Novel enantiopure cyclopentadienyl Ti(IV) oximato compounds as potential anticancer agents

Abstract

The synthesis and characterization of new enantiopure cyclopentadienyl titanium oximato compounds (S,R)-[(η(5)-C5H5)Ti{к(2)NO,(R)NH·HCl}Cl2] (R=Ph (phenyl) 1a·HCl, Bn (benzyl) 1b·HCl, 2-pic (2-picolyl) 1c·HCl), (S,R)-[(η(5)-C5H5)TiCl2{к(2)NO,(Ph)NH}] (1a) and (S,R)-[(η(5)-C5H5)2TiCl{к(2)NO,(R)NH}] (R=Ph 2a, Bn 2b, 2-pic 2c), along with studies on their behavior in D2O at different pD values are reported. The structure of previously described ammonium-oxime (2S,5R)-{NOH,(Bn)NH·HCl} (b·HCl) and novel titanium derivative 1a have been determined by single crystal X-ray crystallography. The effect of the compounds on cytotoxicity, cell adhesion and migration of the androgen-independent prostate cancer PC-3 cells has been assessed. Compounds 2b and 2c are more cytotoxic than additive doses of titanocene dichloride and free oxime proligand, probing the synergistic effect of these novel compounds. The cytotoxicity of 2b and 2c has been further evaluated against human renal Caki-1, colon DLD-1 and triple negative breast MDA-MB-231 cancer cell lines. The activity found for 2c on PC-3 and Caki-1 is higher than that of highly active Titanocene Y (bis-[(p-methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride), while showing selectivity against renal cancer when compared to a non-tumorigenic human renal (HEK-293T) cell line. Compounds 2b and especially 2c are apoptotic in Caki-1 cancer cell lines. Cell adhesion and wound-healing assays confirmed that derivatives 1c·HCl, 2b and 2c affect the adhesion and migration patterns of the PC-3 cell line. Interactions of the novel compounds with plasmid (pBR322) DNA have also been studied, showing that the oximato Ti(IV) derivatives have a weak or no interaction with DNA at physiological pH.

Keywords: Cell adhesion; Cell migration; Chirality; Cyclopentadienyl titanium compounds; DNA; PC-3 and Caki-1 cell lines.