Dibrominated camphoric acid derived salen complexes: Synthesis, characterization and cytotoxic activity

Abstract

Novel brominated salen metal complexes from (1R,3S)-N,N′-bis[5-bromosalicylidene]-1,3-diamino-1,2,2-trimethylcyclopentane and Cu(II), Fe(III) and Mn(III) were synthesized and screened for their in vitro cytotoxic activity against two breast cancer cell lines, HCC1806 and MCF7, and two colon cancer cells lines, LS1034 and WiDr. Results show that the copper complex exhibits the highest cytotoxic activity towards all cell lines studied, presenting IC₅₀ values of 0.95–2.32 μM. The anti-proliferative effect observed with the copper complex constitutes a marked improvement relative to current conventional chemotherapy. A relationship between the biological activity of the most efficient Cu(II) complex and its structure is established using theoretical calculations and electrochemical studies.

Introduction

One of the main causes of death worldwide is cancer. However, drugs presently used in the treatment of this disease suffer from many drawbacks, including diverse side effects and increased resistance of the cancer cells to treatment. Consequently, considerable attention has been given, in recent years, to the use of new compounds, namely, metal complexes, as alternatives for diagnosis and therapy in the medicinal area [1], [2], [3], [4], [5], [6], [7], [8].

Schiff bases and salens have been ligands of choice to prepare metal complexes with potential biological activity, such as anti-inflammatory, antifungal, antimicrobial, antiviral and antioxidant [9], [10], [11]. Particular importance comes from the fact that these complexes have been found to exhibit cytotoxic activity.

Schiff bases and salen ligands are easily obtained from the condensation of aldehydes/ketones with amines. These ligands are especially useful because they can be electronically and sterically fine-tuned by varying the structures of the carbonyl compound and/or the amine. Many types of metals have been used for complexing Schiff bases, including the transition metals Cr, V, Mn, Cu, Ni, Co, Fe, Zn and Mo, which are considered essential to life [11]. Since both structural [12] and electrochemical parameters are important variables in understanding the behavior of these metal complexes [13], the possibility of varying both ligand and metal to change these characteristics allows the synthesis of a myriad of complexes, of great utility in organic synthesis, particularly in catalytic processes and biological studies.

Previously, we described the in vitro cytotoxic activity of Cu(II), Fe(III) and Mn(III) metal complexes of (1R,3S)-N,N′-bis(salicylidene)-1,3-diamino-1,2,2-trimethylcyclopentane against human melanoma, colorectal and breast cancer cell lines. The copper (II) complex showed the highest cytotoxic activity towards all cell lines studied, with IC₅₀ values of 3.32–6.71 μM, constituting a twenty-fold improvement in the anti-proliferative effect when compared with conventional chemotherapy. It has been suggested that the presence of halogen atoms in the structure of some pharmaceuticals may significantly enhance their biological activity, notably, their cytotoxic effects [15], [16], [17]. In fact, a large number of drugs, and drugs under development, involve halogenated structures. Based on this, we have synthesized the new dibrominated salen (1R,3S)-N,N′-bis(5-bromosalicylidene)-1,3-diamino-1,2,2-trimethylcyclopentane, structurally analogous to the ligand used in our previous studies, in order to evaluate whether the presence of bromine in this ligand will enhance the cytotoxicity. The Cu(II), Fe(III) and Mn(III) complexes of this ligand were prepared and screened for their cytotoxic activity against two breast cancer cell lines, HCC1806 and MCF7, and two colon cancer cells lines, LS1034 and WiDr. It is worth highlighting that HCC1806 cells are triple negative, associated with poor prognosis, while LS1034 cells are multidrug resistant.