BSP :: Letters in Drug Design & Discovery Home Page

Contents

RNA Silencing Technologies in Drug Discovery and Target Validation Pp.1-18
Elizabeth Rayburn, Hui Wang, Jie He and Ruiwen Zhang
[Abstract] [Full text article]

Inhibition of Transforming Growth Factor-β Activation is a Novel Effect of Chymase Inactivation Pp.19-22
S. Takai and M. Miyazaki
[Abstract] [Full text article]

In-Vitro Searching for a New Potent Reactivator of Acetylcholinesterase Inhibited by Nerve Agent VX Pp.23-25
K. Kuca, J. Cabal, J. Bajgar and D. Jun
[Abstract] [Full text article]

Farnesyltransferase Inhibitors: Overview of their Action and Role in Solid Malignancy Therapy Pp.26-35
Stefano Margaritora, Alfredo Cesario, Venanzio Porziella, Pierluigi Granone, Alessia Catassi and Patrizia Russo
[Abstract] [Full text article]

2,3,4,5- Tetrahydro- 1-Benzoxepines a Novel Class of Anti-Implantation Agents Pp.36-39
Vishnu K. Tandon and Sanjay Rai
[Abstract] [Full text article]

Design of a Heteroaryl Modified, 1,5-Disubstituted Pyrazole Cyclooxygenase-2 (COX-2) Selective Inhibitor Pp.40-43
M. Ezawa, D.S. Garvey, D.R. Janero, S.P. Khanapure, L.G. Letts, A. Martino, R.R. Ranatunge, D.J. Schwalb and D.V. Young
[Abstract] [Full text article]

L-Carnitine Effect upon Iron Growth Inhibition on Saccharomyces cerevisiae Pp.44-47
C.A. Stella, H.I. Burgos, M. Salellas, M.L. Cristaldo, E.H. Ramos and N. Kriguer
[Abstract] [Full text article]

Design and Synthesis of Combinatorial Scaffolds-Diazepinone and Homopiperazine Pp.48-50
Chung-Ming Sun
[Abstract] [Full text article]

Solution-Phase Parallel Synthesis of N,6-Disubstituted Isoquinuclidines as Ibogaine Analogs Pp.51-54
M.S. Levi, M.O.F. Khan and R.F. Borne
[Abstract] [Full text article]

Synthesis and Biological Activity of C-8 Fluoroaryl Substituted Pyrimidine Linked-Pyrrolobenzodiazepine Conjugates Pp.55-61
Ahmed Kamal, K. Laxma Reddy, V. Devaiah, N. Shankaraiah, M. Shiva Kumar and G. Suresh Kumar Reddy
[Abstract] [Full text article]

Design, Synthesis and Pharmacological Evaluation of New Nonsteroidal Antiinflammatory 1,3,4-Thiadiazole Derivatives Pp.62-67
L.S. Varandas, C.A.M. Fraga, A.L.P. Miranda and E.J. Barreiro
[Abstract] [Full text article]

Pharmacological Profile of New Deamino Analogues of Sabarubicin (MEN 10755) Pp.68-73
M. Bigioni, C. Salvatore, A. Cipollone, M. Berettoni, C.A. Maggi and M. Binaschi
[Abstract] [Full text article]

Exploiting the Ubiquitin-Proteasome Pathway for Anticancer Drug Discovery: Unanswered Questions and Future Directions Pp.74-81
D.M. Smith, K.G. Daniel and Q.P. Dou
[Abstract] [Full text article]

Abstracts

[Back to top]
RNA Silencing Technologies in Drug Discovery and Target Validation
Elizabeth Rayburn, Hui Wang, Jie He and Ruiwen Zhang
[Full text article]

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 pharmacogenomics, and identification of novel targets for therapy. With high specificity and affinity, oligonucleotide therapeutic agents are being developed as novel treatments for various diseases such as cancer, cardiovascular diseases and infectious diseases. These drugs can be used alone or in combination with current treatment strategies including chemotherapy or radiation therapy. However, the potential of these therapeutic agents based on RNA silencing technologies has not yet been fully realized, and further investigations are needed to define their specificity and efficacy, especially in the clinical setting.

[Back to top]
Inhibition of Transforming Growth Factor-β Activation is a Novel Effect of Chymase Inactivation
S. Takai and M. Miyazaki
[Full text article]

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

[Back to top]
In-Vitro Searching for a New Potent Reactivator of Acetylcholinesterase Inhibited by Nerve Agent VX
K. Kuca, J. Cabal, J. Bajgar and D. Jun
[Full text article]

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 appropriate source of the enzyme. According to our results, trimedoxime seems to be the most potent reactivator of VX-inhibited AChE at the concentration 10^-3 M.

