Letters in Drug Design & Discovery - Volume 3, Issue 2, 2006

Interactions of α-amino or guanidino-α-hydroxybutyryl-aminoglycosides with an essential sequence of Rev responsive element (RRE) in HIV-1 mRNA were evaluated using surface plasmon resonance imaging. Aminoglycosides were proved to bind nonspecifically to RRE.

Cannabinoids, the active components of the cannabis plant, have merit as an anti-emetic and appetite stimulant in people with cancer. Recently, interest in cannabinoids has increased since reports that cannabinoids have anti-tumour activity. Although the mechanisms underlying these effects have yet to be fully elucidated, a broad spectrum of effects have been described, and cellular signalling pathways are known to be involved. There are currently two major cannabinoid receptors identified, whose roles in the activation of cell death remains controversial. Agonists to the type-2 receptor that do not have psychotropic effects have been used successfully in vitro, and we await the results of randomised trials using theses agents. The field of research into cannabinoids as anti-cancer agents is in its infancy, and more basic research is required before a good clinical agent can be realised. This article reviews the data currently available on this exciting group of potential anti-neoplastic agent.

A series of new 20-O-linked succinate-based camptothecin ester derivatives were synthesized and their cytotoxicities were tested on five human cancer cell lines by MTT assay. All the derivatives showed moderate antitumor activity in vitro, and they were 20-to-several thousand-fold less toxic than their parent drug.

In this prospective, randomized, double-blinded study, clonidine was found an efficient adjunct to local anesthetics for increasing the intensity of axillary brachial plexus block. Similar clonidine dose had no such effect when administered intramuscularly, suggesting a local, neural effect. Blood absorption was similar in both cases, leading to central action as sedation.

Syntheses of (±)-cis-3-hydroxycarbonyl-7-(phenylacetamido)carbacephem (10), (±)-cis-3- methoxycarbonyl-7-(phenylacetamido)carbacephem (11), (±)-cis-2-chloro-3-hydroxycarbonyl-7-(phenylacetamido) carbacephem (14), and (±)-cis-2-chloro-3-methoxycarbonyl-7-(phenylacetamido)carbacephem (15) were accomplished. These four heretofore undescribed compounds 10, 11, 14, and 15 showed notable activity against Staphylococcus aureus FDA 209P, Escherichia coli ATCC 39188, Pseudomonas aeruginosa 1101-75, Klebsiella pneumoniae NCTC 418 as well as the β-lactamase producing organisms E. coli A9675, P. aeruginosa 18S-H and methicillin-resistant organism S. aureus 95. The electronic activation of lactam moieties of 11 and 15 enhanced remarkably their antibacterial activity relative to those of the 10 and 14. The chlorine atom in 14 and 15, acting as an effective leaving group, also resulted in an increment in the biological activity in comparison with those of the parent carbacephemes 10 and 11. The mode of action related to 14 and 15 can be explained by a non-classical [1,4]-elimination process.

A new series of 5-[N-(3-(5-substituted)-1,3,4-thiadiazolyl)]amino-1-methyl-4-nitroimidazoles (6ah) has been designed, synthesized and examined for their ability against Trypanosoma cruzi. The compounds were prepared by nucleophilic aromatic substitution. Several bases were investigated as proton scavengers, and lithium diisopropylamide (LDA) was found to be the best base giving products in good yields.

A patient with homocystinuria, a risk factor of arterial and venous thrombosis, developed cerebral venous thrombophlebitis before the age of twenty years. As she was B6 sensible, she was given 250 mg/d of pyridoxine and homocysteinemia was well controlled. Unfortunately, at the age of 40, she developed progressive weakness, with a major increase of plasma CPK values (4110 UI/l, normal < 160). Severe rhabdomyolysis was observed, and muscle biopsy showed necrotic fibres. She died of pulmonary embolism. B6 vitamin is not known to be toxic. However, excessive intake can cause ataxia and severe neuropathy. But some authors have reported that a short term administration of 500 mg/d of pyridoxine to a one-month old child caused a rhabdomyolysis, and this observation might evocate a particular susceptibility of our homocystinuric patient to B6 vitamin therapy.

Our CoMSIA model for benzoate and benzolactone mammalian vacuolar type (H+) ATPase inhibitors correlates well with bovine ATPase IC50 data (R2=0.968; Q2=0.553) and reliably predicts human kidney VATPase inhibition by lobatamide compounds (R=0.862). Accurately modeling oximidines (structurally underrepresented in the training set) requires perturbing the model with non-CoMSIA QSAR descriptors.

The bioisosteric replacement of the sulfonyl group, in the previously reported benzenesulfonylamidofluoroquinolones (BSFQs), for a carbonyl group was the principle that led to the design of benzenecarboxamide fluoroquinolones (BCFQs). Six new derivatives were prepared and tested against Grampositive and -negative bacteria. As a result, the activity against Staphylococcus aureus of the new series was comparable with norfloxacin or ciprofloxacin but decreased when compared with BSFQs. These findings are significant since the new BCFQs could be incorporated into the selected family of "dual targeting" AMFQs.

There is increasing evidence that endothelial dysfunction is an independent predictor of outcome in cardiovascular disease. Therefore, the identification of therapeutic strategies enhancing endothelial function might provide salutary effects on the cardiovascular system. This review examines the role of the B-vitamin folic acid in modulating endothelial function.

Retinoic acid analogs, which contain an aromatic ring fixed between the 5 and 8 positions of retinoic acid, were synthesized by a palladium catalyzed coupling reaction between an enol triflate and a tributylstannylolefin and their biological activities were subsequently evaluated. None of the analogs exhibited antiproliferative, differentiation-inducing, or apoptosis-inducing activities in HL 60 cells. However, the 9Z-derivatives of indene and benzofuran showed a strong binding affinity for the RXR receptor compared to that of 9CRA.

E5880, a novel platelet activating factor receptor antagonist, was dispersed in water for use in injectable formulation and the physicochemical properties of the preparation were characterized. The critical concentration for formation of micelles was 0.12 mM. Using area per molecule data, the critical packing parameter was calculated, indicating that the structure of the micelle was spherical and that each micelle contained 49 molecules. The diameter of the micelle was 8.1 nm. Attractive interactions occurred between E5880 molecules in the micelle. The hydrocarbon region in the micelle was more rigid and less hydrated than that of other surfactants, stearyltrimethyl-ammonium chloride and cetyltrimethylammonium chloride.

The cytotoxic activities of a series of HEPT analogues were modeled using 1x, Vw, Xeq along with indicator parameters. Based on the dominance of electro-negativity the data set of 59 compounds has to be divided into two subsets consisting of 48 and 11 compounds respectively. The latter subset was dominated by electronegativity effect (Xeq). Excellent results are obtained in multi-parametric regressions and are discussed critically.