Abstract
The design and synthesis of a novel tert-butyl-calix[4]arene functionalized at 1, 3 positions of the lower rim with two terminal 2-hydroxybenzeledene-thiosemicarbazone moieties is reported. The new ligand with multi-dentate chelating properties was fully characterized by several techniques: ESI-Mass spectroscopy, FT-IR, 1H-NMR, and single crystal X-ray diffraction. The solid state structure confirms that the calix[4]arene macrocycle has the expected open cone conformation, with two opposite phenyl rings inclined outwards with large angles. The conformation of the two alkoxythiosemicarbazone arms produces a molecule with a C2 point group symmetry. An interesting chiral helicity is observed, with the two thiosemicarbazone groups oriented in opposite directions like a two-blade propeller. A water molecule is encapsulated in the center of the two-blade propeller through multiple H-bond coordinations. The antibacterial, antifungal, anticancer, and cytotoxic activities of the calix[4]arene-thiosemicarbazone ligand and its metal derivatives (Co2+, Ni2+, Cu2+, and Zn2+) were investigated. A considerable antibacterial activity (in particular against E. coli, MIC, and MBC = 31.25 μg/mL) was observed for the ligand and its metal derivatives. Significant antifungal activities against yeast (C. albicans) were also observed for the ligand (MIC = 31.25 μg/mL and MBC = 125 μg/mL) and for its Co2+ derivative (MIC = 62.5 μg/mL). All compounds show cytotoxicity against the tested cancerous cells. For the Saos-2 cell line, the promising anticancer activity of ligand L (IC50 < 25 μg/mL) is higher than its metal derivatives. The microscopic analysis of DAPI-stained cells shows that the treated cells change in morphology, with deformation and fragmentation of the nuclei. The hemo-compatibility study demonstrated that this class of compounds are suitable candidates for further in vivo investigations.
Highlights
Calix[4]arenes are macrocyclic compounds prepared by cyclo-condensation of p-tert-butylphenols with formaldehyde under alkaline conditions [1]
While the rigid structure of tert-butyl-calix[4]arenes means that up to four ligands can be introduced onto the framework through the hydroxy groups in a controlled manner, only two thiosemicarbazone groups would be necessary for each calixarene molecule to preorganize a coordination environment for metal ions
We investigated the cytotoxic effects of the ligand and its metal derivatives on human red blood cells (HRBCs) by determination of their hemolysis rate and by application of the DAPI staining method
Summary
Calix[4]arenes are macrocyclic compounds prepared by cyclo-condensation of p-tert-butylphenols with formaldehyde under alkaline conditions [1]. Functionalized calixarenes are able to act as hosts for neutral molecules [15], cations [16,17], and anions [18,19] and offer the possibility to act as multifunctional hosts [20,21] For this reason, they have been widely investigated for applications based on molecular or ion recognition, including the development of highly preorganized chelating ligands for metal coordination [22,23,24,25] and hybrid materials [26,27]. While the rigid structure of tert-butyl-calix[4]arenes means that up to four ligands can be introduced onto the framework through the hydroxy groups in a controlled manner, only two thiosemicarbazone groups would be necessary for each calixarene molecule to preorganize a coordination environment for metal ions. We investigated the cytotoxic effects of the ligand and its metal derivatives on human red blood cells (HRBCs) by determination of their hemolysis rate and by application of the DAPI staining method
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