen bonded to an NH fragment of an organic cation PyTzH + , these cations filling in the spaces formed between two chains ( Figure 2c).
The crystal structures of metal complexes are made up of monomeric [MCl 2 (PyTz)] molecules ( Figure 3) and ethanol solvate molecules, therefore the compounds can be formulated as [PtCl 2 (PyTz)]·C 2 H 6 O (PtPyTz) and [PdCl 2 (PyTz)]·C 2 H 6 O (PdPyTz). As can be seen, PtPyTz and PdPyTz have the same coordination mode, with the metal center located in a slightly distorted square-planar coordination geometry (dihedral angles between planes Cl(1)-M-Cl(2) and N(1)-M-N(3) are 2.6 • in PtPyTz and 3.6 • in PdPyTz). This metal center is surrounded by one PyTz molecule, which behaves as a chelated bidentate ligand coordinated by one pyridinic nitrogen and one thiazinic nitrogen, thus forming a six-membered metallocycle with a near to boat configuration in both complexes. Two chlorine ions in cis disposition complete the coordination environment.  As can be seen in Table 2, M-Cl bond lengths in both complexes are similar to calculated mean values for squared-planar cis complexes with a Cl2N2 coordination environment around M(II) ion (2.298(18) Å for 620 Pt(II) complexes; 2.293(19) Å for 879 Pd(II) complexes) obtained with CONQUEST software from the Cambridge Structural Database (CSD, Version V5.41, Aug2020) [21]. In the same way, the M-Npyridine bond lengths are similar to the average value found for squared-planar complexes with Cl2N2 coordination sphere around M(II) ion (2.020(23) Å for 315 Pt(II) complexes; 2.039(28) Å for 427 Pd(II) complexes) in CSD [21]. However, the Pt-Nthiazine bond distance is slightly shorter than the mean value calculated [2.091(32) Å] for five crystal structures with this type of bond in CSD [21]. Finally, to our best knowledge, PdPyTz is the first crystal structure of a Pd(II) complex having a 1,3-thiazine link to Pd(II) in CSD [21].
With respect to the supramolecular arrangement, the structure is stabilized by intramolecular hydrogen bonds between the oxygen atom from the ethanol and the hydrogen atom bonded to N(2), and between the O-H of the ethanol and Cl(2), building chains along axis b ( Figures S2 and S3 for PtPyTz and PdPyTz, respectively).

Spectroscopic Studies
The ligand PyTz and its Pt(II) and Pd(II) complexes were studied by spectroscopic techniques such as NMR and IR. 1 H and 13 C NMR spectra of the ligand and both complexes are represented in Figures S4-S9 and the 1 H-NMR spectral data for PyTz and its complexes are shown in Table S1. As can be observed, the signals in metal complexes are shifted downfield compared to those corresponding to the free ligand. These differences indicate that the organic ligand is coordinated to the metal center in the N,N-dimethylformamide (DMF) solution for both complexes. Moreover, both the ligand and the complexes were kept in solution for 25 days before being measured by NMR again, which shows the high stability of these complexes in the DMF medium. Finally, the stability of compounds in aqueous media was determined by 1 H-NMR spectroscopy adding 0.55 mL of D2O at a 50 µL of solution of the compound in DMF-d7. Spectra of compounds (Figures S10-S12) are identical after 24 h for PyTz and PdPyTz, which indicates that compounds stay unalterable. However, for PtPyTz the apparition of new signals, clearly after 6 h, shows a certain degree of decomposition.

PtPyTz
Pt As can be seen in Table 2, M-Cl bond lengths in both complexes are similar to calculated mean values for squared-planar cis complexes with a Cl 2 N 2 coordination environment around M(II) ion (2.298(18) Å for 620 Pt(II) complexes; 2.293(19) Å for 879 Pd(II) complexes) obtained with CONQUEST software from the Cambridge Structural Database (CSD, Version V5.41, Aug2020) [21]. In the same way, the M-N pyridine bond lengths are similar to the average value found for squared-planar complexes with Cl 2 N 2 coordination sphere around M(II) ion (2.020(23) Å for 315 Pt(II) complexes; 2.039(28) Å for 427 Pd(II) complexes) in CSD [21]. However, the Pt-N thiazine bond distance is slightly shorter than the mean value calculated [2.091(32) Å] for five crystal structures with this type of bond in CSD [21]. Finally, to our best knowledge, PdPyTz is the first crystal structure of a Pd(II) complex having a 1,3-thiazine link to Pd(II) in CSD [21].   (2) x, y +1, z+1/2 3.136 (2) 135.3 (2) PdPyTz (2) x, y−1, z 3.180 (3) 162.1 (1) With respect to the supramolecular arrangement, the structure is stabilized by intramolecular hydrogen bonds between the oxygen atom from the ethanol and the hydrogen atom bonded to N(2), and between the O-H of the ethanol and Cl(2), building chains along axis b (Figures S2 and S3 for PtPyTz and PdPyTz, respectively).

