Synthesis and cytotoxicity studies of methoxy benzyl substituted titanocenes

From the reaction of 6(2-methoxy-phenyl)fulvene (1a), 6(3-methoxy-phenyl)fulvene (1b), 6(3,4-dimethoxy-phenyl)fulvene (1c) and 6(3,4,5-trimethoxy-phenyl)fulvene (1d) with LiBEt₃H, lithiated cyclopentadienide intermediates 2a-d were synthesised. These intermediates were then transmetallated to titanium with TiCl₄ to give benzyl substituted titanocenes bis-[(2-methoxy-benzyl)cyclopentadienyl]titanium(IV) dichloride (3a), bis-[(3-methoxy-benzyl)cyclopentadienyl]titanium(IV) dichloride (3b), bis-[(3,4-dimethoxy-benzyl)cyclopentadienyl]titanium(IV) dichloride (3c) and bis-[(3,4,5-trimethoxy-benzyl)cyclopentadienyl]titanium(IV) dichloride (3d). The three titanocenes 3a-c were characterised by single crystal X-ray diffraction, while the structure of the fourth titanocene 3d was elucidated through a DFT calculation. All four titanocenes had their cytotoxicity investigated through preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line in order to determine their IC₅₀ values. Titanocenes 3a-d were found to have IC₅₀ values of 97, 159, 88 and 253 μM, respectively. All four titanocene derivatives show significant cytotoxicity improvement when compared to unsubstituted titanocene dichloride.     

Synthesis and preliminary cytotoxicity studies of achiral pyrrolyl-substituted titanocenes

From the reaction of various 6-pyrrolylfulvenes (3a–3d) with Super Hydride (LiBEt₃H), lithiated cyclopentadienide intermediates (4a–4d) were synthesised. These intermediates were then transmetallated with titanium tetrachloride TiCl₄ to yield the pyrrolyl-substituted titanocenes bis-[((1-(4-methoxybenzyl)-pyrrole)2-)cyclopentadienyl]titanium(IV) dichloride (5a), bis-[((1-(4-methoxyphenyl)-pyrrole)2-)cyclopentadienyl]titanium(IV) dichloride (5b), bis-[((2,4-bis(4-methoxyphenyl)-1-methyl-pyrrole)2-)cyclopentadienyl]titanium(IV) dichloride (5c), bis-[((2-(4-methoxyphenyl)-1-methyl-pyrrole)2-)cyclopentadienyl]titanium(IV) dichloride (5d). Titanocene 5b crystallised and was characterised by X-ray crystallography. The four titanocenes 5a–5d were tested for their cytotoxicity through MTT-based in vitro tests on CAKI-1 cell lines in order to determine their IC₅₀ values. Titanocenes 5a–5d were found to have IC₅₀ values of 440 (±35), 68 (±14), 105 (±30), and 36 (±7) μM.     

Novel zirconocene anticancer drugs?

From the reaction of Super Hydride (LiBEt₃H) with 6-(4-methoxyphenyl) fulvene (1a), 6-(2-fluoro-4-methoxyphenyl) fulvene (1b), and 6-(4-N,N-dimethylaminophenyl) fulvene (1c) lithiated cyclopentadienide intermediates (2a-c) were synthesised. These intermediates were then transmetallated to zirconium with ZrCl₄ to give benzyl-substituted zirconocenes bis-[(4-methoxybenzyl)cyclopentadienyl] zirconium(IV) dichloride (3a), bis-[(2-fluoro-4-methoxybenzyl)cyclopentadienyl] zirconium(IV) dichloride (3b) and bis-[(4-N,N-dimethylaminobenzyl)cyclopentadienyl] zirconium(IV) dichloride (3c). All three zirconocenes were characterised by single crystal X-ray diffraction and preliminary in vitro cell tests were performed with the zirconocene derivatives on the LLC-PK cell line in order to determine their cytotoxicity. Zirconocenes 3b and 3c did not show cytotoxicity up to a concentration of 170 μM, while 3a exhibited an IC50 value of 57 μM against LLC-PK.     

