Pyridine-Based NNS Tridentate Chitosan Thiosemicarbazones and Their Copper(II) Complexes: Synthesis, Characterization, and Anticancer Activity

Abstract

Chitosan-functionalized pyridine-based thiosemicarbazones and their copper(II) complexes have been found to own a substantial antiproliferative activity against the tumorigenic Madin Darby canine kidney (MDCK) and MCF-7 cancer cell lines. In the current study, chitosan oligosaccharide (CS) (87% DDA, M_w < 3000 Da) and crab shell chitosan (CCS) (67% DDA, M _w 350 kDa) were functionalized as chitosan pyridine-2-thiosemicarbazones and chitosan 2-acetyl pyridine-2-thiosemicarbazones, and their copper(II) complexes were synthesized. The formation of chitosan thiosemicarbazones and their NNS tridentate behavior to give the square planar copper(II) chitosan thiosemicarbazone complexes were established by spectroscopic studies, powder X-ray diffraction, elemental analysis, and magnetic moment measurements. The thermal study showed a marked stability of these derivatives before the outset of chitosan backbone degradation at 200 °C. The colorimetric MTT assay revealed a higher activity of CS thiosemicarbazones, viz., CSTSC series (IC₅₀ 375-381 μg mL^-1 in the MDCK cell line and 281-355 μg mL^-1 in the MCF-7 cell line) than that of high-molecular-weight CCS thiosemicarbazones, viz., CCSTSC series (IC₅₀ 335-400 μg mL^-1 in the MDCK cell line and 365-400 μg mL^-1 in the MCF-7 cell line), showing an enhanced activity with a decrease in M_w and an increase in DDA of constituent chitosan, a higher activity of both of these series of thiosemicarbazones than that of their native chitosan, viz., CS (IC₅₀ 370 μg mL^-1 in the MCF-7 cell line and >400 μg mL^-1 in the MDCK cell line) and CCS (IC50 > 400 μg mL^-1 in both cell lines), and a higher activity of the Cu-CSTSC complexes (IC₅₀ 322-342 μg mL^-1 in the MDCK cell line and 278-352 μg mL^-1 in the MCF-7 cell line) and Cu-CCSTSC complexes (IC₅₀ 274-400 μg mL^-1 in the MDCK cell line and 231-352 μg mL^-1 in the MCF-7 cell line) than that of their respective ligands.

Figure 1

Synthetic route of chitosan TSCs via the formation of the chitosan thiosemicarbazide intermediate.

Figure 2

Proposed structure of complexes: (a). Cu-CSPCTSC and Cu-CCSPCTSC. (b). Cu-CSAPRTSC and Cu-CCSAPRTSC.