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 mu M, 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 and cytotoxicity studies of new dimethylamino-functionalised and hetero aryl-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 mu M for titanocenes 5a and 5b, respectively. The most cytotoxic titanocene 5c with an IC50 value of 5.5 mu M is found to be almost as cytotoxic as cis-platin, which showed an IC50 value of 3.3 mu M, when tested on the LLC-PK cell line, and titanocene 5c is approximately 400 times better than titanocene dichloride itself. (c) 2007 Elsevier B.V. All rights reserved.

Diheteroarylmethyl substituted titanocenes: a novel class of possible anti-cancer drugs

From the reaction of tert-butyl lithium or n-butyl lithium with N-methylpyrrole (1a), furan (1b) or 2-bromo-thiophen (1c), 2-N-methylpyrrolyl lithium (2a), 2-furyl lithium (2b) or 2-thiophenyl lithium (2c), respectively, was obtained. When reacted with 6-(2-N-methylpyrrolyl) fulvene (3a), 6-(2-furyl) fulvene (3b) or 6-(2-thiophenyl) fulvene (3c), the corresponding lithiated intermediates were formed (4a-c). Titanocenes (5a-c) were obtained through transmetallation with titanium tetrachloride. When these titanocenes were tested against pig kidney epithelial (LLC-PK) cells, inhibitory concentrations (IC50) of 32 mu M, 140 mu M, and 240 mu M, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, compared to their ansa-analogues. (c) 2006 Elsevier B.V. All rights reserved.

Diarylmethyl substituted titanocenes: promising anti-cancer drugs

From the reaction of tert-butyl lithium with p-bromo-N,N-dimethylaniline (1a), p-bromoanisole (1b) or 1-bromo-3,5-dimethoxybenzene (1c), p-N,N-dimethylanityl lithium (2a), p-anisyl lithium (2b) or (3,5-dimethoxyphenyl) lithium (2c), respectively, were obtained. When reacted with 6-(p-N,N-dimethylanilinyl)fulvene (3a), 6-(p-methoxyphenyl)fulvene (3b) or 3,5-(dimethoxyphenyl)fulvene (3c), the corresponding lithiated intermediates were formed (4a-c). Titanium tetrachloride was added "in situ", obtaining titanocenes 5a-C, respectively. When these titanocenes were tested against pig kidney carcinoma (LLC-PK) cells, inhibitory concentrations (IC50) Of 3.8 x 10(-5) M, 4.5 x 10(-5) M, and 7.8 x 10(-5) M, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, compared to their ansa-analogues. (c) 2006 Elsevier Ltd. All rights reserved.

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

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 mu M for titanocenes 5a and 5b respectively. The most cytotoxic titanocene in this paper, 5c showed an IC50 value of 8.4 mu M is found to be almost as cytotoxic as cis-platin, which showed an IC50 value of 3.3 mu M, when tested on the LLC-PK cell line, and titanocene 5c is approximately 250 times better than titanocene dichloride itself.

Novel titanocene anti-cancer drugs and their effect on apoptosis and the apoptotic pathway in prostate cancer cells

Advanced prostate cancer is not curable by current treatment strategies indicating a significant need for new chemotherapeutic options. Highly substituted ansatitanocene compounds have shown promising cytotoxic activity in a range of cancers. The objectives of this study are to examine the effects of these titanocene compounds on prostate cancer cells. Prostate cell lines were treated with three novel titanocene compounds and compared to titanocene dichloride and cisplatin. Percent apoptosis, viability and cell cycle were assessed using propidium iodide DNA incorporation with flow cytometry. Cytochrome C was assessed by western blotting of mitochondrial and cytoplasmic fractions. Apoptosis Inducing Factor was assessed by confocal microscopy. These novel compounds induced more apoptosis compared to cisplatin in a dose dependent manner. Compound Y had the most significant effect on cell cycle and apoptosis. Despite the release of cytochrome C from the mitochondrial fraction there was no inhibition of apoptosis with the pan caspase inhibitor, ZVAD-FMK. AIF was shown to translocate from the cytosol to the nucleus mediating a caspase independent cell death. Bcl-2 over expressing PC-3 cells, which were resistant to cisplatin induced apoptosis, underwent apoptosis following treatment with all the titanocene compounds. This study demonstrates possible mechanisms by which these novel titanocene compounds can mediate their apoptotic effect in vitro. The fact that they can induce more apoptosis than cisplatin in advanced cancer cell lines would confer an advantage over cisplatin. They represent exciting new agents with future potential for the treatment of advanced prostate cancer.

