In the last few years, hundreds of metal compounds have been tested for the potential application against various diseases, among which the cancer treatment [[1], [2], [3], [4], [5]]. Many of them exhibit superior activity and selectivity in addition to a lesser toxicity than standard cisplatin, the first metal-based drug used in therapy [[6], [7], [8], [9], [10]]. As it is known, the primary target for cisplatin is DNA with formation of Pt–DNA adducts through the binding with guanine and adenine bases [11]. However, cisplatin has serious restrictions due to a lot of side effects such as nausea, liver failure, neuro- and nephrotoxicity [[12], [13], [14]] and due to its lack of activity against many cancer cell lines [15]. To overcome these limitations, nowadays attempts are made to build up suitable alternative pathways testing complexes with other metal ions to have similar or greater pharmacological properties aimed at diversified targets [14]; furthermore, new metal-based drugs may also be used in combination with other therapeutic agents or in the cases of drug resistance. Usually, the mechanism of potential metal drugs involves the direct interaction with DNA or the formation of reactive oxygen species (ROS) [16]. Therefore, efficient, little toxic and target-specific metal drugs with anti-cancer activity should preferentially give DNA binding. Intercalation is considered as one of the important types of non-covalent DNA binding compared to groove binding or electrostatic interaction since it customarily leads to cellular degradation [15] and the planarity and coordination geometry of metal species and structural requirements of the ligands are responsible for their intercalating capability. In this context, metal complexes formed by Schiff bases have achieved huge impact for their potential chelating ability, and sizeable biological and antitumor activity [[17], [18], [19], [20]] and, recently, progress in this field has assumed an exponential growth [[21], [22], [23], [24], [25]]. As Schiff base ligands are generally chelating in nature, they can proficiently eliminate inadvertent consequences of free metal ions and can efficiently neutralize different sources responsible for rapid escalation of both malignant and cancer cells [[26], [27], [28], [29]]. Among the ligands belonging to the Schiff bases, hydrazides as well as their derivatives are a class with a wide range of biological properties, such as antiproliferative and antioxidant activities [[30], [31], [32], [33], [34], [35], [36]].

Despite of their biological essentiality, abundance in nature, affordability, low toxicity and high activity, elements of the first transition series have been tested less than those of second and third series as possible pharmaceuticals. Among them, copper complexes show a greater potential for the use as anti-cancer agents due to the two different metal oxidation states with comparable stability and to the flexibility of geometries and coordination numbers [37]. Often, they show high solubility and large affinity for DNA or proteins [[38], [39], [40]]. As a matter of fact, the discriminating permeability of cancer cell membranes to various copper complexes has prompted the modern-day research to design potential Cu-based drugs with higher activity and less side-effect than Pt and platinum-group elements [41].

In comparison to cisplatin and other platinum compounds, copper complexes formed by Schiff bases normally exhibit similar antiproliferative activity and often display lower host toxicity [8,[42], [43], [44], [45]]. In particular, several copper(II) complexes containing hydrazide ligands display a wide spectrum of biological properties [[46], [47], [48]].

In continuation of our previous works [49] with copper(II) hydrazides, in this paper two new hydrazide ligands N′-[(E)-(pyridin-2-yl)methylidene]octanehydrazide (Hpmoh) and N′-[(1E)-1-(pyridin-2-yl)ethylidene]octanehydrazide (Hpeoh) and their copper(II) complexes [Cu(Hpmoh)(NO3)(NCS)] (1) and [Cu(peoh)2(N3)2] (2) were synthesized and characterized by various physico-chemical techniques, single crystal X-ray diffraction (XRD) analysis and computational methods (Density Functional Theory, DFT). The binding with CT-DNA was evaluated by UV–Vis and fluorescence titrations as well as by docking simulations. Finally, both complexes 1 and 2 were examined for anti-cancer activity on MDA-MB-231 (human breast adenocarcinoma) and A375 (malignant melanoma) cell lines through in vitro MTT assay. MDA-MB-231 is a triple negative breast cancer cell line that does not express estrogen receptor, progesterone receptor or human epidermal growth factor receptor; these features make this type of tumor more aggressive than receptor positive breast cancers and so difficult to treat that there are no effective targeted therapies. A375 is the deadliest form of skin cancer and is responsible for the majority of deaths from this type of disease. Moreover, A375 cells were chosen because recently it has been shown that Cu(II) compounds are very active against them, with IC50 lower than 10 μM (cisplatin, for comparison, has IC50 = 11.2 μΜ) [50], while MDA-MB-231 were considered for comparison and to give new insights into which cells might be most sensitive to copper compounds. The results could accelerate the development of potential copper-based drugs against these diseases.