Synthesis, crystal structure, cytotoxicity and DNA interaction of 5,7-dichloro-8-quinolinolato-lanthanides

Abstract

Four isostructural lanthanide complexes with 5,7-dichloro-8-quinolinoline (H-ClQ): [Sm(ClQ)₃(H₂O)₂]·1.33EtOH·0.33H₂O (1), [Eu(ClQ)₃(H₂O)₂]·0.5EtOH, (2), [Tb(ClQ)₃(H₂O)₂]·0.5EtOH (3) and [Ho(ClQ)₃(H₂O)₂]·H₂O (4) were synthesized, in which the lanthanide was coordinated by three ${\text{ClQ}}^{-}$ anions and two aqua ligands. The in vitro cytotoxicities of complexes 1−4 against five human tumor cells were evaluated. The IC₅₀ values of complexes 1−4 against BEL7404, HeLa and A549 were in the range 1.2–6.3, 3.5–6.6 and 10.8–25.2 μM, respectively; except for complex 3 toward BEL7404, they all exhibited enhanced cytotoxicity in comparison to H-ClQ. The binding properties of complexes 1−4 to DNA examined by various methods indicated that complexes 1−4 interacted with DNA more strongly than free quinolinoline, and intercalation was the most probable binding mode for both the complexes and quinolinoline.

Introduction

Developing active transition metal anticancer complexes has attracted significant interests among the bio-inorganic chemists over the world, particularly, after the success of the combination of the anticancer agent cisplatin and the related platinum complexes in tumor treatment. One of the central research themes in bio-inorganic chemistry today is to try to develop other active transition metal anticancer complexes that possess a better efficiency [1], [2], [3], [4], [5]. The lanthanide complexes as the potential anticancer drugs are particularly promising due to the remarkable lanthanide antitumor activity [6], [7], [8], [9]. During the past twenty years, a number of lanthanide complexes have been synthesized and their cytotoxicities evaluated. The examples include the La(III) complexes with the ligands of 1,10-phenanthroline [10], coumarines [11], [12], cerium(III) and the neodymium(III) complexes with the ligand of 5-aminooritic acid [13], and many other lanthanide complexes [14], [15].

Heterocyclic compounds, due to their anticancer activity, have been widely studied in drug discovery and development. One such compound is the clioquinol (5-chloro-7-iodo-quinolin-8-ol), an 8-hydroxyquinoline derivative, which demonstrated anticancer activity in vitro and in vivo [16]. The clioquinol was previously used as an antibiotic for the treatment and prevention of intestinal amebiasis, and has been studied in the clinical trials for Alzheimer's disease [17]. In addition, a series of anticancer activity studies of the combination of the clioquinol- or halo-substituted 8-hydroxylquinoline with Cu(II) and Zn(II) ions have been conducted over the past decade by Dou, Shaw and Ding et al. [18], [19], [20], [21]. The structures of many 8-hydroxylquinoline rare earth complexes have been reported, including Sc(III) [22], La(III) [23], Gd(III) [24], [25], Yb(III) [25], Er(III) [26] quinolinolates. However, to the best of our knowledge, the anticancer activity of the substituted quinoline–lanthanide chelates has still not been explored. Recently, our group discovered and reported the high cytotoxicity of three dihalo-substituted 8-quinolinolato-lanthanides [27] as well as of the complex of a dinuclear nickel(II) with 5,7-dichloro-8-quinolinoline (H-ClQ) [28]. As a part of our continuing work on the synthesis, characterization and application of the metal complexes with dihalo-substituted 8-quinolinoline, herein, we report the synthesis and characterization of four new 5,7-dichloro-8-quinolinolato-lanthanides as well as their in vitro cytotoxicity against five selected tumor cell lines. Their binding properties to DNA were investigated by means of UV–visible (UV–vis), fluorescence, circular dichroism (CD) spectroscopy, DNA viscosity experiment and agarose gel electrophoresis assay.