Synthesis and cytotoxicity studies of new dimethylamino-functionalised and heteroaryl-substituted titanocene anti-cancer drugs

From the carbolithiation of N,N-dimethylamino fulvene (3a) and different ortho-lithiated heterocycles (furan, thiophene and N-methylpyrrole), the corresponding lithium cyclopentadienide intermediate (4a-c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl₄ resulting in dimethylamino-functionalised titanocenes 5a-c. When these titanocenes were tested against LLC-PK cells, the IC₅₀ values obtained were of 240, and 28 μM for titanocenes 5a and 5b, respectively. The most cytotoxic titanocene 5c with an IC₅₀ value of 5.5 μM is found to be almost as cytotoxic as cis-platin, which showed an IC₅₀ value of 3.3 μM, when tested on the LLC-PK cell line, and titanocene 5c is approximately 400 times better than titanocene dichloride itself.     

Novel benzyl-substituted vanadocene anticancer drugs

From the reaction of 6-(p-methoxyphenyl) fulvene (1a), 6-(3,4-dimethoxyphenyl) fulvene (1b) and 6-(3,4,5-trimethoxyphenyl) fulvene (1c) with LiBEt₃H, lithiated cyclopentadienide intermediates (2a–c) were synthesised. These intermediates were then transmetallated to vanadium with VCl₄ to yield the benzyl-substituted vanadocenes bis-[(p-methoxybenzyl)cyclopentadienyl] vanadium(IV) dichloride (3a), bis-[(3,4-dimethoxybenzyl)cyclopentadienyl] vanadium(IV) dichloride (3b), and bis-[(3,4,5-trimethoxybenzyl)cyclopentadienyl] vanadium(IV) dichloride (3c). The two vanadocenes 3a and 3c were characterised by single crystal X-ray diffraction. All three vanadocenes had their cytotoxicity investigated through MTT based preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line in order to determine their IC50 values and compare them with the corresponding titanocene dichloride derivatives. Vanadocenes 3b–c were found to have IC50 values of 9.1 and 8.3 μM, while 3a showed a superior value of 3.0 μM, respectively.     

Synthesis and cytotoxicity studies of novel anion‐exchanged Titanocene Y derivatives

Starting from the potential anticancer drug candidate Titanocene Y {bis‐[(4‐methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride}, anion exchange experiments were performed using silver malonate (1a) or silver cyclobutane‐1,1‐malonate (1b) in order to yield bis‐[(4‐methoxy‐benzyl)cyclopentadienyl] titanium(IV) malonate (2a) and bis‐[(4‐methoxy‐benzyl)cyclopentadienyl] titanium(IV) cyclobutane‐1,1‐malonate (2b). In addition, Titanocene Y was reacted with salicylic acid (3a) or 3,5‐dinitro‐salicylic acid (3b) in the presence of diethylamine to synthesize bis‐[(4‐methoxy‐benzyl)cyclopentadienyl] titanium(IV) salicylate (4a) or bis‐[(4‐methoxy‐benzyl)cyclopentadienyl] titanium(IV) 3,5‐dinitro‐salicylate (4b). These titanocenes had their cytotoxicity investigated through preliminary in vitro testing on the LLC‐PK (pig kidney epithelial) cell line in an MTT‐based assay in order to determine their IC50 values. Titanocenes 2a–b and 4a were found to have IC50 values of 74 ( ± 13) µM , 18 ( ± 5) µM and 49 ( ± 11) µM on the LLC‐PK cell line, while compound 4b was found to have lost all its cytotoxic activity on this cell line. Copyright © 2010 John Wiley & Sons, Ltd.     

