Interactions of Schiff base type compounds and their coordination complexes with the anticancer drug cisplatin

University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000, Novi Sad, Serbia.  University of Novi Sad, Faculty of Sciences, Department of Physics, Trg Dositeja Obradovića 4, 21000, Novi Sad, Serbia  University of Szeged, Faculty of Medicine, Department of Medical Microbiology and Immunobiology, Szeged, Hungary, H-6720 Szeged, Dóm tér 10


Figure S1 DTG curves of the L ligand and its complexes 1-4
Except complex 3 the crystal and molecular structures of all the compounds were determined 1 .According to X-ray structural data only compound 2 contains coordinated MeOH.The other compounds crystallized without any solvent.The thermogravimetric curves of all the complexes are in the agreement with the structural data, but the irregularity in DTG curve (Figure S1) for 1 up to 210 o C refers to solvent traces trapped within the crystal lattice.In compound 2 the coordinated MeOH evaporates at rather a high temperature (118 o C onset), though its amount (m exp = 3.2 %, m calcd = 8.65 %) is significantly less than the stoichiometric one, probably as a consequence of its evaporation accompanied with structural rearrangement of the lattice 1,2 .
* L stands for the 2-acetylpyridine-aminoguanidine ligand, while 1, 2, 3 and 4 denote its copper complexes containing co-ligands: two chlorides, a chloride and a nitrate, a chloride and a bromide and two thiocyanate ions, respectively.
Electronic Supplementary Material (ESI) for New Journal of Chemistry.This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018 The desolvated complex is stable to 214 o C onset.The complexes 1-3 are stable up to ca. 200 o C. Above this temperature, they decompose in exothermic processes even in the inert atmosphere of N 2 .Complex 4 however, has a significantly lower thermal stability and starts to decompose at 159 o C in an endothermic process.Around 300 o C a small exothermic peak appears, otherwise, the decomposition is accompanied with low enthalpy change compared to those in the other compounds.The complex containing nitrate ion practically burns out in the temperature range of 220 -250 o C (Figure S2).

Figure S2 DSC curves of L and its complexes 1-4
While the thermal curves of the complexes are in the agreement with the structure and composition determined by X-ray structure analysis, the composition of the ligand, L, found on the basis of thermogravimetric data shows a substantial difference.The mass loss of 12.6 % up to 100 o C refers to the presence of a solvent.Coupled TG/MS measurements (Figure S3) unambiguously refer to the presence of water (the intensity ratio of m/z = 17 and 18 agrees with that given in the NIST Database) 3 with a calculated composition of L·2H 2 O (m exp = 12.6 %, m calcd = 12.59 %).The decomposition of the dehydrated ligand starts above 200 o C with the evolution of HCl and scission of the amine groups which is supported by the changing of the intensity ratio of m/z = 17 compared to m/z = 18.The decomposition of the complexes starts with the amino group removal (see Figure S4 for compound 4).Here, the different shape of curves for the fragments with m/z = 36 and m/z = 38 clearly refers to a different origin of the fragments than HCl and whose source is probably the organic part of the ligand.
In one of our previous studies of macrocyclic copper(II) complexes 4 we found that with decreasing thermal stability the antiproliferative activity of the complexes against HeLa cell line also decreases.The decrease in the thermal stability (in accordance with the HSAB principle) could be correlated to the increasing stability constants of the water-soluble coordination compounds.This may refer to the importance of the dissociation of the molecules in the mechanism of cytotoxicity.
Neither of the tested complexes here is water soluble and their stability constants were not determined.However, if we present the interactions of all Cu(II) complexes with CD or Dox one can see that the onset temperatures of the compounds with cisplatin follow the trend of interaction with the drug.Because the drug and the compounds are of similar type one can expect a similar type of interactions between the acting compounds and the target T-lymphoma cells, also.As the thermal stability reflects the bond strength, consequently the interactions depend on the bond strength, most probably those with unidentate coordinated ions.

Figure S3
Figure S3 The fragmentation of L Fig S4 The fragmentation of 4-L.