Tuning the steric and electronic parameters of mixed-donor palladium(II) complexes: coordination chemistry, substitution kinetics and biological activities.
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2021
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Abstract
Reactions of 2,6-bis(benzimidazol-2-yl)pyridine (L1), 2,6-bis(benzoxazol-2-yl)pyridine (L2), and 2,6-bis(benzothiazol-2-yl)pyridine (L3) with [Pd(NCMe)2Cl2] in the presence of NaBF4 afforded the corresponding Pd(II) complexes, [Pd(L1)Cl]BF4, PdL1; [Pd(L2)Cl]BF4, PdL2; [Pd(L3)Cl]BF4, PdL3; respectively, while reaction of bis[(1H-benzimidazol-2-yl)methyl]amine (L4) with [Pd(NCMe)2Cl2] afforded complex [Pd(L4)Cl]Cl, PdL4. Characterisation of the complexes was accomplished using NMR, IR, MS, elemental analyses and single crystal X-ray crystallography. Ligand substitution kinetics of these complexes by biological nucleophiles thiourea (Tu), L-methionine (L-Met) and guanosine 5′-diphosphate disodium salt (5-GMP) were examined under pseudo-first order conditions. The reactivity of the complexes decreased in the order: PdL1 > PdL2 > PdL3 > PdL4, ascribed to electronic effects. Density functional theory (DFT) supported this trend. Studies of interaction of the Pd(II) complexes with calf thymus DNA (CT-DNA) revealed strong binding affinities via intercalative binding mode. Molecular docking studies established associative non-covalent interactions between the Pd complexes and DNA. The in vitro cytotoxic activities of PdL1-PdL4 were assessed in cancer cell lines HeLa and MRC5-SV2 and a normal cell line MRC-5, using 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. PdL1 exhibited cytotoxic potency and selectivity against HeLa cell that was comparable to cisplatin’s. Complex PdL1, unlike cisplatin, did not significantly induce caspase-dependent apoptosis.
Treatment of 2,6-bis[(1H-pyrazol-1-yl)methyl]pyridine (L5), bis[2-(1H-pyrazol-1-yl)ethyl]amine (L6), bis[2-(1H-pyrazol-1-yl)ethyl]ether (L7), bis[2-(1H-prazol-1-yl)ethyl]sulphide (L8) with [PdCl2(NCMe)]2 in the presence of NaBF4 led to the formation of the respective Pd(II) complexes, [Pd(L5)Cl]BF4 (PdL5), [Pd(L6)Cl]BF4 (PdL6), [Pd(L7)Cl]BF4 (PdL7), [Pd(L8)Cl]BF4 (PdL8) in moderate to high yields. The complexes were structurally characterised using NMR spectroscopy, mass spectrometry, elemental analysis, and single crystal X-ray crystallography. The solid‐state structures of complexes PdL5-PdL8 confirmed a tridentate coordination mode, with one chloro ligand completing
the coordination sphere to afford square planar complexes. The substitution kinetics of the complexes with the biological nucleophiles thiourea (Tu), L-methionine (L-Met) and guanosine 5′-diphosphate disodium salt (5’-GMP) follow the order; PdL6 < PdL7 < PdL8, and PdL6 < PdL5. The kinetic reactivity is dependent on the electronic effects of the spectator ligand(s), and the trend is supported by the DFT electronic descriptors. The interaction of the complexes with calf thymus (CT-DNA), and bovine serum albumin (BSA) suggest intercalation mode of interaction, and the order of their interactions is consistent with the kinetic reactivity. The complexes exhibited lower cytotoxic effects in comparison to cisplatin against the proliferation of HeLa cancer cells.
The carboxamide complexes, [Pd(L9)Cl] (PdL9); [Pd(L10)Cl] (PdL10); [Pd(L11)Cl] (PdL11); and [Pd(L12)Cl] (PdL12) were prepared by reacting the corresponding ligands N-(pyridin-2-ylmethyl)pyrazine-2-carboxamide (L9), N-(quinolin-8-yl)pyrazine-2-carboxamide (L10), N-(quinolin-8-yl)picolinamide (L11) and N-(quinolin-8-yl)quinoline-2-carboxamide (L12) with [PdCl2(NCMe)]2. Structural characterisation of the compounds was achieved by NMR and FT-IR spectroscopies, elemental analyses and single crystal X-ray crystallography. The solid-state structures of complexes PdL10-PdL12 established the formation of one tridentate ligand unit, and Cl atom around Pd(II) ion, giving a square planar geometry. Electrochemical investigations of PdL9-PdL12 showed irreversible one-electron oxidation reactions. Kinetics reactivity of the complexes towards bio-molecules; thiourea (Tu), L-methionine (L-Met) and guanosine 5′-diphosphate disodium salt (5’-GMP) decreased in the order: PdL9 > PdL10 > PdL11 > PdL12, in tandem with the density functional theory (DFT) data. The complexes bind favourably to calf thymus (CT-DNA), and bovine serum albumin (BSA), and the order of their interactions agree with the substitution kinetics trends. The in vitro cytotoxic activities of PdL9-PdL12 were examined in cancer cell lines A549, PC-3, HT-29, Caco-2, and HeLa, and a normal cell line, KMST-6. Overall, PdL9 and PdL11 displayed potent cytotoxic effects on A549, PC-3 HT-29 and Caco-2 comparable to cisplatin. All the investigated complexes exhibited lower toxicity on normal cells than cisplatin.
Complexes [Pd(L13)Cl]BF4 (PdL13), [Pd(L14)Cl]BF4 (PdL14), [Pd(L15)Cl]BF4 (PdL15) and [Pd(L16)Cl]BF4 (PdL16) were derived from the reactions of the precursor PdCl2(NCCH3)2 with ligands 2,6-bis(3-methylimidazolium-1-yl)pyridine dibromide (L13), 2,6-bis(3-ethylimidazolium-1-yl)pyridine dibromide (L14), 2,6-bis(1-methylimidazole-2-thione)pyridine (L15), and 2,6-bis(1-ethylimidazole-2-thione)pyridine (L16), respectively. The compounds were fully characterised by 1H, 13C NMR and IR spectroscopy, mass spectrometry, elemental analyses, as well as single crystal X-ray crystallography. The solid state structure of PdL14 established the formation of one tridentate ligand unit, and Cl atom around Pd(II) ion, giving a distorted square planar geometry. Kinetic reactivity of the complexes with the nucleophiles thiourea (Tu), L-methionine (L-Met) and guanosine 5′-diphosphate disodium salt (5-GMP) decreased in the order: PdL13 > PdL14 > PdL15 > PdL16. The reactivity of the complexes was largely dependent on the electronic and steric effects of the chelate ligands. Density functional theory (DFT) simulations showed that alkyl substituents on the spectator ligand(s) and the size of the chelate chelate rings have a direct electronic (σ-donor capacity) and steric (ring size) significance on the substitution kinetics patterns. The interactions of the complexes with Calf thymus DNA (CT-DNA), and bovine serum albumin (BSA) binding titrations revealed strong and favourable binding. The in vitro antiproliferative activities of complexes PdL13-PdL16 on cervical cancer (HeLa) cell line, indicated lower cytotoxic effects than cisplatin.
Description
Doctoral Degree. University of KwaZulu-Natal, Pietermaritzburg.