Antitumor activity of vanadocene Y and its selenocyanate derivative in xenografted caki-1 tumors in mice

The para-methoxybenzyl-substituted vanadocene dichloride (Vanadocene Y) (1) and its diselenocyanate (Selenocyanato-Vanadocene Y) (2) were tested in vitro in an anti-angiogenesis assay against human umbilical vein endothelial cells (HUVEC) delivering IC50 values of 0.92 ± 0.03 μM (1) and 37 ± 11 μM (2). In a cytotoxicity assay against the human renal cancer cells, CAKI-1, the compounds demonstrated IC50 values of 0.55 ± 0.09 μM (1) and 0.25 ± 0.03 μM (2). Then both compounds were given at their maximum tolerable dose, MTD, of 20 mg/kg/d (1) or 40 mg/kg/d (2) on four consecutive days or at 50% of the MTD on five consecutive days per week for three weeks to overall four cohorts of eight CAKI-1 tumor-bearing female NMRI:nu/nu mice each, while a further cohort was treated with solvent only. Both MTD-treated mouse cohorts showed a statistically significant tumor growth reduction with respect to the solvent-treated control group with an optimal T/C value of 47% on day 39 of the experiment. Immunohistological analysis revealed that the expression of the proliferation marker Ki-67 was reduced due to long-term treatment with 2.     

Novel organotin antibacterial and anticancer drugs

From the reaction of 6-(p-methoxyphenyl) fulvene (1a), 6-(p-N,N-dimethylaminophenyl) fulvene (1b) and 6-(3,4-dimethoxyphenyl) fulvene (1c) with LiBEt₃H, lithiated cyclopentadienide intermediates (2a–c) were synthesised. These intermediates were then transmetallated to tin with SnCl₄ to yield tetra-substituted bis(cyclopentadienyl)tin dichloride complexes (3a–c). Further reaction with tin tetrachloride yielded the benzyl-substituted derivatives bis-[(p-methoxybenzyl)cyclopentadienyl] tin(IV) dichloride (4a), bis-[(p-N,N-dimethylaminobenzyl)cyclopentadienyl] tin(IV) dichloride (4b), and bis-[(3,4-dimethoxyphenyl)cyclopentadienyl] tin(IV) dichloride (4c). Preliminary antibacterial tests were carried out using the Kirby–Bauer disk-diffusion method, in which 4a–c showed little to no activity against the Gram-negative bacterium Escherichia coli, but medium activity against Gram-positive bacteria (MRSA, MSSA). In addition, the organotin complexes had their cytotoxicity investigated through preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line in order to determine their IC50 values. Compound 4c showed no cytotoxic activity, while 4a and 4b were found to have IC50 values of 15 and 205 μM, respectively.     

Novel titanocene anti-cancer drugs derived from fulvenes and titanium dichloride

Starting from 6-(p−N,N-dimethylanilinyl)fulvene (1a) or 6-(pentamethylphenyl)fulvene (1b) [1,2-di(cyclopentadienyl)-1,2-di(p−N,N-dimethylaminophenyl)ethanediyl] titanium dichloride (2a) and [1,2-di(cyclopentadienyl)-1,2-bis(pentamethylphenyl)ethanediyl] titanium dichloride (2b) and their corresponding dithiocyanato complexes (3a, 3b) were synthesized. Titanocene 2b did not show a cytotoxic effect, but when 2a was tested against pig kidney carcinoma cells (LLC-PK) or human ovarian carcinoma cells (A2780/cp70) inhibitory concentrations (IC₅₀) of 2.7 × 10⁻⁴ and 1.9 ×  10⁻⁴ M, respectively, were observed.     

Novel achiral indole-substituted titanocenes: Synthesis and preliminary cytotoxicity studies

A series of eight new titanocene dichloride derivatives has been synthesised and characterized. Four compounds from the series are lypophilic indole-functionalised titanocenes and four are hydrochloride salts of their dimethylaminomethyl-functionalised counterparts, which are water soluble. The compounds were tested for their in vitro cytotoxicities against the human kidney cancer cell line CAKI-1 and their results are compared with previously synthesised structural analogues. Surprisingly, two of the compounds showed no activity against the CAKI-1 cell line; however six compounds exhibited medium to high potency with IC50 values as low as 7.0 μM. These six complexes were tested further on this cell line using the co-solvent Soluphor P, which has been shown to improve both solubility and cytotoxicity of similar complexes. One of the compounds carrying a N-methylindole-substituent was obtained in the form of single crystals and allowed for the characterisation by X-ray crystallography; the compound crystallised in the space group P2₁/n (#14) with four molecules present in the monoclinic unit cell.     

