Anticancer drugs based on alkenyl and boryl substituted titanocene complexes

The alkenyl-substituted titanocene complex [Ti(eta(5)-C5H5)(eta(5)-C5H4{CMe2(CH2CH2CH=CH2)})Cl-2] (1) has been synthesized and characterized using traditional methods. The reaction of 1 with 9-BBN gave the boryl substituted complex[Ti(eta(5)-C5H5)(eta(5)-C5H4{CMe2(CH2CH2CH2CH2BC8H14)})Cl-2] (2). The cytotoxic activity of 1 and 2 was tested against tumour cell lines human adenocarcinoma HeLa, human myelogenous leukemia K562, human malignant melanoma Fem-x, human breast carcinoma MDA-MB-361 and normal immunocompetent cells peripheral blood mononuclear cells PBMC and compared with those of the reference complexes [Ti(eta(5)-C5H5)(2)Cl-2] (R1), [Ti(eta(5)-C5H4Me)(2)Cl-2](R-2) and [Ti(eta(5)-C5H5)(eta(5)-C5H4SiMe3)Cl-2] (R3). Complex 1 showed higher cytotoxic activities on HeLa, Fem-x and K562 (IC50 values from 96.6 +/- 3.4 to 149.2 +/- 2.9 mu M) than the reference complexes R1, R2 and R3 which presented IC50 values from 173.3 +/- 6.0 to > 200 mu M. On the other hand, boryl substituted complex 2, present slightly lower cytotoxic activities than 1 on HeLa, Fem-x and K562 (IC50 values from 155.6 +/- 5.5 to 167.9 +/- 4.2 mu M). However, 2 was the most active of the studied complexes against MDA-MB-361 (IC50 value of 161.1 +/- 0.1 mu M). Structural studies based on DFT calculations of 1 and 2 have also been carried out in order to gain a possible insight into the relationship between metal complex structure and cytotoxicity. (c) 2009 Elsevier B.V. All rights reserved.