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.     

Photochemical reactions of bis(η5-cyclopentadienyl)- titanium dichloride

Irradiation of benzene solutions 10^?3M in both titanocene-d₁₀ dichloride and titanocene dichloride with light of wavelengths 313, 360, 400, and 520 nm leads to the formation of titanocene-d₅ dichloride with quantum yields of 0.02, 0.005, 0.01 and 0.007 mol Ei^?1, respectively. Photodecomposition of titanocene dichloride is negligible even at much longer photolysis times than those required for isotopic equilibration. Photolysis of benzene solutions 10^?2M in titanocene dichloride and 1.0 M in methanol leads to the formation of cyclopentadienyl(methoxo)titanium dichloride with a quantum yield of about 0.08 mol Ei^?1 when the irradiating wavelength is 313 nm.     

有机钛化学——Ⅰ.钛催化卤代烃还原反应的研究

本文报导了用多种不同的钛催化体系对卤代烃进行还原反应的结果。观察到二氯二茂钛、某些二氯二(取代茂基)钛和二茂钛甲基烯丙基配合物在异丙基溴化镁的存在下对卤代烃的还原是高效均相催化剂。在某些情怳下,有机溴化物和碘化物可以在非常温和的条件下被定量地还原。我们比较了不同类型的卤代芳烃、卤代烷烃和二卤代烃的还原,对催化剂用量和反应温度的影响也进行了研究。文中讨论了反应机理,认为以Cp₂TiH为催化反应的活性种,先是RX对Cp₂TiH氧化加成,再发生RH的还原消除,然后在格氏试剂的存在下Cp₂TiH再生,从而构成催化循环。     

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.     

Proliferative and anti-proliferative effects of titanium- and iron-based metallocene anti-cancer drugs

In previous work we have found that Cp₂TiCl₂ and its corresponding derivative of tamoxifen, Titanocene tamoxifen, show an unexpected proliferative effect on hormone dependent breast cancer cells MCF-7. In order to check if this behavior is a general trend for titanocene derivatives we have tested two other titanocene derivatives, Titanocene Y and Titanocene K, on this cell line. Interestingly, these two titanocene complexes behave in a totally different manner. Titanocene K is highly proliferative on MCF-7 cells even at low concentrations (0.5 μM), thus behave almost similarly to Cp₂TiCl₂. This proliferative effect is also observed in the presence of bovine serum albumin (BSA). In contrast, Titanocene Y alone has almost no effect on MCF-7 at a concentration of 10 μM, but exhibits a significant dose dependent cytotoxic effect of up to 50% when incubated with BSA (20-50 μg/mL). This confirms the crucial role played by the binding to serum proteins in the expression of the in vivo, cytotoxicity of the titanocene complexes. From the hydridolithiation reaction of 6-p-anisylfulvene with LiBEt₃H followed by transmetallation with iron dichloride [bis-[(p-methoxy-benzyl)cyclopentadienyl]iron(II)] (Ferrocene Y) was synthesised. This complex, which was characterised by single crystal X-ray diffraction, contains the robust ferrocenyl unit instead of Ti associated with easily leaving groups such as chlorine and shows only a modest cytotoxicity against MCF-7 or MDA-MB-231 cells.     

Formation of pyrrolidines by the titanocene(II)-promoted intramolecular reaction of N-[3,3-bis(phenylthio)propyl]anilides

The reaction of anilides with the titanium carbene complexes generated by the desulfurization of thioacetals with the titanocene(II) species Cp₂Ti[P(OEt)₃]₂ produced the corresponding enamines. Unusual formation of pyrrolidines was observed when N-[3,3-bis(phenylthio)propyl]anilides were treated with the titanocene(II) reagent.     

