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.

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.

A demonstration of attentional bias, using a novel dual task paradigm, towards clinically salient material in recovering alcohol abuse patients?

Background. This study examined whether alcohol abuse patients are characterized either by enhanced schematic processing of alcohol related cues or by an attentional bias towards the processing of alcohol cues. Method. Abstinent alcohol abusers (N = 25) and non-clinical control participants (N = 24) performed a dual task paradigm in which they had to make an odd/even decision to a centrally presented number while performing a peripherally presented lexical decision task. Stimuli on the lexical decision task comprised alcohol words, neutral words and non-words. In addition, participants completed an incidental recall task for the words presented in the lexical decision task. Results. It was found that, in the presence of alcohol related words, the performance of patients on the odd/even decision task was poorer than in the presence of other stimului. In addition, patients displayed slower lexical decision times for alcohol related words. Both groups displayed better recall for alcohol words than for other stimuli. Conclusions. These results are interpreted as supporting neither model of drug cravings. Rather, it is proposed that, in the presence of alcohol stimuli, alcohol abuse patients display a breakdown in the ability to focus attention.

Novel polyvinylpyrrolidones to improve delivery of poorly-water soluble drugs; from design to synthesis and evaluation

Polyvinylpyrrolidone is a widely used in tablet formulations with the linear form acting as a wetting agent and disintegrant whereas the cross-linked form is a super-disintegrant. We have previously reported that simply mixing the commercial cross-linked polymer with ibuprofen disrupted drug crystallinity with consequent improvements in drug dissolution behavior. In this study, we have designed and synthesized novel cross-linking agents containing a range of oligoether moieties which have then be polymerized with vinylpyrrolidone to generate a suite of novel excipients with enhanced hydrogen-bonding capabilities. The polymers have a porous surface and swell in most common solvents and in water; properties which suggest their value as disintegrants. The polymers were evaluated in simple physical mixtures with ibuprofen as a model poorly-water soluble drug. The results show that the novel PVPs induce the drug to become “X-ray amorphous”, which increased dissolution to a greater extent than that seen with commercial cross-linked PVP. The polymers stabilize the amorphous drug with no evidence for recrystallization seen after 20 weeks storage.

Insights into dietary flavonoids as molecular templates for the design of anti-platelet drugs

Flavonoids are low-molecular weight, aromatic compounds derived from fruits, vegetables, and other plant components. The consumption of these phytochemicals has been reported to be associated with reduced cardiovascular disease (CVD) risk, attributed to their anti-inflammatory, anti-proliferative, and anti-thrombotic actions. Flavonoids exert these effects by a number of mechanisms which include attenuation of kinase activity mediated at the cell-receptor level and/or within cells, and are characterized as broad-spectrum kinase inhibitors. Therefore, flavonoid therapy for CVD is potentially complex; the use of these compounds as molecular templates for the design of selective and potent small-molecule inhibitors may be a simpler approach to treat this condition. Flavonoids as templates for drug design are, however, poorly exploited despite the development of analogues based on the flavonol, isoflavonone, and isoflavanone subgroups. Further exploitation of this family of compounds is warranted due to a structural diversity that presents great scope for creating novel kinase inhibitors. The use of computational methodologies to define the flavonoid pharmacophore together with biological investigations of their effects on kinase activity, in appropriate cellular systems, is the current approach to characterize key structural features that will inform drug design. This focussed review highlights the potential of flavonoids to guide the design of clinically safer, more selective, and potent small-molecule inhibitors of cell signalling, applicable to anti-platelet therapy.

'Score it upon my taille': the use (and abuse) of tallies by the medieval Exchequer

The paper traces the evolution of the tally from a receipt for cash payments into the treasury, to proof of payments made by royal officials outside of the treasury and finally to an assignment of revenue to be paid out by royal officials. Each of these processes is illustrated by examples drawn from the Exchequer records and explains their significance for royal finance and for historians working on the Exchequer records.

Assembly of an injectable noncytotoxic peptide-based hydrogelator for sustained release of drugs

A new synthetic tripeptide-based hydrogel has been discovered at physiological pH and temperature. This hydrogel has been thoroughly characterized using different techniques including field emission scanning electron microscopic (FESEM) and high-resolution transmission electron microscopic (HR-TEM) imaging, small- and wide-angle X-ray diffraction analyses, FT-IR, circular dichroism, and rheometric analyses. Moreover, this gel exhibits thixotropy and injectability. This hydrogel has been used for entrapment and sustained release of an antibiotic vancomycin and vitamin B12 at physiological pH and temperature for about 2 days. Interestingly, MTT assay of these gelator molecules shows almost 100% cell viability of this peptide gelator, indicating its noncytotoxicity.

Effects of drugs that potentiate GABA on extinction of positively-reinforced operant behaviour

Extinction following positively reinforced operant conditioning reduces response frequency, at least in part through the aversive or frustrative effects of non-reinforcement. According to J.A. Gray's theory, non-reinforcement activates the behavioural inhibition system which in turn causes anxiety. As predicted, anxiolytic drugs including benzodiazepines affect the operant extinction process. Recent studies have shown that reducing GABA-mediated neurotransmission retards extinction of aversive conditioning. We have shown in a series of studies that anxiolytic compounds that potentiate GABA facilitate extinction of positively reinforced fixed-ratio operant behaviour in C57B1/6 male mice. This effect does not occur in the early stages of extinction, nor is it dependent on cumulative effects of the compound administered. Potentiation of GABA at later stages has the effect of increasing sensitivity to the extinction contingency and facilitates the inhibition of the behaviour that is no longer required. The GABAergic hypnotic, zolpidem, has the same selective effects on operant extinction in this procedure. The effects of zolpidem are not due to sedative action. There is evidence across our series of experiments that different GABA-A subtype receptors are involved in extinction facilitation and anxiolysis. Consequently, this procedure may not be an appropriate model for anxiolytic drug action, but it may be a useful technique for analysing the neural bases of extinction and designing therapeutic interventions in humans where failure to extinguish inappropriate behaviours can lead to pathological conditions such as post-traumatic stress disorder.

Subtype-selective GABAergic drugs facilitate extinction of mouse operant behaviour

Several recent studies have shown that reducing gamma-aminobutyric acid (GABA)-mediated neurotransmission retards extinction of aversive conditioning. However, relatively little is known about the effect of GABA on extinction of appetitively motivated tasks. We examined the effect of chlordiazepoxide (CDP), a classical benzodiazepine (BZ) and two novel subtype-selective BZs when administered to male C57Bl/6 mice during extinction following training on a discrete-trial fixed-ratio 5 (FR5) food reinforced lever-press procedure. Initially CDP had no effect, but after several extinction sessions CDP significantly facilitated extinction, i.e. slowed responding, compared with vehicle-treated mice. This effect was not due to drug accumulation because mice switched from vehicle treatment to CDP late in extinction showed facilitation immediately. Likewise, this effect could not be attributed to sedation because the dose of CDP used (15 mg/kg i.p.) did not suppress locomotor activity. The two novel subtype-selective BZ partial agonists, L-838417 and TP13, selectively facilitated extinction in similar fashion to CDP. The non-GABAergic anxiolytic buspirone was also tested and found to have similar effects when administered at a non-sedating dose. These studies demonstrate that GABA-mediated processes are important during extinction of an appetitively motivated task, but only after the animals have experienced several extinction sessions.