Methoxy-phenyl substituted ansa-titanocenes as potential anti-cancer drugs derived from fulvenes and titanium dichloride

Starting from 6-(4'-methoxyphenyl)fulvene (1a), 6-(2',4',6'-trimethoxyphenyl)fulvene (1b), or 6-(3',5'-dimethoxyphenyl)fulvene (1c), [1,2-di(cyclopentadienyl)-1,2-di(4'-methoxyphenyl)-ethanediyl] titanium dichloride (2a), [1,2-di(cyclopentadienyl)-1,2-bis(2',4',6'-trimethoxyphenyl)-ethanediyl] titanium dichloride (2b), and [1,2-di(cyclopentadienyl)-1,2-bis(3',5'-dimethoxyphenyl)-ethanediyl] titanium dichloride (2c) were synthesised. When titanocenes 2a-c were tested against pig kidney carcinoma cells (LLC-PK) inhibitory concentrations (IC50) of 2.8 x 10(-4), 3.6 x 10(-4) and 2.1 x 10(-4) M, respectively, were observed.     

Novel benzyl-substituted molybdocene 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 molybdocene using MoCl₄ (synthesized in situ) to yield the benzyl-substituted molybdocenes bis-[(p-methoxybenzyl)cyclopentadienyl] molybdenum (IV) dichloride (3a), bis-[(3,4-dimethoxybenzyl)cyclopentadienyl] molybdenum (IV) dichloride (3b), and bis-[(3,4,5-trimethoxybenzyl)cyclopentadienyl] molybdenum (IV) dichloride (3c). The molybdocene 3a was characterised by single crystal X-ray diffraction. All three molybdocenes had their cytotoxicity investigated through MTT based preliminary in vitro testing on the human renal cell line Caki-1 in order to determine their IC50 values and compare them with the corresponding titanocene and vanadocene dichloride derivatives. Molybdocenes 3b-c were found to have the same IC50 values of 290 μM, while 3a yielded a value of 84 μM, respectively     

Synthesis and characterization of deuterium-labelled (fulvene)M(CO)3 complexes (M = Cr, Mo)

The preparation and characterization of a series of deuterium-labelled (fulvene)M(CO)₃ (M = Cr, Mo) complexes is reported. (η⁵-6-Dimethylaminofulvene-d₂)Cr(CO)₃ and (η⁵-6-dimethylaminofulvene-d₂)Mo(CO)₃ were obtained in high yields by reacting the deuterated fulvene ligands with (MeCN)₃M(CO)₃ (M = Cr, Mo). In addition, syntheses of 6,6-diphenylfulvene-d₁₀ and 6,6-diphenyl-1,2-benzofulvene-d₁₀ as well as the corresponding tricarbonylchromium complexes are described.     

Preparation of planar chiral ferrocenes containing a fluorous alcohol function

Ferrocene reacts with hexafluoroacetone trihydrate in refluxing octane to afford >80% yields of [CpFe(η⁵-C₅H₄C(CF₃)₂OH)] (X-ray), carrying out the reactions at 180 °C gives an additional 5% yield of [Fe(η⁵-C₅H₄C(CF₃)₂OH)₂] (X-ray).The mono alcohol is lithiated with Bu^tOK/BuⁿLi/TMEDA affording partial conversion to mixtures of [CpFe(1,2-η⁵-C₅H₃C(CF₃)₂OH)(X)] and [Fe(η⁵-C₅H₄X)(1,2-η⁵-C₅H₃C(CF₃)₂OH)(X)] (X = SMe, CPh₂OH) upon reaction with Me₂S₂ or OCPh₂.For X = CPh₂OH both structures are crystallographically characterised.Enantiopure [CpFe(1,2-η⁵-C₅H₃C(CF₃)₂OH)(SMe)] can be prepared from (R)-[CpFe(η⁵-C₅H₄S(O)C₆H₄Me)] via [CpFe(1,2-η⁵-C₅H₃S(O)C₆H₄Me)(C(CF₃)₂OH)] (X-ray) or [CpFe(1,2-η⁵-C₅H₃S(O)C₆H₄Me)(SMe)].Related procedures allow the preparation of [CpFe(1,2-η⁵-C₅H₃CPh₂OH)(Y)] (Y = SMe, CHO (X-ray), C(CF₃)₂OH) and[CpFe(1,2-η⁵-C₅H₃C(CF₃)₂OH)(CHO)].     

