Synthesis and cytotoxicity studies of achiral azaindole-substituted titanocenes

Abstract

From the reaction of 1-methyl-1 H-pyr-rolo[2,3-b]pyridine (1a),1-(methoxymethyl)-1 H-pyrrolo[2,3-b]pyridine (1b), 1-isopropyl-1 H-pyrrolo[2,3-b]pyridine (1c), and 1-(4-methoxybenzyl)-1 H-pyrrolo[2,3-b]pyridine (1d) under Vilsmeier–Haak conditions, the corresponding aldehydes in position 3 (2a–2d) were synthesized. These aldehydes were transformed in the corresponding fulvenes (3a–3d) by the Knoevenagel condensation and treated with Li[BEt3H] to obtain the corresponding lithiated cyclopentadienide intermediates (3′a–3′d). These intermediates were, finally transmetallated to titanium with TiCl4 to yield the 7-azaindol-3-yl-substituted titanocenes bis {[(1-methyl-1-H-pyrrolo[2,3-b]pyridin-3-yl)methyl] cyclopentadienyl} titanium(IV) dichloride (4a), bis{[(1-methoxymethyl-1-H-pyrrolo[2,3-b]pyridin-3-yl)methyl]cyclopentadienyl} titanium(IV)dichloride (4b), bis{[(1-Isopropyl-1-H-pyrrolo[2,3-b]pyridin-3-yl)methyl]cyclopentadienyl} titanium(IV) dichloride (4c), and bis{[(4-methoxybenzyl-1-H-pyrrolo[2,3-b]pyridin-3-yl)methyl]cyclopentadienyl} titanium(IV) dichloride (4d). All the titanocenes had their cytotoxicity investigated through MTT-based preliminary in vitro testing on the Caki-1 cell lines to determinate their IC50 values. Titanocenes 4a–4c were found to have IC50 values of 120 ± 10, 83 ± 13, and 54 ± 12, µM respectively, whereas 4d showed no cytotoxic activity. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 22:148–157, 2011; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.20668