Proliferative and antiproliferative effects in substituted titanocene anticancer drugs

Substituted titanocenes like ansa-titanocenes, diarylmethyl-substituted and benzyl-substituted titanocenes, are known for their cytotoxic potential and they can be synthesised using 6-arylfulvenes. Nevertheless, in the case of using 6-(4-morpholin-4yl-phenyl) fulvene (5a) or 6-{[bis-(2-methoxyethyl)amino]phenyl} fulvene (5b) the synthetic possibilities seem to be limited, but the morpholino and the bis-(2-methoxyethyl)amino substituent are in terms of an improved water solubility and drug availability in the cell very interesting groups. The corresponding benzaldehydes, which are the starting material for the synthesis of these fulvenes, were not commercially available and therefore, a modified synthetic approach had to be introduced. Nevertheless, the reactivity of the obtained fulvenes was unexpected and only the ansa-titanocene bis-[{[bis-(2-methoxyethyl)amino]phenyl}cyclopentadienyl] titanium(IV) dichloride (6b) and the benzyl-substituted titanocene [1,2-di(cyclopentadienyl)-1,2-di(4-morpholin-4yl-phenyl)-ethanediyl] titanium dichloride (8a) could be obtained and characterised. When the benzyl-substituted titanocene (8a) was tested against pig kidney cells (LLC-PK) an anti-proliferative effect, resulting in an IC₅₀ value of 25 μM, was observed. This IC₅₀ value is in the lower range of the cytotoxicities evaluated for titanocenes up to now. The ansa-titanocene (6b) showed surprisingly, when tested on the same cell line, a proliferative effect.     

The synthesis and cytotoxic evaluation of a series of benzodioxole substituted titanocenes

Using 6‐benzo[1,3]dioxolefulvene ( 1a ), a series of benzodioxole substituted titanocenes was synthesized. The benzyl‐substituted titanocene bis[(benzo[1,3]dioxole)‐5‐methylcyclopentadienyl] titanium (IV) dichloride ( 2a ) was synthesized from the reaction of Super Hydride with 1a . An X‐ray determined crystal structure was obtained for 2a . The ansa‐titanocene {1,2‐di(cyclopentadienyl)‐1,2‐di‐(benzo[1,3]dioxole)‐ethanediyl} titanium(IV) dichloride ( 2b ) was synthesized by reductive dimerisation of 1a with titanium dichloride. The diarylmethyl substituted titanocene bis(di‐(benzo[1,3]dioxole)‐5‐methylcyclopentadienyl) titanium(IV) dichloride ( 2c ) was synthesized by reacting 1a with the para‐lithiated benzodioxole followed by transmetallation with titanium tetrachloride. When titanocenes 2a–c were tested against pig kidney (LLC‐PK) cells inhibitory concentrations (IC₅₀) of 2.8 × 10^?4, 1.6 × 10^?4 and 7.6 × 10^?5 M , respectively, were observed. These values represent improved cytotoxicity against LLC‐PK, when compared with unsubstituted titanocene dichloride, but are not as impressive as values obtained for titanocenes previously synthesized using the above methods. Copyright © 2006 John Wiley & Sons, Ltd.     

Heteroaryl substituted ansa‐titanocene anti‐cancer drugs derived from fulvenes and titanium dichloride

Starting from 2‐furylfulvene (1a) , 2‐thiophenylfulvene (1b) , and 1‐methyl‐2‐pyrrolylfulvene (1c), [1,2‐di(cyclopentadienyl)‐1,2‐di‐(2‐furyl)ethanediyl] titanium dichloride (2a) , [1,2‐di(cyclopentadienyl)‐1,2‐di‐(2‐thiophenyl)ethanediyl] titanium dichloride (2b) , and [1,2‐di(cyclopentadienyl)‐1,2‐bis‐(1‐methyl‐2‐pyrrolyl)ethanediyl] titanium dichloride (2c) were synthesized. When titanocenes (2a–c) were tested against pig kidney carcinoma cells (LLC‐PK), inhibitory concentrations (50%) of 4.5 × 10^?4 M , 2.9 × 10^?4 M and 2.0 × 10^?4 M respectively were observed. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis and cytotoxicity studies of achiral azaindole‐substituted titanocenes

