Letters in Drug Design & Discovery - Volume 2, Issue 1, 2005

With the completion of the Human Genome Project, there is an increasing, substantial need to apply RNA silencing technologies to post-genome research. In this review, we focus on three silencing technologies: antisense, RNA interference, and ribozymes. These RNA silencing approaches are designed to specifically block gene expression, and have applications in investigations of gene function, pharmacogenetics and pharmac Read More

Chymase activates latent transforming-growth factorβ to transforming-growth factorβ in vitro. Recent papers demonstrate that transforming-growth factorβ levels and tissue fibrosis were significantly reduced by chymase inhibitors in the experimental models. Thus, transforming-growth factorβ-related diseases such as fibrosis may become a novel target of chymase inhibitors.

Organophosphorus compounds, especially nerve agents, inhibit enzyme acetylcholinesterase (AChE; EC 3.1.1.7) in an irreversible manner. Atropine plus an oxime reactivator are used as an effective treatment of organophosphate poisoning. In this work, we have evaluated reactivation potency of twenty reactivators of different chemical structures in reactivation of VX-inhibited AChE. Rat brain AChE homogenate was used as the Read More

Nowadays, molecular targeted cancer therapies represent the core of translational research. Protein prenylation [covalent binding of either a farnesyl (15-C) or a geranylgeranyl (20-C) group to the cysteine residue located in the Tetrapeptide CAAX] is required for the localization and function of different proteins critical to signal transduction pathways and cytoskeleton organization. In this group of molecules we find th Read More

5- Substituted 2,3,4,5- Tetrahydro- 1-benzoxepine derivatives have been synthesized as novel antiimplantation agents. The synthesized compounds were evaluated for their anti-implantation activity in mature female Sprague-Dawley rats. The most active compounds in this series 10d and 11d, are 67% active in preventing implantation in rats at 10 mgkg-1 dose. We also found that the other compounds of the series have lesser Read More

Vicinal 1-(4-methylsulfonyl)benzene-5-(3-pyridyl) substituted pyrazole compound containing a nitric oxide (NO)-donating group at the 3-position of the pyrazole ring was synthesized and evaluated for its ability to inhibit COX isozymes in human whole blood. We report here the synthesis of 4-{3-[(1Z)-4- (nitrooxy)but-1-enyl]-5-(3-pyridyl)pyrazolyl}-1-(4-methylsulfonyl)benzene (9) and its COX-2 inhibitory potency.

Abnormal levels of L-carnitine are known to be the cause of several diseases. Considering that the yeast Saccharomyces cerevisiae presents the enzymes and systems required by this compound, we decided to use this microorganism as a model system to study iron growth inhibition in media with L-carnitine. Also, the L-carnitine effect on mitochondria metabolism was evaluated through the fluorescence signal of the lipophilic Read More

A general method for the construction of diazepinone and homopiperazine scaffolds has been developed by utilizing Beckmann rearrangement as the key step in the design. Using this methodology, the synthesis of a diverse diazepinone library with three points of diversity has been achieved starting from readily available 4-piperidone.

The naturally-occurring alkaloid ibogaine, found in the West African shrub Tabernanthe iboga, possesses the ability to diminish self-administration of substances of abuse, such as cocaine, heroin and alcohol. This was the lead structure for the design of a 75-member library of N,6-disubstituted isoquinuclidines. A solution-phase method for their synthesis is described.

Synthesis of C-8 fluoroaryl substituted pyrimidine linked-PBD conjugates are described. The compounds are prepared with varying degrees of linker length in order to probe the structural requirements for optimal in vitro antitumour activity. These compounds have been tested against a panel of 60 human cancer cell lines, and it is demonstrated that compound 5b with four carbon spacer exhibited promising in vitro anticancer ac Read More

In this work we reported the design, synthesis and evaluation of the anti-inflammatory, analgesic, and antiplatelet properties of new 1,3,4-thiadiazole derivatives, structurally planed by exploiting the molecular hybridization approach between diuretic drug acetazolamide and a 1,3-benzodioxole COX-2 inhibitor, previously developed. The in vivo pharmacological evaluation of these new compounds lead us to identify Read More

Sabarubicin (MEN 10755) is the progenitor of a third generation of synthetic anthracycline oligosaccharides. Sabarubicin deamino analogues MEN 10959 and MEN 12297 were evaluated for topoisomerase II poisoning, cytotoxic potency and antitumor activity in human xenografts. The new analogues were able to induce DNA cleavage mediated by both DNA topoisomerase IIα and β and a good correlation was found regardi Read More

The ubiquitin-proteasome pathway is a dynamic and complex cellular process that regulates the levels of 80-90% of the proteins in the cell. To date, most of the pharmacological development for manipulation of this pathway has centered on inhibition of the active sites in the 20S proteasome. However, there are many other targets available for drug development in the ubiquitin-proteasome pathway. Each target could different Read More