Heteroaryl substituted titanocenes as potential anti-cancer drugs

From the reaction of Super Hydride (LiBEt(3)H) with 6-(furyl)fulvene (1a), 6-(thiophenyl)fulvene (1b) or 6-(N-methyl-pyrrole)fulvene (1c) the corresponding lithium cyclopentadienide intermediates (2a-c) were obtained. These intermediates were reacted with titanium tetrachloride and bis-[(furyl-2-cyclopentadienylmethane)] titanium(IV) dichloride (3a) and bis-[(thiophenyl-2-cyclopentadienylmethane)] titanium(IV) dichloride (3b) and bis-[(N-methylpyrrole-2-cyclopentadienylmethane)] titanium(IV) dichloride (3c) were obtained and subsequently characterised by X-ray crystallography. When titanocenes 3a-c were tested against pig kidney (LLC-PK) cells inhibitory concentrations (IC(50)) of 1.6x10(-4)M, 1.5x10(-4)M and 9.1x10(-4)M, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, when compared to their corresponding ansa substituted analogues and also in comparison to unsubstituted titanocene dichloride.     

Novel achiral titanocene anti-cancer drugs synthesised from bis-<Emphasis Type="Italic">N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>-dimethylamino fulvene and lithiated heterocyclic compounds

Abstract From the carbolithiation of 6-bis-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 bis-N,N-dimethylamino-functionalised titanocenes 5a–c. When these titanocenes were tested against LLC-PK cells, the IC₅₀-values obtained were of 240, and 270 μM for titanocenes 5b and 5c, respectively. The most cytotoxic titanocene in this paper, 5a with an IC₅₀-value of 36 μM was found to be approximately six times less cytotoxic than its mono-N,N-dimethylamino substituted analogue Titanocene C (IC₅₀ = 5.5 μM) and almost ten times less cytotoxic than cisplatin, which showed an IC₅₀-value of 3.3 μM, when tested on the LLC-PK cell line. Graphical abstract Bis-(bis- (N,N-dimethylamino)-2-(N′-methylpyrrolyl)methylcyclopentadienyl) titanium (IV) dichloride, {η⁵-C₅H₄-CH[N(CH₃)₂]₂[C₅H₃NCH₃]}₂TiCl₂ was synthesised starting from 6-bis-(N,N-dimethylamino) fulvene and 2-N-methylpyrrolyl lithium. Herein, we present the synthesis and DFT structure of the titanocene and two further derivatives followed by MTT-based cytotoxicity tests on pig kidney epithelial (LLC-PK) cells. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Synthesis, characterization and applications in ethylene polymerization of asymmetric ansa-titanocene complexes. Molecular structure of [Ti{Me2Si(η-C5Me4)(η-C5H3iPr)}Cl2]

The ansa-titanocene complexes, [Ti{Me₂Si(η⁵-C₅Me₄)(η⁵-C₅H₃R)}Cl₂] (R = Me (5), iPr (6), tBu (7), SiMe₃ (8)), were obtained from the reaction of Li₂{Me₂Si(C₅Me₄)(C₅H₃R)} (R = Me (1), iPr (2), tBu (3), SiMe₃ (4)) with [TiCl₄(THF)₂], respectively. Compounds 5-8 have been tested as catalysts in the polymerization of ethylene and compared with the ansa-titanocene complexes [Ti{Me₂Si(η⁵-C₅H₄)₂}Cl₂] and [Ti{Me₂Si(η⁵-C₅Me₄)(η⁵-C₅H₄)}Cl₂]. The resulting polyethylene showed molecular weights of about 200 000 g mol⁻¹ and polydispersity values of approximately 3. In addition, the molecular structure of 6 has been determined by single crystal X-ray diffraction studies.     

Synthesis, characterization and cytotoxic effect of ring-substituted and ansa-bridged vanadocene complexes

The cytotoxic effect of vanadocene dichloride (Cp₂VCl₂, 1) and its ring-substituted, (η⁵-C₅H₄Me)₂VCl₂ (2), (η⁵-C₅Me₅)₂VCl₂ (3), (η⁵-C₅H₄R)₂VCl₂ (4: R = MeOCH₂CH₂-, 5: R = 2-MeOC₆H₄CH₂-, 6: R = 4-MeOC₆H₄CH₂-) and ansa-bridged analogs Me₂C(η⁵-C₅H₄)₂VCl₂ (7) and Me₄C₂(η⁵-C₅H₄)₂VCl₂ (8) was investigated. Synthesis of two new methoxy-functionalized compounds (4 and 5) is described. They were characterized by spectroscopic methods and X-ray diffraction analysis. The cytotoxicity studies were performed with leukemic cells MOLT-4.     

