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

Abstract

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.

Cytotoxic Effects of New Palladium(II) Complexes with Thiazine or Thiazoline Derivative Ligands in Tumor Cell Lines

“…Moreover, compared to closer structures to the ones presented in this work, we were not able to improve the biological activity of a complex previously synthesized by our lab (PdTdTn) on the U937 cell line [ 13 ]. In contrast, for other palladium(II) complexes already reported by our lab (PdPyTz), it was possible to improve the IC 50 values in all three cell lines used in the present work [ 14 ]. Particularly, the complexes with phenyl groups decrease the IC 50 in the HL-60 cell line at 50 µM.…”

“…After checking the data obtained from the Cambridge Structural Database (CSD, Version v5.42, September 2022) [ 25 ] for square planar cis-complexes with a Cl 2 N 2 coordination environment around Pd(II), it can be affirmed that all the Pd-Cl distances are similar to the mean values found [2.294(19) Å for 944 Pd(II) complexes], like what happens for Pd-N pyrazole bond distances with respect to the mean value calculated [2.031(19) Å for 109 Pd(II) complexes] in CSD [ 25 ]. As for the Pd-N thiazoline , bond distances are slightly shorter than the average values calculated for this type of bond in CSD [ 25 ]: 2.037(59) Å for 14 Pd(II) complexes, unlike Pd-N thiazine lengths, which are barely larger than the only complex found in CSD: 2.0160 Å [ 14 ].…”

“…Furthermore, our previous results showed that a thiazoline-based Pd(II) complex decreases cell viability, triggers caspase-9-dependent apoptosis, and elicits oxidative DNA damage of human leukemic HL-60 cells, without affecting the viability of freshly isolated human leukocytes [ 12 ]. Similarly, a Pd(II) complex with a thiazoline derivative ligand decreased cell viability of histiocytic lymphoma U-937 cells, which was associated with caspase-3 and -9 activation and intracellular ROS production [ 13 ], whereas a Pd(II) complex with a thiazine-pyridine derivative ligand did not induce remarkable cytotoxicity in HL-60, U-937 and SK-OV 3 (ovarian adenocarcinoma) cells [ 14 ].…”

Pro-Apoptotic and Anti-Migration Properties of a Thiazoline-Containing Platinum(II) Complex in MDA-MB-231 Breast Cancer Cells: The Role of Melatonin as a Synergistic Agent

“…To examine the cytotoxic effects of the drugs on the different cell lines, the MTS method was performed by means of the CellTiter 96 AQueous One Solution Cell Proliferation assay (Promega, Madrid, Spain), as previously reported [ 6 , 7 ]. The experiments were run in triplicate and cells were challenged with the different drugs for 24 h.…”

“…For instance, platinum(II) complexes have been synthesized with bioactive bidentate ligands derived from heterocyclic N-donors, such as the heterocycles of pyrazole [ 2 ] and thiazoline [ 3 ], which have shown promising antitumor properties and may lay the foundation for designing new ligands that coordinate the platinum(II) ion. In this sense, our research group has recently synthesized complexes of platinum(II) with ligands of this nature that reportedly produced cytotoxic effects in human leukemic HL-60 [ 4 ], histiocytic lymphoma U-937 [ 5 ], ovarian adenocarcinoma SK-OV-3, and cervical epithelial HeLa cells [ 6 , 7 ], these effects being dependent on apoptosis induction, caspase cascade activation, increased intracellular reactive oxygen species (ROS) generation, and/or DNA oxidative damage [ 4 , 5 , 7 ].…”