Spectroscopic Studies
The ligand PyTz and its Pt(II) and Pd(II) complexes were studied by spectroscopic techniques such as NMR and IR. 1 H and 13 C NMR spectra of the ligand and both complexes are represented in Figures S4-S9 and the 1 H-NMR spectral data for PyTz and its complexes are shown in Table S1. As can be observed, the signals in metal complexes are shifted downfield compared to those corresponding to the free ligand. These differences indicate that the organic ligand is coordinated to the metal center in the N,N-dimethylformamide (DMF) solution for both complexes. Moreover, both the ligand and the complexes were kept in solution for 25 days before being measured by NMR again, which shows the high stability of these complexes in the DMF medium. Finally, the stability of compounds in aqueous media was determined by 1 H-NMR spectroscopy adding 0.55 mL of D 2 O at a 50 µL of solution of the compound in DMF-d 7 . Spectra of compounds (Figures S10-S12) are identical after 24 h for PyTz and PdPyTz, which indicates that compounds stay unalterable. However, for PtPyTz the apparition of new signals, clearly after 6 h, shows a certain degree of decomposition.
The IR spectra of complexes PtPyTz and PdPyTz (Figures S13-S16) showed several strong-medium ν(NH) absorption between 3262 and 3126 cm −1 , while only a medium band at 3181 cm −1 was observed for the uncoordinated PyTz ligand. Moreover, a strong ν(C=N) absorption (at 1631 cm −1 in PtPyTz and at 1629 cm −1 in PdPyTz) could be observed. These bands were shifted to higher wavenumbers relative to the imine function of the free ligand (1593 cm −1 ). Both facts could be correlated with the change of tautomeric form from iminotetrahydro-1,3-thiazine for the free ligand to the amino-5,6-dihydro-4H-1,3-thiazine when the ligand is coordinated to a metallic center. Likewise, the bands corresponding to the in-plane stretching vibrations of the pyridine ring were also shifted, in general, to lower wavenumbers compared with the ones of the uncoordinated ligand. Consequently, coordination via the nitrogen atom of the pyridine ring of the ligand can be deduced.
In the low-frequency region, the C1 symmetry of Pt(II) and Pd(II) complexes predicted the appearance of four bands assignable to metal-ligand stretching vibrations, ν(M-ligand) in IR [27,28]. However, for cis complexes, it could be expected two vibrations ν(M-Cl) corresponding to symmetric and asymmetric stretching mode (314 and 328 cm −1 for PtPyTz, 323 and 330 cm −1 for PdPyTz) [29][30][31][32][33]. Likewise, in this type of complexes, two bands for each vibration ν(M-N) are expected, although it can be normally only observed one of them. In this case, the bands which appeared at 259 and 252 cm −1 in PtPyTz and at 254 cm −1 in PdPyTz spectra were attributed to ν(M-N pyridine ) vibrations [29], while the bands detected at 243 and 232 cm −1 in PtPyTz and at 242 and 233 cm −1 in PdPyTz were assigned to ν(M-N thiazine ) vibrations [23,24].

In Silico ADME Prediction
The SwissADME web tool was used to compute physiochemical properties and the Absorption, Distribution, Metabolism, and Excretion (ADME) parameters [34]. From this computation, the pharmacokinetics and drug-likeness of compounds were predicted. The obtained results are presented in Table S2. It should be noted that the compounds were evaluated according to Lipinski's rule of five [35] and PAINS alerts [36], having zero violations or alerts. When compared to the allowed values for polarity (TPSA ≤ 140 Å 2 ), lipophilicity (logP o/w < 5), solubility (log s ≥ −6), size (M w ≤ 500 g/mol) and flexibility (number of rotable bonds ≤ 9), all compounds show calculated values within these ranges. Finally, compounds showed a high gastrointestinal absorption potential and blood-brain barrier crossing ability. These results lead to the conclusion that the investigated compounds could be good candidates as anticancer drugs.