Mononuclear arene ruthenium complexes containing 5,6-diphenyl-3-(pyridine-2-yl)-1,2,4-triazine as chelating ligand: Synthesis and molecular structure

The mononuclear cations of the general formula [(η⁶-arene)RuCl(pdpt)]⁺ (pdpt = 5,6-diphenyl-3-(pyridine-2-yl)-1,2,4-triazine; arene = C₆H₆ (1); C₆H₅Me (2); p-PrⁱC₆H₄Me (3); C₆Me₆ (4)) have been synthesised from 5,6-diphenyl-3-(pyridine-2-yl)-1,2,4-triazine (pdpt) and the corresponding chloro complexes [(η⁶-C₆H₆)Ru(μ-Cl)Cl]₂, [(η⁶-C₆H₅Me)Ru(μ-Cl)Cl]₂, [(η⁶p-PrⁱC₆H₄Me)Ru(μ-Cl)Cl]₂ and [(η⁶-C₆Me₆)Ru(μ-Cl)Cl]₂, respectively. The X-ray crystal structure analyses of [1][PF₆] · (C₆H₆)_2.5 and [2][PF₆] · (CH₃CN)₂ reveal a typical piano-stool geometry around the metal centre and in the crystal packing a complexed networks of intermolecular interactions.     

Evidence for σ → η3 rearrangement reaction in gaseous ions from Fe,Mn and Re allylic derivatives

The fragmentation pathways of (η³-C₃H₄X)FeCO)₂NO, (σ-C₃H₄X)Fe(CO)₂(NO)L, (η³-C₃H₄X)Fe(CO)(NO)L, (σ-C₃H₄X)Fe(CO)₂(NO)L′, (η³- C₃H₄X)Fe(CO)(NO)L′, (σ-C₃H₅)M(CO)₅, (η³-C₃H₅)M(CO)₄, (σ-CH₂CHC(Me)₂)Mn(CO)₅, (η³-CH₂ CHC(Me)₂)Mn(CO)₄, (X=2-Cl; L=PPh₃; L′= P(OMe)₃; M=Mn, Re) have been investigated by mass spectrometry. In the σ derivatives the molecular ion loses CO or the allylic ligand, while in the η³ derivative loss of a CO group is the only fragmentation mode of the molecular ion. Electron impact as well as methane chemical ionization mass spectra have been reported. Kinetic energy release of selected metastable ions indicates that a σ → η³ rearrangement reaction occurs.     

Plasticity of the five-membered chelate ring in [PdCl2(1,2-(PR2)2-1,2-C2B10H10)] complexes (R = H or Pr)

Gradient-corrected density functional theory applied to 1,2-diphosphino-1,2-dicarba-closo-dodecaborane, 1,2-(PH₂)₂-1,2-C₂B₁₀H₁₀, and its respective PdCl₂ complex presents a clear picture of the effect of complexation on the P-C_c-C_c-P fragments (C_c = cage carbon C1 or C2) in the structures. The complexation results in clear closing in the P-C_c-C_c angles and shortening of C_c-C_c bond, but only minor changes take place in the P-C_c-C_c-P torsion angle. Furthermore, complexation brings along shortening of the P-C_c bonds with concomitant increase of covalency, as revealed by atoms-in-molecules calculations. Although there is also change in the C_c-C_c distance in the cage, no significant change is involved in the bonding. These findings are compared with the results obtained by single-crystal X-ray study for [PdCl₂(1,2-(PⁱPr₂)₂-1,2-C₂B₁₀H₁₀)] and additional calculations carried out for [PdCl₂(1,2-(PH₂)₂-C₂H₄)].     

Synthesis of cyclopentadienyl ruthenium(II) complexes containing tethered functionalities

The reaction of [C₅H₄(CH₂)_nX]Tl (1: n = 2, X = NMe₂, OMe, CN; n = 3, X = NMe₂) with [(η⁶-C₆H₆)RuCl(μ-Cl)]₂, 2, afforded the sandwich compounds [{η⁵-C₅H₄(CH₂)_nX}Ru(η⁶-C₆H₆)]PF₆, 3, and [η⁵-C₅H₄(CH₂)_nX]₂Ru, 4. Photolytic cleavage of 3 in acetonitrile afforded the tethered products [{η⁵:κN-C₅H₄(CH₂)_nX}Ru(CH₃CN)₂]PF₆, 5.     