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     

Syntheses of methylene-bridged ansa-zirconocene complexes and copolymerization studies of ethylene and norbornene

Methylene-bridged ansa-metallocene complexes bearing substituents on the cyclopentadienyl (Cp) and fluorenyl (Flu) moieties, namely methylene[9-(2,7-di-tert-butyl)fluorenyl(2-(1,3-dimethylcyclopentadienyl))]zirconium dichloride (1a) and its analogue, methylene[(9-(2,7-di-tert-butyl)fluorenyl(2-(1-methyl-3-phenyl)cyclopentadienyl))]zirconium dichloride (2a), have been prepared from (2,7-di-tert-butyl)-9-prop-2-ynyl-9H-fluorene (2). This procedure includes the use of 3-bromo-1-propyne which affords the methylene bridging unit by way of an intermolecular Pauson-Khand reaction in which norbornadiene and a pendant alkyne cyclize to form a ring that later becomes a substituted cyclopentadienyl group. Ethylene-norbornene (E-N) copolymerization was then carried out using these new complexes (1a and 1b) in the presence of methylaluminoxane (MAO) as a cocatalyst; these activities can be compared to that of isopropylene[9-fluorenyl-cyclopentadienyl]zirconium dichloride (3a). The activity of catalyst 1a was comparable to that of 3a but much higher than that of 2a. In addition, 1a shows higher norbornene insertion performance, and gives an E-N copolymer with a higher glass transition temperature (T_g) than 2a under identical conditions; both 1a and 2a give a lower T_g polymer than 3a does.     

Synthesis of the new ring system pyrrolizino[2,3-b]indol-4(5H)-one

Derivatives of the new ring system pyrrolizino[2,3-b]indol-4(5H)-one were prepared in four steps starting from substituted benzonitriles bearing a functionalized amino group in the adjacent position. The unsubstituted- and the dimethoxy-pyrrolizinoindolones 5a and 5b exhibited modest activity against the HL-60(TB) human leukemia cell line, whereas the N-methylated dimethoxy-pyrrolizinoindolone 6b showed to be selective against MOLT-4 leukemia, A549/ATCC, HOP-92, and NCI-H460 non-small cell lung cancer, and CAKI-1 renal cancer cell lines.     

Synthesis and preliminary cytotoxicity studies of indole-substituted vanadocenes

Abstract  

From the reaction of various 6-indolylfulvenes (1a–1e) with Super Hydride (LiBEt₃H), followed by transmetallation with vanadium tetrachloride (VCl₄), six indole-substituted vanadocenes; bis-[(1-methylindol-2-yl)methylcyclopentadienyl] vanadium (IV) dichloride (3a), bis-[(1-methyl-5-methoxyindol-2-yl)methylcyclopentadienyl] vanadium (IV) dichloride (3b), bis-[(1-methylindol-3-yl)methylcyclopentadienyl] vanadium (IV) dichloride (3c), bis-[(1-methyl-5-methoxyindol-3-yl)methylcyclopentadienyl] vanadium (IV) dichloride (3d), a dihydrochloride derivative of bis-[(1-methyl-3-dimethylaminomethylindol-2-yl)methylcyclopentadienyl] vanadium (IV) dichloride (3e), and bis-[(1-methyl-5-methoxyindol-3-yl)methylcyclopentadienyl] vanadium (IV) diselenocyanate (3f), were synthesised. The six vanadocenes 3a–f were tested for their cytotoxicity through MTT-based in vitro tests on CAKI-1 cell lines in order to determine their IC50 values. Vanadocenes 3a–f were found to have IC50 values of 48 (±4), 24 (±4), 9.2 (±1.8), 2.5 (±0.8), 2.3 (±0.7) and 22 (±7) μM.     

