Alkenyl-substituted titanocene dichloride complexes: Stability studies, binding and cytotoxicity

Abstract

Four alkenyl-substituted titanocene dichloride complexes {[}Ti(eta(5)-C5H5)\{eta(5)-C5H4(CMeR(CH2CH2CH=CH2))\}Cl-2] (R = Me (8), Ph (9)) and {[}Ti(eta(5)-C5H5)\{eta(5)-C5H3(CMeR(CH2CH2CH=CH2))(SiMe3)\}] (R = Me (10), Ph (11)) have been synthesized and characterized. The cytotoxic activity of 8-11 has been tested against human tumour cell lines from four different tissue origins {[}8505C (anaplastic thyroid cancer), DLD-1 (colon cancer), FaDu (head and neck cancer), A2780 (ovarian cancer) and A549 (lung carcinoma)] and compared with those of the reference complexes {[}Ti(eta(5)-C5H5)(2)Cl-2] and cisplatin. The majority of the studied titanocene compounds are more active than the reference complex {[}Ti(eta(5)-C5H5)(2)Cl-2] indicating that the presence of alkenyl substituents leads to an increase in the cytotoxic activity. In addition, the presence of a trimethylsilyl group on the cyclopentadienyl ring also leads to an increase in the cytotoxic activity of 10 with respect to 8. The contrary is observed for 9 and 11 (except on the DLD-1 cell line) with 9 (without -SiMe3) being more active than 11 (with -SiMe3). However, all synthesized complexes, exhibited lower cytotoxic activity than cisplatin. Stability and binding studies based on cyclic voltammetry and UV-visible spectroscopy have been carried out in order to explore possible interactions between titanocene derivatives and various intracellular molecules, such as the nitrogenous bases cytosine and thymine, the nucleotides adenosine and guanosine, and single-strand fish sperm DNA (FS-DNA). These experiments have allowed us to construct models to examine the interactions and action mechanisms of titanocene complexes inside the cells. In addition, this is one of the first studies on the interactions of titanocene derivatives with DNA fragments using cyclic voltammetry. (c) 2014 Elsevier B.V. All rights reserved.