Binding and hydrolysis studies of antitumoural titanocene dichloride and Titanocene Y with phosphate diesters

The interaction of the antitumoural metallocene dihalides, titanocene dichloride (Cp₂TiCl₂) and Titanocene Y (bis-[(p-methoxybenzyl)cyclopentadienyl]titanium(IV) chloride), with bis(4-nitrophenyl) phosphate (BNPP), which is a widely used model for the phosphate diester linkages in DNA, has been studied. Cp₂TiCl₂ has been shown to promote the cleavage of the phosphate diester in weakly acidic solution. At pH 4, 37 °C, a 10⁶-fold rate acceleration over the uncatalysed reaction was observed under pseudo-first-order conditions, when freshly prepared solutions of Cp₂TiCl₂ were applied. The activity of aged solutions dropped significantly due to the formation of insoluble precipitates of hydrolysed Ti species. The precipitates isolated from aged solutions were shown to act as moderately active, heterogeneous catalysts for BNPP cleavage. By contrast, no hydrolysis of the phosphate diester could be observed in the presence of Titanocene Y. Implications for the mode of action of the apoptosis-inducing metallocene dihalides are discussed.     

Synthesis of Me2LSn(o-CH3-C2B10H10): Crystal structure of Sn ← O intramolecularly coordinated organotin compound containing 1-methyl-o-carborane

The synthesis and molecular structure of Me₂LSn(1-Me-1,2-C₂B₁₀H₁₀) (3), L is 2,6-(t-BuOCH₂)₂C₆H₃⁻, the precursor for the synthesis of other Sn ← O intramolecularly coordinated organotin(IV) compounds containing 1-methyl-o-carborane (1-Me-1,2-C₂B₁₀H₁₁) is reported. Compound 3 was characterized by the help of ¹H, ¹¹B, ¹³C, ¹¹⁹Sn NMR spectroscopy and X-ray diffraction technique. For the preparation of 3, a novel triorganotin(IV) compound Me₂LSnCl (2) has been prepared since the reaction of sterically more demanding Ph₂LSnCl (1) with 1-Me-1,2-C₂B₁₀H₁₀Li did not occur.     

Studies on structures and electron affinities of the simplest alkyl dithio radicals and their anions with gaussian-3 theory and density functional theory

The equilibrium geometries and electron affinities of the R-SS/R-SS^-(R=CH₃, C₂H₅, n-C₃H₇, i-C₃H₇, n-C₄H₉, t-C₄H₉, n-C₅H₁₁) species have been studied using the higher level of the Gaussian-3(G3) theory and 21 carefully calibrated pure and hybrid density functionals (five generalized gradient approximation (GGA) methods, seven hybrid GGAs, three meta GGA methods, and six hybrid meta GGAs) in conjunction with diffuse function augmented double-ζ plus polarization (DZP++) basis sets. The geometries are fully optimized with each method and discussed. The reliable adiabatic electron affinity has been presented by means of the high level of G3 technique. With the DZP++ DFT method, three measures of neutral/anion energy differences reported in this work are the adiabatic electron affinity, the vertical electron affinity, and the vertical detachment energy. The adiabatic electron affinities, obtained at the BP86, M05-2X, B3LYP, M06, B98, M06-2X, mPW1PW91, HCTH, B97-1, M05, PBE1PBE, and VSXC methods, are in agreement with the G3 results. These methods perform better for EA prediction and are considered to be reliable.     

Synthesis and structural investigation of vanadocene(IV) complexes of non-linear pseudohalides

Two series of vanadocene complexes of the type (Cp′ = η⁵-C₅H₅, η⁵-C₅H₄Me; X = dicyanamide, tricyanomethanide, dicyanonitrosomethanide) were prepared by the reaction of appropriate vanadocene dichloride complex with alkali salt of non-linear pseudohalide. The bonding mode of pseudohalide ligands was determined by spectroscopic measurements and X-ray diffraction analyses.     

Rifamycins: an insight into biological activity based on structural investigations

The structures of two compounds of the antibiotic rifamycin series have been studied by X-ray methods: rifamycin B, C₃₉H₄₉NO₁₄, which is active on bacterial RNA polymerase, and rifamycin Y, C₃₉H₄₇NO₁₅, which is devoid of any antibacterial activity. In both cases their p-iodoanilide derivative has been used and the final crystal structure data are now given.A comparative study of the structures of rifamycin B and rifamycin Y, and of the structures of two other ansa-compounds with similar activity on bacterial RNA polymerase, tolypomycin Y and streptovaricin C, together with the analysis of the activity ratios of a series of semisynthetic rifamycins, makes it possible to suggest that the following constitutional and conformational features are common to all the ansa-compounds with anti-bacterial activity: (i) a naphthoquinone or naphthohydroquinone nucleus with free oxygen functions, O(1) and O(2), on C(1) and C(8) respectively: (ii) an amide nitrogen attached to C(2); (iii) a 17-membered chain bridging the chromophoric group; (iv) two free hydroxyl groups attached to atoms C(21) and C(23) of the ansa-bridge and in the same relative positions with respect to each other and with respect to O(1) and O(2). However, the constitution and the conformation of the remaining part of the ansa-bridge can be rather different in different compounds.     

