Marko Antonijević1*, Ana Antonijević2, Jovana Bogojeski3, Milica Kosović Perutović2, Nedeljko Latinović4, Zorica Leka2 and Goran Kaluđerović5
1Institute for Information Technologies, University of Kragujevac, Jovana Cvijića bb, 34000 Kragujevac, Serbia
2Faculty of Metallurgy and Technology, University of Montenegro, Podgorica, Montenegro
3Faculty of Science, University of Kragujevac, Kragujevac, Serbia
4Biotechnical Faculty, University of Montenegro, Podgorica, Montenegro
5Department of Engineering and Natural Sciences, University of Applied Sciences Merseburg, Eberhard-Leibnitz-Straße 2, 06217 Merseburg, Germany
mantonijevic [at] uni.kg.ac.rs
Abstract
Two novel mixed-ligand zinc(II) complexes, NH4[Zn(idadtc)(en)] (1) and NH4[Zn(idadtc)(en)2] (2), incorporating iminodiacetato-dithiocarbamato (idadtc3−) and ethylenediamine (en) ligands, were synthesized under varied stoichiometric and solvent conditions. Structural characterization was performed using FT-IR and NMR spectroscopy, supported by DFT calculations at the B3LYP-D3BJ/6-311++G(d,p) level with the CPCM solvation model. Toxicological profiles were predicted via ProTox III and pharmacokinetic behavior was evaluated using SwissADME. Binding affinities toward human serum albumin (HSA) and calf thymus DNA (CT-DNA) were quantified by spectrofluorometric titration and UV-Vis absorption spectroscopy. Molecular docking was performed using AutoDock 4.2 against HSA (PDB: 2BXD) and CA II (PDB: 1CA2), CA IX (PDB: 3DD0) and CA XII (PDB: 1JD0).
DFT optimization confirmed tetrahedral ZnN2S2 geometry for 1 and octahedral ZnN4S2 geometry for 2; theoretical and experimental NMR chemical shifts showed excellent agreement. Both complexes displayed low predicted toxicity (LD50 ≈ 4860 mg kg−1; GHS class IV) and favorable pharmacokinetic profiles. Spectrofluorometric analyses revealed moderate HSA binding (KSV = 2.2–2.4 × 104 M−1) and CT-DNA affinity (Kb = 1.3–1.5 × 104 M−1). Molecular docking with HSA yielded binding energies of −8.01 and −9.62 kcal mol−1 for 1 and 2, respectively, with key interactions involving residues GLU188, LYS195, LYS436, and GLU292. Docking against three carbonic anhydrase isoforms revealed notable affinities: for CA II, binding energies were −7.85 and −8.68 kcal mol−1; for tumor-associated CA IX, −8.37 and −6.27 kcal mol−1; and for CA XII, −9.69 and −7.04 kcal mol−1 for 1 and 2, respectively. Complex 1 showed preferential binding toward tumor-associated CA IX and CA XII over CA II, consistent with its compact tetrahedral ZnN2S2 geometry enabling access to their sterically restricted active sites, in contrast to the bulkier octahedral 2 (ZnN4S2) which favors the more accessible CA II active site.
The ability to direct coordination geometry through simple variation of ligand stoichiometry and solvent demonstrated the high coordination flexibility of the Zn(II)–dithiocarbamato framework. Combined with high aqueous solubility, low toxicity, moderate HSA and DNA recognition, and selective affinity of complex 1 toward tumor-associated carbonic anhydrase isoforms, these complexes represent promising scaffolds for further bioinorganic and anticancer investigations.
Keywords: Dithiocarbamates, DFT, molecular docking, anticancer
Acknowledgement: This research was supported by the German Academic Exchange Service (DAAD HAW International HOME and EURABridge Projekt-IDs: 57561680 and 57656312).