Study of the anticancer properties of optically active titanocene oximato compounds.

Abstract New water soluble and optically active cyclopentadienyl titanium derivatives [(η5-C 5 H 5) 2 Ti{(1 R, 4 S)-ĸON,(R)NH}Cl] (R = Bn (Benzyl) 1a ', 2-pic (2-picolylamine) 1b ') have been synthesized. The novel compounds along with those previously described [(η5-C 5 H 5) 2 Ti{(1 S, 4 R)-ĸON,(R)NH}Cl] (R = Bn 1a , 2-pic 1b) were evaluated by polarimetry, ultra-violet and circular dichroism spectroscopy. The structure of 1b was determined by single crystal X-ray crystallography and showed a unique terminal monohapto Ti O disposition of the oximato ligand. All enantiomers have been tested against several cancer cell lines in vitro : prostate PC-3 and DU-145, lung A-549, pancreas MiaPaca-2, colorectal HCT-116, leukemia Jurkat and cervical HeLa. In addition, 1a , 1b and 1b ' were tested against non-tumorigenic prostate RWPE-1 cell line. After 24 h of incubation, 1b and 1b ' were moderately active against Jurkat and A-549 cells. The anti-proliferative effect of titanium compounds on prostate PC-3, DU-145 and RWPE-1 cell lines was also assessed after 72 h of drug exposure. The cytotoxic profile of the enantiomers was similar, exception made for the PC-3 cells, with S,R- isomers exhibiting cytotoxicities 2 to 3 times higher than R,S -compounds. Under these conditions, derivative 1b showed calculated IC 50 values better than those of Tacke's Titanocene-Y (bis-[(p -methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride) on both the prostate PC-3 and DU-145 cells. 1a and 1b cytotoxic behaviour shows certain selectiveness, with activities 2–4 times lower on normal prostate RWPE-1 than on cancer PC-3 cells. Furthermore, 1b produces higher cytotoxicity on prostate PC-3, DU-145 and RWPE-1 cells than the additive dose of titanocene dichloride and pro-ligand b·HCl. Additionally, compound-DNA interactions have been investigated by equilibrium dialysis, Fluorescence Resonance Energy Transfer (FRET) melting assays and viscometric titrations, which suggest that these metal complexes and/or their hydrolysis products bind DNA either in the minor groove or externally. Graphical abstract Image 1 Highlights • Synthesis of novel enantiopure titanocene amino-oximato compounds is reported. • The X-ray crystal structure of one of the compounds shows a unique monohapto Ti-ON coordination. • One enantiomer shows IC 50 values lower than Titanocene-Y on both PC-3 and DU-145 cells. • One enantiomer is more active than additive doses of Ti(η5-C 5 H 5)Cl 2 and oxime pro-ligand. [ABSTRACT FROM AUTHOR]