Abstract
Copper is an endogenous metal ion that has been studied to prepare a new antitumoral agent with less side-effects. Copper is involved as a cofactor in several enzymes, in ROS production, in the promotion of tumor progression, metastasis, and angiogenesis, and has been found at high levels in serum and tissues of several types of human cancers. Under these circumstances, two strategies are commonly followed in the development of novel anticancer Copper-based drugs: the sequestration of free Copper ions and the synthesis of Copper complexes that trigger cell death. The latter strategy has been followed in the last 40 years and many reviews have covered the anticancer properties of a broad spectrum of Copper complexes, showing that the activity of these compounds is often multi factored. In this work, we would like to focus on the anticancer properties of mixed Cu(II) complexes bearing substituted or unsubstituted 1,10-phenanthroline based ligands and different classes of inorganic and organic auxiliary ligands. For each metal complex, information regarding the tested cell lines and the mechanistic studies will be reported and discussed. The exerted action mechanisms were presented according to the auxiliary ligand/s, the metallic centers, and the increasing complexity of the compound structures.
Highlights
The fortuitous discovery of the anticancer properties of cisplatin (Figure 1a) has represented a milestone in the chemotherapeutic treatment of several types of tumors [1]
A common approach exploited in the design of novel anticancer metallodrugs consists in substituting Pt(II) with endogenous metal ions, with the aim of interfering at DNA level through alternative mechanisms compared to Pt(II)-based drugs, or by targeting completely different biological molecules and pathways
Two different strategies are commonly followed in the development of novel anticancer Copper-based drugs: (1) sequestration of free Copper ions in excess by using metal chelators; (2) synthesis of Copper complexes that trigger cell death through accumulation of the metal ion and induction of ROS production [14]
Summary
The fortuitous discovery of the anticancer properties of cisplatin (Figure 1a) has represented a milestone in the chemotherapeutic treatment of several types of tumors (ovarian, testicular and lung, among others) [1]. High levels of Copper were found in serum and tissues of several types of human cancers [12,13] Based on these findings, two different strategies are commonly followed in the development of novel anticancer Copper-based drugs: (1) sequestration of free Copper ions in excess by using metal chelators; (2) synthesis of Copper complexes that trigger cell death through accumulation of the metal ion and induction of ROS production [14]. Shi et al have synthesized a panel of mixed complexes having general formula [Cu(LPTn)x(X)y](Y)z (Figure 3), where LPTn are phenanthroline derivatives having alkyl chains of different lengths Both cellular uptake and activity on cervical (Hela) and ovarian (SKOV-3) cancer cells appear directly correlated with the lipophilicity of the LPTn ligand, while all of them showed mild toxicity towards healthy HK-2 cells. H: CCRF-CEM (0.18 ± 0.01), CCRF-SB (0.20 ± 0.01), SKMES-1 (2.25 ± 0.02), DU-145 (4.00 ± 0.02), HEP-G2
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