Structure–antiproliferative activity studies onl-proline- and homoproline-4-N-pyrrolidine-3-thiosemicarbazone hybrids and their nickel(ii), palladium(ii) and copper(ii) complexes

Abstract

Two water-soluble thiosemicarbazone-proline (H2L(1)) and thiosemicarbazone-homoproline hybrids (H2L(2)) were synthesised. By reaction of H2L(1) with NiCl2·6H2O, PdCl2 and CuCl2·2H2O in ethanol, the series of square-planar complexes [Ni(H2L(1))Cl]Cl·1.3H2O (1·1.3H2O), [Pd(H2L(1))Cl]Cl·H2O (2·H2O) and [Cu(H2L(1))Cl]Cl·0.7H2O (3·0.7H2O) was prepared, and starting from H2L(2) and CuCl2·2H2O in methanol, the complex [Cu(H2L(2))Cl2]·H2O (4·H2O) was obtained. The compounds have been characterised by elemental analysis, spectroscopic methods (IR, UV-vis and NMR spectroscopy), ESI mass spectrometry and single crystal X-ray crystallography (H2L(1), 1, 2 and 4). As a solid, 1 is diamagnetic, while it is paramagnetic in methanolic solution. The effective magnetic moment of 3.26 B.M. at room temperature indicates the change in coordination geometry from square-planar to octahedral upon dissolution. The in vitro anticancer potency of ligand precursors H2L(1) and H2L(2) and metal complexes 1-4 was studied in three human cancer cell lines (A549, CH1 and SW480) and in noncancerous murine embryonal fibroblasts (NIH/3T3), and the mechanism of cell death was also assayed by flow cytometry. Clear-cut structure-activity relationships have been established. The metal ions exert marked effects in a divergent manner: copper(ii) increases, whereas nickel(ii) and palladium(ii) decrease the cytotoxicity of the hybrids. The antiproliferative activity of H2L(1) and metal complexes 1-3 decreases in all three tumour cell lines in the following rank order: 3 > H2L(1) > 1 > 2. The role of square-planar geometry in the underlying mechanism of cytotoxicity of the metal complexes studied seems to be negligible, while structural modifications at the terminal amino group of thiosemicarbazide and proline moieties are significant for enhancing the antiproliferative activity of both hybrids and copper(ii) complexes.

Effects of Terminal Substitution and Iron Coordination on Antiproliferative Activity of l‐Proline‐salicylaldehyde–Thiosemicarbazone Hybrids

“…Protonation of N4a makes this atom chiral in addition to C14a. Both atoms adopt the same S configuration as observed recently in complexes of nickel(II), palladium(II), and copper(II) with the same type of proline–thiosemicarbazone hybrids , . Opposite configurations of these two atoms are also well documented in the literature , …”

“…The chiral proligands l ‐Pro‐STSC ( H 2 L 1 ) and Pyrr‐ l ‐Pro‐STSC ( H 2 L 2 ) have been synthesized as described previously , . The reaction of l ‐Pro‐MSA with 4‐phenyl‐3‐thiosemicarbazide in ethanol/water mixture and 4‐(1‐naphthyl)‐3‐thiosemicarbazide in ethanol afforded H 2 L 3 and H 2 L 4 in 64 and 65 % yield, respectively.…”

“…The replacement of the phenolic moiety (in l ‐Pro‐STSC) by pyridine [in 3‐methyl‐( S )‐pyrrolidine‐2‐carboxylate‐2‐formylpyridine thiosemicarbazone, l ‐Pro‐FTSC] did not significantly improve the cytotoxic properties of the hybrids, most probably because of further enhancement of the hydrophilic character . The structural modifications at the terminal N atom of the TSC moiety in l ‐Pro‐STSC and coordination to essential metals had a beneficial impact on the cytotoxicity, while the changes on the proline moiety of the hybrids reduced antiproliferative activity . The results prompted us to extend the series of l ‐Pro‐STSC conjugates by attachment of aromatic groups at the terminal N atom of TSCs to increase their lipophilic character, and hopefully their cytotoxic potency.…”

A novel class of thiosemicarbazones show multi-functional activity for the treatment of Alzheimer's disease

“…However, there is a large variation in the Cu-S coordinate bond length within these analogues (2.226(2)−2.2785(8) Å) with the bond in [Cu(SBPT)Cl 2 ] being the longest of the series. Interestingly, other chlorido thiosemicarbazone Cu complexes are genuinely square planar [53]. Hence, it appears that the negative charge of the weakly coordinated axial chlorido ligand in [Cu(SBPT)Cl 2 ] is responsible for elongating the Cu-S bond in this structure (Fig.…”

Synthesis and Characterization of Palladium(II) Complexes with Thiosemicarbazones

“…Various transition metals such as organotin(IV), iron(II), copper(II), zinc(II), nickel(II), palladium, platinum, ruthenium, etc. have been incorporated into thiosemicarbazones and their applications have been studied [11][12][13][14][15]. Palladium(II) derivatives were found to be more preferred for cancer treatment because of their structural analogy with Pt(II) complexes and some complexes show The complexes were found to be diamagnetic, four coordinated mononuclear neutral molecules with square planar or distorted square planar geometry.…”