Biological Activity
Finally, the cytotoxic potential of the ligand PyTz and its Pt(II) and Pd(II) complexes was evaluated against four selected human tumor cell lines, namely U-937 histiocytic lymphoma, HL-60 promyelocytic leukemia, HeLa epithelial cervix carcinoma, and SK-OV-3 ovary adenocarcinoma cells (Figure 4).  The Pt(II) complex PtPyTz proved to be more promising as an anticancer drug since it depicted great cytotoxic potential against all tumor cell lines tested (Figure 4). The Pt(II) complex was more selective towards leukemic cell lines U-937 and HL-60 (IC50 values were 26.36 ± 2.56 µM and 39.25 ± 3.86 µM, respectively; Table 3), and a bit less efficient against solid tumor cell lines HeLa and SK-OV-3 (IC50 values were 63.38 ± 5.63 µM and 77.97 ± 6.36 µM, respectively; Table 3). On the contrary, the Pd(II) complex PdPyTz showed low cytotoxic potential, the most remarkable cell killing ability being displayed against HeLa cells (IC50 values were 78.62 ± 8.21 µM; Table 3 and Figure 4). The effect of the ligand PyTz was comparable to that of PdPyTz in all four tumor cell lines ( Figure 4 and Table 3), which confirms the slight antitumor actions of the Pd(II) complex. Likewise, both PtPyTz and PdPyTz showed moderate toxicity against epithelial non-tumor MCF10A cell line (IC50 values were 75.94 ± 7.74 µM and 81.54 ± 8.29 µM, respectively; Table 3 and Figure 4); however, the effective doses of Pt(II) complex, especially those against leukemic cell lines U-937 and HL-60 (26.36 and 39.25 µM, respectively), had negligible effects on cell viability of MCF10A epithelial cells. In any case, the standard chemotherapeutic agent cisplatin exhibited lower IC50 values than the PyTz-containing complexes towards the four tumor cell lines (Table 3), although it also showed higher toxicity against MCF10A non-tumor cells ( Table 3). The fact that Pt(II) complexes are considerably more active than their Pd(II) counterparts has been previously reported for different organometallic compounds, such as pyrazole-based complexes [37] and complexes with tertiary arsenic ligands [38]. Nonetheless, other studies have reported Pd(II) complexes with both superior [39] and similar [2,40] biological activity to that of analogue Pt(II) complexes, thereby suggesting that the cytotoxic effect can be modulated by either the central metal or the ligand (the former being the case in the present study).  The Pt(II) complex PtPyTz proved to be more promising as an anticancer drug since it depicted great cytotoxic potential against all tumor cell lines tested (Figure 4). The Pt(II) complex was more selective towards leukemic cell lines U-937 and HL-60 (IC 50 values were 26.36 ± 2.56 µM and 39.25 ± 3.86 µM, respectively; Table 3), and a bit less efficient against solid tumor cell lines HeLa and SK-OV-3 (IC 50 values were 63.38 ± 5.63 µM and 77.97 ± 6.36 µM, respectively; Table 3). On the contrary, the Pd(II) complex PdPyTz showed low cytotoxic potential, the most remarkable cell killing ability being displayed against HeLa cells (IC 50 values were 78.62 ± 8.21 µM; Table 3 and Figure 4). The effect of the ligand PyTz was comparable to that of PdPyTz in all four tumor cell lines ( Figure 4 and Table 3), which confirms the slight antitumor actions of the Pd(II) complex. Likewise, both PtPyTz and PdPyTz showed moderate toxicity against epithelial non-tumor MCF10A cell line (IC 50 values were 75.94 ± 7.74 µM and 81.54 ± 8.29 µM, respectively; Table 3 and Figure 4); however, the effective doses of Pt(II) complex, especially those against leukemic cell lines U-937 and HL-60 (26.36 and 39.25 µM, respectively), had negligible effects on cell viability of MCF10A epithelial cells. In any case, the standard chemotherapeutic agent cisplatin exhibited lower IC 50 values than the PyTz-containing complexes towards the four tumor cell lines (Table 3), although it also showed higher toxicity against MCF10A nontumor cells ( Table 3). The fact that Pt(II) complexes are considerably more active than their Pd(II) counterparts has been previously reported for different organometallic compounds, such as pyrazole-based complexes [37] and complexes with tertiary arsenic ligands [38]. Nonetheless, other studies have reported Pd(II) complexes with both superior [39] and similar [2,40] biological activity to that of analogue Pt(II) complexes, thereby suggesting that the cytotoxic effect can be modulated by either the central metal or the ligand (the former being the case in the present study).  , horse serum and L-glutamine were procured from ThermoFisher Scientific (Barcelona, Spain). Hydrocortisone, insulin, epidermal growth factor (EGF) and cholera toxin were bought from Sigma (Madrid, Spain). CellTiter 96 AQueous One Solution Cell Proliferation Assay was acquired from Promega (Madrid, Spain). All reagents and solvents were purchased from commercial suppliers and used without further purification.