Titanocene (III) chloride mediated radical induced synthesis of (−)-methylenolactocin and (−)-protolichesterinic acid

Enantioselective synthesis of two anti-tumor antibiotics, (−)-methylenolactocin and (−)-protolichesterinic acid, has been achieved through titanocene(III) chloride mediated radical cyclization reaction starting from commercially available d-mannitol. Titanocene(III) chloride (Cp₂TiCl) was prepared in situ from commercially available titanocene dichloride (Cp₂TiCl₂) and zinc dust in THF.     

On the reversibility of the first electron transfer involving titanocene dichloride

The 1e reduction of titanocene dichloride (Cp₂TiCl₂) in DMF has been examined in detail. The reaction is reversible, in contradiction of a recent report.     

The catalytic activity of alkali metal alkoxides and titanium alkoxides in the hydrosilylation of unfunctionalized olefins

The catalytic activities of titanium alkoxides and alkali metal alkoxides for hydrosilylation of unfunctionalized olefins have been studied. Titanium(IV) alkoxides showed excellent catalytic activity, while alkali metal alkoxides have low catalytic activity for the hydrosilylation of olefins. However, by using titanocene dichloride as an additive, alkali metal alkoxides showed also excellent catalytic property for hydrosilylation. In comparison with titanium alkoxides, no α-adduct was obtained by using alkali metal alkoxides/Cp₂TiCl₂ as catalysts.     

Benzyl-substituted titanocene dichloride anticancer drugs: From lead to hit

Through the reaction of Super Hydride (LiBEt₃H) with 6-phenyl-substituted fulvenes followed by transmetallation to TiCl₄ ten novel benzyl-substituted titanocene dichloride derivatives were synthesised. 6(4-morpholinomethyl-phenyl) fulvene (6g) and (bis-[(4-methoxymethyl-benzyl)cyclopentadienyl]titanium(IV) dichloride) (8a) were characterised by single crystal X-ray diffraction. All of the titanocenes had their cytotoxicity investigated through preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line and CAKI-1 human kidney cell human carcinoma cell line in an MTT based assay in order to determine their IC50 values. The titanocenes synthesised were found to have IC50 values ranging from 2.3 (±0.3) μM (comparable to cisplatin) to others which show no anti-proliferative activity on this cell line in standard DMSO formulations on LLC-PK cell line. Eight of the titanocenes were found to be completely water-soluble and had IC50 values of 6.5 (±0.7) μM to no activity when using medium only for formulation. On the CAKI-1 cell line, IC50 values of 7.8 (±1.4) μM to no activity were found using DMSO formulation, while IC50 values of 0.55 (±0.32) μM to no activity were measured using just medium as the formulation reagent. Some of the titanocenes show significant cytotoxicity improvement when compared directly to the lead compound Titanocene Y (bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride) and are more cytotoxic than cisplatin. Bis-[(4-diethylaminomethyl-benzyl)cyclopentadienyl]titanium(IV) dichloride (8d) at this preliminary stage seems to be the most promising of the ten compounds prepared and exhibits nanomolar activity against CAKI-1.     

ansa-metallocene derivatives: XI. Synthesis and crystal structure of a chiral ansa-titanocene derivative with trimethylene-bridged tetrahydroindenyl ligands

The chiral ansa-titanocene derivative 1,3-propanediylbis(4,5,6,7-tetrahydro-1-indenyl)titanium(IV) dichloride has been prepared by reaction of the dilithium salt of 1,3-bis(indenyl)propane with TiCl₄ and subsequent hydrogenation. The product has been shown by an X-ray diffraction study to be the R,S metal-ring linkage isomer; in this trimethylene-bridged ansa-metallocene the axial symmetry previously observed for te ethylene-bridged congener is destroyed by a non-symmetric location of the (CH₂)₃ bridge.     

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.      

Hydroalumination of olefins catalyzed by immobilized titanium compounds

SiO₂-supported titanium chloride ($\text{1}$) and polystyrene-supported titanocene dichloride ($\text{2}$) and ($\text{3}$) were synthesized. These heterogenized titanium compounds are excellent catalysts for hydroalumination of olefins.     

