Synthesis, characterization and toxicity studies of pyridinecarboxaldehydes and L-tryptophan derived Schiff bases and corresponding copper (II) complexes

Abstract

Schiff bases and their metal-complexes are versatile compounds exhibiting a broad range of biological activities and thus actively used in the drug development process. The aim of the present study was the synthesis and characterization of new Schiff bases and their copper (II) complexes, derived from L-tryptophan and isomeric (2-; 3-; 4-) pyridinecarboxaldehydes, as well as the assessment of their toxicity in vitro. The optimal conditions of the Schiff base synthesis resulting in up to 75-85% yield of target products were identified. The structure-activity relationship analysis indicated that the location of the carboxaldehyde group at 2-, 3- or 4-position with regard to nitrogen of the pyridine ring in aldehyde component of the L-tryptophan derivative Schiff bases and corresponding copper complexes essentially change the biological activity of the compounds. The carboxaldehyde group at 2- and 4-positions leads to the higher cytotoxic activity, than that of at 3-position, and the presence of the copper in the complexes increases the cytotoxicity. Based on toxicity classification data, the compounds with non-toxic profile were identified, which can be used as new entities in the drug development process using Schiff base scaffold.

Keywords: HeLa; KCL-22; L-tryptophan; Schiff base; copper (II) complex; cytotoxicity; synthesis.

Figure 1.

Suggested structure of the 2pyr.Trp ( A), 3pyr.Trp ( B) and 4pyr.Trp ( C) Schiff bases.

Figure 2.

Suggested structure of Cu-2pyr.Trp ( A), Cu-3pyr.Trp ( B), Cu-4pyr.Trp ( C) metallocomplexes.

Figure 3.

The cytotoxicity of 2pyr.Trp ( A) and Cu-2pyr.Trp ( B) in HeLa and KCL-22 cell lines. Dose-response curves were obtained after 48 hours of treatment with Schiff base 2pyr.Trp and its copper(II) complex Cu-2pyr.Trp at the concentration range of 0.1–1000 µM/mL. Cell viability was expressed as a percentage of the negative control (cell cultures with no treatment). Doses inducing 50% inhibition of cell viability (the IC ₅₀ value) were calculated to determine the cytotoxicity of 2pyr.Trp and Cu-2pyr.Trp. The IC ₅₀ value estimated for 2pyr.Trp in KCL-22 cell line was equal to 56±9.1 μM/mL, whereas the viability of HeLa cells was more than 90% at the highest concentration tested ( A). The IC ₅₀ values estimated for Cu-2pyr.Trp were equal to 7±1.7 μM/mL and 80±7.5 μM/mL for HeLa and KCL-22 cell lines, respectively ( B).

Figure 4.

The cytotoxicity of 3pyr.Trp ( A) and Cu-3pyr.Trp ( B) in HeLa and KCL-22 cell lines. Dose-response curves were obtained after 48 hours of treatment with Schiff base 3pyr.Trp and its copper(II) complex Cu-3pyr.Trp at the concentration range of 0.1–1000 µM/mL. Cell viability was expressed as a percentage of the negative control (cell cultures with no treatment). Doses inducing 50% inhibition of cell viability (the IC ₅₀ value) were calculated to determine the cytotoxicity of 3pyr.Trp and Cu-3pyr.Trp. The non-cytotoxic profile was observed for 3pyr.Trp in both cell lines, since the viability of HeLa and KCL-22 cells was around 100% at the highest concentration tested ( A). The Cu-3pyr.Trp demonstrated the increased cytotoxic activity against both cell lines, however, the IC ₅₀ value was possible to estimate only for HeLa cells (500±5.6 μM/mL), since the viability of KCL-22 cells was more than 60% at the highest concentration tested ( B).

Figure 5.

The cytotoxicity of 4pyr.Trp ( A) and Cu-4pyr.Trp ( B) in HeLa and KCL-22 cell lines. Dose-response curves were obtained after 48 hours of treatment with Schiff base 4pyr.Trp and its copper(II) complex Cu-4pyr.Trp at the concentration range of 0.1–1000 µM/mL. Cell viability was expressed as a percentage of the negative control (cell cultures with no treatment). Doses inducing 50% inhibition of cell viability (the IC ₅₀ value) were calculated to determine the cytotoxicity of 4pyr.Trp and Cu-4pyr.Trp. The IC ₅₀ value estimated for 4pyr.Trp in KCL-22 cell line was equal to 100±6.5 μM/mL, whereas the viability of HeLa cells was more than 60% at the highest concentration tested ( A). The IC ₅₀ values estimated for Cu-4pyr.Trp were equal to 10±5 μM/mL and 30±3.8 μM/mL for HeLa and KCL-22 cell lines, respectively ( B).

Figure 6.. Comparison of Schiff bases and copper(II) complexes cytotoxicity in HeLa and KCL-22 cell lines.

*p<0.01.