Mapping the pathway of heteroborane isomerisation: Two parallel “1,2 → 1,7” isomerisations of a crowded molybdacarborane and the isolation of isomerisation intermediates

The reaction between [7,8-Ph₂-7,8-nido-C₂B₉H₉]²⁻ and [(η-C₇H₇)Mo(MeCN)₃]⁺ affords five products. Four have been isolated and shown to be structural isomers of (η-C₇H₇)MoPh₂C₂B₉H₉. Compound 1 has a pseudocloso structure. In solution it gives way to the non-icosahedral compound 2 which in turn rearranges into the “1,2 → 1,7” C-atom isomerised compound 5 having a 2,1,8-MoC₂B₉ structure. A further “1,2 → 1,7” C-atom isomerised species, compound 4, is also isolated but has a 1,2,4-MoC₂B₉ architecture. Compound 4 forms via an intermediate 3, which is too unstable to characterise. Structurally the sequence of compounds 1, 2 and 5 maps well onto the sequential diamond-square-diamond isomerisation mechanism of 1,2-closo-C₂B₁₀H₁₂ into 1,7-closo-C₂B₁₀H₁₂ proposed by Wales. An alternative pathway from the notional first product of the metallation, 1,2-Ph₂-3-(η-C₇H₇)-3,1,2-closo-MoC₂B₉H₉, is required to rationalise the intermediate compound 3 and, from it, compound 4.     

Study of the cytotoxicity and particle action in human cancer cells of titanocene-functionalized materials with potential application against tumors

Titanocene dichloride [Ti(η⁵-C₅H₅)₂Cl₂] (1), has been grafted onto dehydrated hydroxyapatite (HAP), Al₂O₃ and two mesoporous silicas MSU-2 (Michigan State University Silica type 2) and HMS (Hexagonal Mesoporous Silica), to give the novel materials HAP/[Ti(η⁵-C₅H₅)₂Cl₂] (S1) (1.01 wt.% Ti), Al₂O₃/[Ti(η⁵-C₅H₅)₂Cl₂] (S2) (2.36 wt.% Ti), HMS/[Ti(η⁵-C₅H₅)₂Cl₂] (S3) (0.75 wt.% Ti) and MSU-2/[Ti(η⁵-C₅H₅)₂Cl₂] (S4) (0.74 wt.% Ti), which have been characterized by powder X-ray diffraction, X-ray fluorescence, nitrogen gas sorption, multinuclear magic angle spinning NMR spectroscopy, IR spectroscopy, thermogravimetry analysis, UV spectroscopy, scanning electronic microscopy and transmission electronic microscopy. The cytotoxicity of the titanocene-functionalized materials toward human cancer cell lines from five different histogenic origins: 8505 C (anaplastic thyroid cancer), A253 (head and neck cancer), A549 (lung carcinoma), A2780 (ovarian cancer) and DLD-1 (colon cancer) has been determined. M₅₀ values (quantity of material needed to inhibit normal cell growth by 50%) and Ti-M₅₀ values (quantity of anchored titanium needed to inhibit normal cell growth by 50%) indicate that the activity of S1-S4 against studied human cancer cells depended on the surface type as well as on the cell line. In addition, studies on the titanocene release and the interaction of the materials S1-S4 with DNA show that the cytotoxic activity may be due to particle action, because no release of titanium complexes has been observed in physiological conditions, while electrostatic interactions of titanocene-functionalized particles with DNA have been observed.     

Chelate ring size and effect of N-substituents as limiting factors for the formation of cationic chloro-diamine-η2-ethene-platinum(II) complexes

The nature of the diamine plays a very critical role in stabilizing the cationic species [Pt(η²-C₂H₄)Cl(diamine)]⁺ containing a highly reactive olefin. Hence while N,N,N′,N′-tetramethyl-1,2-diaminoethane (tmen) gave a species isolatable in a pure form, N,N,N′,N′-tetramethyl-1,3-diaminopropane (tmpm) and unsubstituted 1,2-diaminoethane (en) were unable to act as bidentate and gave, as isolatable species, only complexes of the type cis-[Pt(η²-C²H⁴)Cl²(Hdiamine)]⁺ in which the diamine is protonated and acts as monodentate towards platinum. These results are explained in terms of greater conformational stability of five- versus six-membered chelate rings and of gem-dimethyl substituted towards unsubstituted ring systems (Thorpe-Ingold effect).