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.     

Synthesis, structure and biological activity of amide-functionalized titanocenyls: Improving their cytotoxic properties

Nine amide-functionalized titanocenyls have been synthesized and characterized by spectroscopic and analytical methods and the solid state structure of Cp(CpCO-NH-C₆H₄-OCF₃)TiCl₂ was determined by single crystal X-ray diffraction. X-ray analysis of Cp(CpCO-NH-C₆H₄-OCF₃)TiCl₂ showed that titanium is in a pseudo tetrahedral geometry and contains a Ti-O(amide) coordination. In principle, Ti-O coordination should provide more hydrolytic stability to the corresponding titanocenyls than titanocene dichloride. The cytotoxic activities of these amide-functionalized titanocenyls on HT-29 colon cancer cell line were determined by MTT assay to elucidate structure-activity relationship. All complexes were more cytotoxic than titanocene dichloride and there is no correlation between the para substituents on the phenyl ring and their cytotoxicities.     

Interaction of dicyclopentadienyltitanium dichloride with bis(triethylgermyl)-cadmium and -mercury

The reaction of dicyclopentadienyltitanium dichloride with bis(triethylgermyl)mercury in benzene solution at 20° yields metallic mercury quantitatively, titanocene monochloride and triethylchlorogermane. The reaction of dicyclopentadienyltitanium dichloride with bis(triethylgermyl)cadmium leads to the formation of a complex of the following general composition: [Cp₂TiCl₂ - Cd(GeEt₃)₂]. The reactivity of this complex has been studied: in toluene solution at 20° it decomposes slowly to yield metallic cadmium, triethylchlorogermane and Cp₂TiCl(GeEt₃).     

Titanocene dichloride route to a tetranuclear oxo-bridged monocyclopentadienyl titanium(IV) calix[4]arene complex

Lithiation of p-tBu-calix[4]arene followed by reaction with titanocene dichloride affords a novel tetranuclear titanium(IV) monocyclopentadienyl complex, wherein a single calix[4]arene in a cone conformation provides O-phenoxy coordination to four titanium atoms, with additional mu-oxo bridging between titanium centres in an eight membered ring.     

Titanocene-catalyzed regioselective syn-hydrosilation of alkynes

[reaction: see text] The titanium catalyst, which was generated in situ from titanocene dichloride and 2 equiv of butyllithium, was found to catalyze hydrosilation of a variety of alkynes with excellent regio- and syn-selectivity.     

Titanocene(III) mediated radical cyclizations of epoxides for the synthesis of medium-sized cyclic ethers

Titanocene(III) chloride (Cp₂TiCl) mediated 7-exo and 8-endo radical cyclizations of epoxides towards the synthesis of 7- and 8-membered cyclic ethers have been described. Titanocene(III) chloride was prepared in situ from commercially available titanocene dichloride (Cp₂TiCl₂) and activated zinc dust in THF.     

Effect of trimethylaluminum on the polymerization of ethylene with the catalytic system Bis[N-(3,5-di-tert-butylsalicylidene)-2,3,5,6-tetrafluoroanilinato]titanium(IV) dichloride-methylaluminoxane

The effect of trimethylaluminum in commercial methylaluminoxane on the molecular-mass characteristics of polyethylene formed with the phenoxyimine titanium catalyst bis[N-(3,5-di-tert-butylsalicylidene)-2,3,5,6-tetrafluoroanilinato]titanium(IV) dichloride activated by methylaluminoxane of varying purity is studied. It is shown that, all other conditions being equal, an increase in the content of trimethylaluminum in the reaction solution leads to an appreciable decrease in the molecular mass of the polymer. With an increase in the time of polymerization, the molecular mass tends to increase, while overall polydispersity indexes M _w/M _n remain substantially less than 2. The causes of the above effects are discussed.