Current Medicinal Chemistry - Volume 10, Issue 7, 2003

Thrombin has become an important target for designing antithrombotic drugs in the recent years. Thus, we have undertaken a QSAR analysis aimed at individuating the physicochemical properties governing the inhibitory activity of such compounds. The QSAR equations for ten series of derivatives have been calculated and discussed. The series studied are all those that we found in the literature suitable for a QSAR study. The equations we obtained show that the main physicochemical properties affecting the inhibitory activity are almost the same for all the series and can be individuated by the use of proper parameters. The conclusions of this analysis can be summarized as follows: a) hydrophobicity plays a critical role, b) steric factors are also significant but in some cases the collinearity between steric and hydrophobic parameters does not allow one to draw any final conclusion.

Breast cancer is an example of a solid tumour which is well treated in the early stages of disease by surgical excision, but once metastatic spread has occurred, medical therapies (chemotherapy and radiotherapy) are highly toxic, expensive and palliative. It is known that certain tumours exhibit specific patterns of metastasis, chemokines may provide a molecular answer to this mystery. Chemokines and their receptors play important roles in the various stages of tumour development and metastasis. Chemokines interact with their specific receptors as well as interacting with the glycosaminoglycan (GAG) component of proteoglycan. We discuss the basic metastatic process and the involvement of chemokines in breast cancer biology. Finally, we summarize potential therapeutic applications of chemokines and chemokine / glycosaminoglycan interactions including chemokine agonists, antagonists, anti-sense therapy, immunotherapy and soluble GAGs, as well as future perspectives in this field.

Activation of transcription factors such as NF-κB occurs through signaling pathways involving sequential phosphorylation of a variety of substrates by distinct kinases. Proper assemby and activation of these kinases require interaction with non-enzymatic and essential partners named scaffold proteins. Here, we describe how the NF-κB activating scaffold proteins involved in the signaling pathways triggered by the proinflammatory cytokines TNFα, IL-1β and by the CD40 ligand play such roles. We also illustrate the human genetic diseases that are linked to mutations affecting genes coding for these proteins. We suggest that these scaffold proteins may be specifically targeted by novel therapeutical agents for the treatment of inflammation or cancers.

More than fifty years following the discovery that botulinum neurotoxins inhibit neuromuscular transmission, these powerful poisons have become drugs with many indications. First used to treat strabismus, local injections of botulinum neurotoxin are now considered a safe and efficacious treatment for neurological and non-neurological conditions. One of the most recent achievements in the field is the observation that botulinum neurotoxin is a treatment for diseases of the gastrointestinal tract. Botulinum neurotoxin is not only potent in blocking skeletal neuromuscular transmission, but also block cholinergic nerve endings in the autonomic nervous system. The capability to inhibit contraction of smooth muscles of the gastrointestinal tract was first suggested based on in vitro observations and later demonstrated in vivo, it has also been shown that botulinum neurotoxin does not block non adrenergic non cholinergic responses mediated by nitric oxide. This has further promoted the interest to use botulinum neurotoxin as a treatment for overactive smooth muscles and sphincters, such as the lower esophageal sphincter to treat esophageal achalasia, or the internal anal sphincter to treat anal fissure.Information on the anatomical and functional organization of innervation of the gastrointestinal tract is a prerequisite to understand many features of botulinum neurotoxin action on the gut and the effects of injections placed into specific sphincters. This review presents current data on the use of botulinum neurotoxin to treat diseases of the gastrointestinal tract and summarizes recent knowledge on the pathogenesis of disorders of the gut due to a dysfunction of the enteric nervous system.