Investigations on the Anticancer Potential of Benzothiazole-Based Metallacycles

Abstract

A series of 2-phenylbenzothiazole derivatives and their corresponding organometallic ruthenium(II) and osmium(II) complexes were synthesized, designed to exploit both, the attributes of the half-sandwich transition metal scaffold and the bioactivity spectrum of the applied 2-phenylbenzothiazoles. All synthesized compounds were characterized via standard analytical methods. The obtained organometallics showed antiproliferative activity in the low μM range and are thus at least an order of magnitude more potent than the free ligands. ESI-MS measurements showed that the examined compounds were stable in aqueous solution over 48 h. Additionally, their binding preferences to small biomolecules, their cellular accumulation and capacity of inducing apoptosis/necrosis were investigated. Based on the fluorescence properties of the selected ligand and the corresponding ruthenium complex, their subcellular distribution was studied by fluorescence microscopy, revealing a high degree of colocalization with acidic organelles of cancer cells.

Keywords: anticancer; benzothiazoles; metallacycles; osmium complexes; ruthenium complexes.

Chart 1

Chemical structures of BOLD-100, RM175, RAPTA-T, and a biologically active C,N-chelate half-sandwich Ru(II) complex (Yellol et al., 2015).

Scheme 1

Synthesis of compounds 1a−6b and the supposed behavior in biological media.

Figure 1

Crystal structures of L5, 1a, and 1b drawn at the 50% probability level. Hydrogen atoms are omitted for clarity.

Figure 2

Brightfield and fluorescence microscopy images of SW480 cells treated with L6 and 6a (green), stained with LysoTracker Red (red), and merged images revealing an extensive colocalization of fluorescence (yellow).