X-ray Diffraction
Crystals of the precursor PyTzHCl·2H 2 O and the complexes PtPyTz and PdPyTz were obtained as mentioned above. Crystal, structure determination and refinement data are reported in Table 4.
Data were collected on a Bruker Kappa APEXII CCD diffractometer, using graphitemonochromated Mo-Kα radiation (λ = 0.71073 Å). All data were corrected for Lorentz and polarization effects, while absorption corrections were performed by means of SAD-ABS [42] program. The structures were solved by direct methods and subsequent Fourier differences using the SHELXS-14 [43] program and refined by full-matrix least-squares on F2 with SHELXL-18 [44], included in WINGX [45] package, assuming anisotropic displacement parameters for non-hydrogen atoms. All hydrogen atoms attached to carbon or nitrogen atoms were positioned geometrically, with U iso values derived from U eq values of the corresponding carbon and nitrogen atoms. Hydrogen atoms of the water molecules were detected by Fourier differences and were refined with isotropic temperature factors. Crystallographic data for precursor PyTzHCl·2H 2 O and for complexes PtPyTz and PdPyTz were deposited at the CCDC (Cambridge Crystallographic Data Center, Cambridge, UK) with CCDC numbers 2055561, 2055559 and 2055560, respectively.

In Vitro Cytotoxicity Assay
The cytotoxic effects of the different compounds were evaluated on all four cell lines by means of the CellTiter 96 AQueous One Solution Cell Proliferation Assay, which is based on the reduction of an MTS tetrazolium compound. Cells were seeded in 96-well plates at a density of 8 × 10 3 cells/well (HeLa and MCF10A), 6 × 10 3 cells/well (SK-OV-3), 1.5 × 10 4 cells/well (U-937) or 2.5 × 10 4 cells/well (HL-60). After treating cultures for 24 h, assays were performed by adding 10 µL of the CellTiter 96 AQueous One Solution Reagent directly to culture wells, incubating for 15 min (HeLa), 30 min (SK-OV-3), 1 h (U-937 and MCF10A) or 2 h (HL-60) at 37 • C, and then recording absorbance on a microplate reader (Infinite M200; Tecan Gorup Ltd., Männedorf, Switzerland) at both a test wavelength of 490 nm and a reference wavelength of 650 nm to subtract background. All analyses were run in triplicate. The cell viability was calculated as percentage of control values (untreated samples).

Statistical Analysis
Data are presented as mean ± standard deviation (SD). To compare the different treatments, statistical significance was calculated by one-way analysis of variance (ANOVA) followed by Tukey's test. IC 50 values obtained from the dose-response curve of each compound were calculated by fitting the curve to the data using nonlinear regression to generate a four-parameter sigmoid dose-response equation. p < 0.05 was considered to indicate a statistically significant difference. The statistics software used was GraphPad Prism 7.04 for Windows.

Conclusions
New platinum(II) and palladium(II) complexes containing a thiazine-pyridine derivative ligand, PyTz, were prepared and characterized. It should be noted that PdPyTz is the first crystal structure that is described with Pd(II) linked to a nitrogen atom belonging to a 1,3-thiazine heterocycle. With regard to the antiproliferative activity, our findings show that the newly developed chemotherapeutic agent PtPyTz has greater cytotoxic activity than the PyTz-containing Pd(II) complex and the PyTz free ligand in all four human tumor cell lines tested, being more effective in leukemic cell lines than in those derived from solid tumors and non-tumor cell line. This suggests that the cytotoxic effect of these complexes is modulated by the central metal.