Synthesis and Cytotoxicity Studies of New (Dimethylamino)‐Functionalised and 7‐Azaindole‐Substituted ‘Titanocene’ Anticancer Agents (7‐Azaindole=1H‐Pyrrolo[2,3‐b]pyridine)

From the carbolithiation of 1‐(cyclopenta‐2,4‐dien‐1‐ylidene)‐N,N‐dimethylmethanamine (=6‐(dimethylamino)fulvene; 3 ) and different lithiated azaindoles 2 (1‐methyl‐7‐azaindol‐2‐yl, 1‐[(diethylamino)methyl]‐7‐azaindol‐2‐yl, and 1‐(methoxymethyl)‐7‐azaindol‐2‐yl), the corresponding lithium cyclopentadienide intermediates 4a – 4c were formed (7‐azaindole=1H‐pyrrolo[2,3‐b]pyridine). The latter underwent a transmetallation reaction with TiCl₄ resulting in the (dimethylamino)‐functionalised ‘titanocenes’ 5a – 5c . When the ‘titanocenes’ 5a – 5c were tested against LLC‐PK cells, the IC₅₀ values obtained were of 8.8, 12, and 87 μM , respectively. The most cytotoxic ‘titanocene’, 5a , with an IC₅₀ value of 8.8 μM is nearly as cytotoxic as cis‐platin, which showed an IC₅₀ value of 3.3 μM when tested on the epithelial pig kidney LLC‐PK cell line, and ca. 200 times better than ‘titanocene dichloride’ itself.     

Synthesis and cytotoxicity studies of new dimethylamino-functionalised and indolyl-substituted titanocene anti-cancer drugs

Abstract From the carbolithiation of 6-N,N-dimethylamino fulvene (3a) and different ortho-lithiated indole derivatives (5-methoxy-N-methylindole, N-methylindole and N,N-dimethylaminomethylindole), the corresponding lithium cyclopentadienide intermediate (4a–c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl₄ resulting in dimethylamino-functionalised titanocenes (5a–c). When these titanocenes were tested against LLC-PK cells, the IC₅₀ values obtained were of 37 and 71 μM for titanocenes 5a and 5b respectively. The most cytotoxic titanocene in this paper, 5c showed an IC₅₀ value of 8.4 μM is found to be almost as cytotoxic as cis-platin, which showed an IC₅₀ value of 3.3 μM, when tested on the LLC-PK cell line, and titanocene 5c is approximately 250 times better than titanocene dichloride itself. Graphical Abstract Bis-(N,N-dimethylamino-2-(N-methylindolyl)methylcyclopentadienyl) titanium (IV) dichloride was synthesised starting from 2-(N-methylindolyl) lithium and 6-N,N-dimethylamino fulvene. Herein, we present the synthesis and DFT structure of the titanocene and two further derivatives followed by MTT-based cytotoxicity tests on LLC-PK cells.      

Synthesis and characterization of cyclopentadienyl/alkoxo titanium dichlorides: structural analysis of monocyclopentadienyl titanium dichlorides with ligands derived from menthol and borneol

A variety of monocyclopentadienyl alkoxo titanium dichloride and bisalkoxo titanium dichloride complexes have been prepared and characterized by spectroscopic techniques. The titanium derivatives containing both cyclopentadienyl and various alkoxo ligands [Ti(η⁵-C₅H₅)(OR)Cl₂] (1-5) have been synthesized from the reaction of [Ti(η⁵-C₅H₅)Cl₃] with 1 equivalent of the corresponding alcohol in THF in the presence of triethylamine (ROH = Adamantanol, 1R,2S,5R-(−)-menthol, 1S-endo-(−)-borneol, cis-1,3-(−)-benzylideneglycerol, 1,2:3,4-di-O-isopropylidene-α-d-galactopyranose). The bisalkoxo titanium dichloride derivatives [TiCl₂(OR)₂] (6-10) have been prepared by a redistribution reaction between Ti(OR)₄ and TiCl₄ compounds 6-8 (OR = Adamantanoxy, (1R,2S,5R)-(−)menthoxy, (1S-endo)-(−)-borneoxy) and by reaction of [Ti(OR)₂(OPrⁱ)₂]₂ with CH₃COCl compounds 9 and 10 (OR = 1,2:3,4-di-O-isopropylidene-α-d-galactopyranoxy, and 1,2:5,6-di-O-isopropylidene-α-d-glucofuranoxy). The molecular structures of 2 and 3 have been determined by single crystal X-ray diffraction studies.