Insight into the Anticancer Activity of Copper(II) 5-Methylenetrimethylammonium-Thiosemicarbazonates and Their Interaction with Organic Cation Transporters

Abstract

A series of four water-soluble salicylaldehyde thiosemicarbazones with a positively charged trimethylammonium moiety ([H2LR]Cl, R = H, Me, Et, Ph) and four copper(II) complexes [Cu(HLR)Cl]Cl (1–4) were synthesised with the aim to study (i) their antiproliferative activity in cancer cells and, (ii) for the first time for thiosemicarbazones, the interaction with membrane transport proteins, specifically organic cation transporters OCT1–3. The compounds were comprehensively characterised by analytical, spectroscopic and X-ray diffraction methods. The highest cytotoxic effect was observed in the neuroblastoma cell line SH-5YSY after 24 h exposure and follows the rank order: 3 > 2 > 4 > cisplatin > 1 >>[H2LR]Cl. The copper(II) complexes showed marked interaction with OCT1–3, comparable to that of well-known OCT inhibitors (decynium 22, prazosin and corticosterone) in the cell-based radiotracer uptake assays. The work paves the way for the development of more potent and selective anticancer drugs and/or OCT inhibitors.

Copper(II) Complexes Containing Natural Flavonoid Pomiferin Show Considerable In Vitro Cytotoxicity and Anti-inflammatory Effects

“…In accordance with these outcomes, we have focused on the study of heteroleptic copper(II) complexes containing heterocyclic diimine N-N donor ligands together with quinolinone derivatives as O-O donor ligands of the composition [Cu(qui)(phen)]Y•xH 2 O, where Hqui = 2-phenyl-3-hydroxy-4(1H)-quinolinone, Y = NO 3 or BF 4 , and phen = 1,10-phenanthroline and its derivatives. These complexes revealed significant in vitro cytotoxicity against human cancer cell lines, such as A549 lung carcinoma, HeLa cervix epithelioid carcinoma, G361 melanoma cells, A2780 ovarian carcinoma, A2780cis cisplatin-resistant ovarian carcinoma, LNCaP androgen-sensitive prostate adenocarcinoma and THP-1 monocytic leukemia, with the best IC 50 reaching the values of 0.36-0.73 µM against A2780 and A2780R [14] and against HOS lung osteosarcoma, MCF-7 breast adenocarcinoma as published for complexes of [Cu(qui)(phen)]NO 3 •xH 2 O [15], and for complexes of [Cu(qui)(phen)]BF 4 •xH 2 O [16]. Very promising results were also found in the case of similar 1,10-phenanthroline complexes having a composition of [Cu(quin)(phen)]NO 3 •yH 2 O, where Hquin stands for variously N-substituted derivatives of 2-(4-amino-3,5-dichlorophenyl)-3-hydroxy-4(1H)-quinolinone-7-carboxamide, which showed significant in vitro cytotoxicity of IC 50 ≈ 1-7 µM on HOS, MCF-7, G361, HeLa, A2780 and A2780R [17].…”

“…Moreover, copper-containing complexes or materials also behave as bearers of high thermal and electrical conductivity, or catalytic and sensory features. As examples, the following papers could be mentioned to show the current strives on the design of copper(II) complexes showing some of the above mentioned properties, mainly the antiproliferative one [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. To date, one of the most intensively studied groups of copper(II) complexes in terms of their possible clinical use as anticancer agents is the copper(II) complexes called Casiopeínas ® , whose composition can be expressed by the formulas [Cu( N – N )( N – O )] + and/or [Cu( N – N )( O – O )] + , where ( N – N ) represents an aromatic heterocyclic diimine, such as 2,2′-bipyridine (bpy) or 1,10-phenanthroline (phen), ( N – O ) and ( O – O ) stands for an amino acid, and acetylacetone, respectively [ 11 ].…”

Coumarin-Based Triapine Derivatives and Their Copper(II) Complexes: Synthesis, Cytotoxicity and mR2 RNR Inhibition Activity

“…Characteristic for Cu(II), the intensity of the room temperature X-band EPR spectrum of 2 decreased upon stepwise application of a negative potential at the first reduction peak, indicating the formation of a d 10 EPRsilent Cu(I) species (see inset in Figure 3b). Endogenous thiols are likely able to reduce copper(II) complexes of TSCs [68] to less stable copper(I) species that may dissociate. The released proligand can act as an Fe-chelator as was already unambiguously confirmed for other TSCs, including morpholine-thiosemicarbazone hybrids [26] and 3-amino-2pyridinecarboxaldehyde-S-methylisothiosemicarbazone [64], and consequently may reduce the tyrosyl radical in R2 RNR.…”

Antiproliferative Activity and DNA Interaction Studies of a Series of N4,N4-Dimethylated Thiosemicarbazone Derivatives

“…Some structural features that appear to be essential for the biological activity of TSC have been identified: in the thiocarbonyl group, the exchange of the sulphur with selenium or oxygen; the change of the attachment point of the TSC moiety in the parent aldehyde or ketone; and the substitution on the terminal N4 position [ 8 ]. Other factors include electron density distributions, the nature of the substituents, the geometry and symmetry of the starting ligand, the metal binding ability, the solubility, and the possibility of interaction with the cell membrane [ 9 ].…”