[Back to top]
Farnesyltransferase Inhibitors: Overview of their Action and Role in Solid Malignancy Therapy
Stefano Margaritora, Alfredo Cesario, Venanzio Porziella, Pierluigi Granone, Alessia Catassi and Patrizia Russo
[Full text article]

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 the Ras proteins. Due to the functional role of Ras farnesylation, farnesyltransferase (FTase) inhibition was thought to be a strategy for interfering with Ras-dependent transformation. When farnesylation is blocked, the function of Ras protein is severely impaired because of the inability of the nonfarnesylated protein to anchor to the membrane. The biology of FTase inhibitors (FTIs) is fascinating since, after substantial investigation and their use in several clinical trials, their exact mechanism of action still remains unclear. In addiction to the RAS ones, FTIs can block the farnesylation of several additional proteins. There are approximately 250 human proteins with literal carboxyl-terminal CAAX motifs (according to Swiss-prot data base). However, most of these contain amino acids at the -AAX positions that make them poor substrates for FTase. At present, several CAAXcontaining farnesylated human proteins are currently under investigation as FTIs targets including RhoB, the centromere binding proteins CENP-E and CENP-F, the phosphatase PRL1, 2 and 3, the chaperone protein DnaJ, and Rheb. While the FTIs clearly do not or only partly target Ras, these agents appear to have clinical activity in leukemias and in some solid tumors. This article reviews preclinical and clinical data pertinent to the use of FTIs in solid tumors with special regards to lung cancer where the possible role of FTIs is investigated in the light of possible “translational” trials.

[Back to top]
2,3,4,5- Tetrahydro- 1-Benzoxepines a Novel Class of Anti-Implantation Agents
Vishnu K. Tandon and Sanjay Rai
[Full text article]

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 anti-implantation activity compared to the most potent anti-implantation drug Centchroman 5.

[Back to top]
Design of a Heteroaryl Modified, 1,5-Disubstituted Pyrazole Cyclooxygenase-2 (COX-2) Selective Inhibitor
M. Ezawa, D.S. Garvey, D.R. Janero, S.P. Khanapure, L.G. Letts, A. Martino, R.R. Ranatunge,D.J. Schwalb and D.V. Young
[Full text article]

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.

[Back to top]
L-Carnitine Effect upon Iron Growth Inhibition on Saccharomyces cerevisiae
C.A. Stella, H.I. Burgos, M. Salellas, M.L. Cristaldo, E.H. Ramos and N. Kriguer
[Full text article]

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 cation rhodamine 123. For this purpose, cells were grown in a synthetic medium with glycerol as carbon source, supplemented with either 3.0 mM or 6.0 mM L-carnitine. Results obtained showed a decrease in the extent of iron inhibition by L-carnitine addition. In diseases where iron accumulation alters mitochondrial function, a treatment based on the exogenous supply of L-carnitine may be considered.

[Back to top]
Design and Synthesis of Combinatorial Scaffolds-Diazepinone and Homopiperazine
Chung-Ming Sun
[Full text article]

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.

[Back to top]
Solution-Phase Parallel Synthesis of N,6-Disubstituted Isoquinuclidines as Ibogaine Analogs
M.S. Levi, M.O.F. Khan and R.F. Borne
[Full text article]

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.

[Back to top]
Synthesis and Biological Activity of C-8 Fluoroaryl Substituted Pyrimidine Linked-Pyrrolobenzodiazepine Conjugates
Ahmed Kamal, K. Laxma Reddy, V. Devaiah, N. Shankaraiah, M. Shiva Kumar and G. Suresh Kumar Reddy
[Full text article]

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 activity in comparison to the other analogues (5a and 5c).

[Back to top]
Design, Synthesis and Pharmacological Evaluation of New Nonsteroidal Antiinflammatory 1,3,4-Thiadiazole Derivatives
L.S. Varandas, C.A.M. Fraga, A.L.P. Miranda and E.J. Barreiro
[Full text article]

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 the para-fluoro-substituted derivative 8b as a new prototype, more active that celecoxib at the same molar concentration.

[Back to top]
Pharmacological Profile of New Deamino Analogues of Sabarubicin (MEN 10755)
M. Bigioni, C. Salvatore, A. Cipollone, M. Berettoni, C.A. Maggi and M. Binaschi
[Full text article]

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 regarding their cytotoxic activity. The two analogues possess also a different spectrum of antitumor activity, compared to sabarubicin.

[Back to top]
Exploiting the Ubiquitin-Proteasome Pathway for Anticancer Drug Discovery: Unanswered Questions and Future Directions
D.M. Smith, K.G. Daniel and Q.P. Dou
[Full text article]

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 differentially effect protein degradation and cellular responses. This review examines the potential points of regulation within ubiquitin-proteasome pathway that could lead to changes within specific subpopulations of proteins. Such a specific inhibition of the proteasome pat

hway could provide a host of new therapies with more predictable and controllable toxicities. Furthermore, this review discusses the participation of individual proteins, as well as the protein network, to elicit the cellular responses induced by proteasome inhibitors.