Which drugs cause preventable admissions to hospital? A systematic review

Aim: Previous systematic reviews have found that drug-related morbidity accounts for 4.3% of preventable hospital admissions. None, however, has identified the drugs most commonly responsible for preventable hospital admissions. The aims of this study were to estimate the percentage of preventable drug-related hospital admissions, the most common drug causes of preventable hospital admissions and the most common underlying causes of preventable drug-related admissions. Methods: Bibliographic databases and reference lists from eligible articles and study authors were the sources for data. Seventeen prospective observational studies reporting the proportion of preventable drug-related hospital admissions, causative drugs and/or the underlying causes of hospital admissions were selected. Included studies used multiple reviewers and/or explicit criteria to assess causality and preventability of hospital admissions. Two investigators abstracted data from all included studies using a purpose-made data extraction form. Results: From 13 papers the median percentage of preventable drug-related admissions to hospital was 3.7% (range 1.4-15.4). From nine papers the majority (51%) of preventable drug-related admissions involved either antiplatelets (16%), diuretics (16%), nonsteroidal anti-inflammatory drugs (11%) or anticoagulants (8%). From five studies the median proportion of preventable drug-related admissions associated with prescribing problems was 30.6% (range 11.1-41.8), with adherence problems 33.3% (range 20.9-41.7) and with monitoring problems 22.2% (range 0-31.3). Conclusions: Four groups of drugs account for more than 50% of the drug groups associated with preventable drug-related hospital admissions. Concentrating interventions on these drug groups could reduce appreciably the number of preventable drug-related admissions to hospital from primary care.

Water reuse for irrigation in Jordan: plant beneficial nutrients, farmers’ awareness and management strategies

The reuse of treated wastewater (reclaimed water) is particularly well suited for irrigated agriculture as it often contains significant quantities of plant essential nutrients. This work has shown that reclaimed water in Jordan can have adequate concentrations of potassium, phosphate, sulphate and magnesium to meet all or part of the crop’s requirements. To fully benefit from these inputs farmers must have an awareness of the water quality and reduce the application of chemical fertilisers accordingly. Interviews with farmers have shown that 75 per cent of farmers indirectly using reclaimed water are aware of the nutrients. Farmers’ decision making as to the application of chemical fertilisers appears to be influenced by a range of factors which include the type of crops being cultivated, the provision of training on nutrient management and the availability of information on the nutrient content of the reclaimed water.

Synthesis and X-ray crystal structure of the triethylammonium magnesium β-octamolybdate(VI)salt[Et3NH]2[Mg(H2O)6Mo8O26]·2H2O

[Et3NH]4[Mo8O26] reacted with MgCl2 giving the triethylammonum magnesium β-octamolybdate(VI) salt [Et3NH]2[Mg(H2O)6Mo8O26]·2H2O (3) and the triethylammonium hydronium β-octaamolybdate(VI) salt [Et3NH]3[(H3O)Mo8O26·2H2O (4), respectively. A small amount of [Et3NH]2[Mo6O269] was formed as a by-product. The salts 3 and 4 were characterized by X-ray crystallography. The [Mg(H2O)6Mo8O26]2− moiety in 3 is polymeric, with each octahedral [Mg(H2O)6]2+ ion sandwiched between two β[Mo8O26]4− ions, being hydrogen bonded to three terminal MOO oxygen atoms on one face of each β[Mo8O26]4− ion. The X-ray crystal structure of 4 corresponds to the reported previously. IR and conductivity data are given for 3 and 4.

Molybdate and tungstate transfer by rat ileum competitive inhibition by sulphate

For both MoO42− and WO42− the maximum rate of uptake by the small intestine of the rat (studied in vitro using the everted sac technique) occurs in the lower ileum. Kinetic constants, derived by a least squares procedure, are compared with those previously obtained for SO42− transport. For both and , , with only small differences between sacs IV and V. Mutual inhibition of MoO42− and WO42− transport and inhibition of both by SO42− are competitive processes. This is shown by the generally good agreement between values and derived values and by V values in the presence and absence of the inhibiting species. The three ions SO42−, MoO42− and WO42− are probably transferred across the intestine by a common carrier system. Implications for the sulphate-molybdenum interaction in molybdosis are discussed.