Synthesis and structural and DNA binding studies of mono‐ and dinuclear copper(II) complexes constructed with ─O and ─N donor ligands: Potential anti‐skin cancer drugs

Abstract

Mononuclear and dinuclear copper(II) complexes with thiophenecarboxylic acid, [Cu(3‐TCA)2(2,2′‐bpy)] (1), [Cu(3‐Me‐2‐TCA)2(H2O)(2,2′‐bpy)] (2), [Cu(5‐Me‐2‐TCA)2(H2O)(2,2′‐bpy)] (3) and [Cu2(2,5‐TDCA)(DMF)2(H2O)2(2,2′‐bpy)2](ClO4)2 (4) (where 3‐TCA = 3‐thiophenecarboxylic acid; 3‐Me‐2‐TCA = 3‐methyl‐2‐thiophenecarboxylic acid; 5‐Me‐2‐TCA = 5‐methyl‐2‐thiophenecarboxylic acid; 2,5‐TDCA = thiophene‐2,5‐dicarboxylic acid; 2,2′‐bpy = 2,2′‐bipyridyl; DMF = N,N‐dimethylformamide), were synthesized. Compounds 1–4 were extensively characterized using both analytical and spectroscopic methods. Additionally, the solid‐state structures of 1 and 4 were unambiguously established from single‐crystal X‐ray diffraction studies. The hexacoordinated Cu(II) centre in 1 (CuO4N2) is a distorted octahedral geometry whereas the pentacoodinated 4 (CuO3N2) has distorted square pyramidal geometry. Compounds 1 and 4 exhibit intermolecular hydrogen bonding which leads to the formation of two‐ and three‐dimensional supramolecular architectures, respectively. Spectrophotometric and computational investigations suggest that these compounds bind with DNA in minor groove binding such that Kb = 4.9 × 105 M−1 and Ksv = 3.4 × 105 M−1, and binding score of −5.26 kcal mol−1. The binding affinity of these complexes to calf thymus DNA is in the order 2 > 3 > 4 > 1. Methyl‐substituted thiophene ring increases the DNA binding affinity whereas unsubstituted thiophene ring DNA binding rate is reduced. The methyl group on the thiophene ring would sterically hinder π–π stacking of the ring with DNA base pairs, and subsequently they are involved in hydrophobic interaction with the DNA surface rather than partial intercalative interaction. Compounds 1–4 show pronounced activity against B16 mouse melanoma skin cancer cell lines as measured by MTT assay yielding IC50 values in the micromolar concentration range. The compounds could prove to be efficient anti‐cancer agents, since at a concentration as low as 2.1 μg ml−1 they exerted a significant cytotoxic effect in cancer cells whereas cell viability was not affected in normal cells.

Copper(II) Complexes with Mixed Heterocycle Ligands as Promising Antibacterial and Antitumor Species

“…It is worth mentioning that for other copper compounds tested on melanoma cells the reported IC 50 values were similar [ 39 , 40 , 41 ] or even higher [ 42 ] compared with the values found for complexes ( 1 ) and ( 2 ).…”

Biological Activity of Triazolopyrimidine Copper(II) Complexes Modulated by an Auxiliary N-N-Chelating Heterocycle Ligands

“…For B16 cells, when treated with (2), the cell viability decreased to 5%, with IC 50 values of 6.88 µg/mL (7.6 µM) after 24 h treatment and 4.15 µg/mL (4.58 µM) after 48 h, respectively (Table 3). The ligand dmtp did not affect the viability of either BJ or B16 cells at 24 or 48 h. It is worth mentioning that for other copper compounds tested on melanoma cells, the reported IC 50 values were similar [35][36][37][38][39][40][41][42][43], and only one study reported lower values [38] compared with those found for complex (1).…”

“…The Cu(II) systems represent beneficial species from this point of view, considering their reduced systemic toxicity [16]. Thus, several Cu(II) complexes were studied and proved to be as effective for melanoma treatment [18,29,[35][36][37][38][39][40][41][42][43]-some having, in addition, low toxicity on normal cells [18,29,[39][40][41][42][43].…”

Antiproliferative Copper(II) Complexes Bearing Mixed Chelating Ligands: Structural Characterization, ROS Scavenging, In Silico Studies, and Anti-Melanoma Activity

“…Other Cu(II) compounds active in the micromolar range on B16 melanoma cell lines have been developed based on pyrazole [19], pyridine [20][21][22], thiophenecarboxylato [23] derivatives, or even doxorubicin, a well-known organic-based antitumor drug [24].…”