Mini Reviews in Medicinal Chemistry - Volume 1, Issue 4, 2001

This review describes the recent developments in the field of polyamine toxins, with focus on structure activity relationship investigations, including studies of importance of the polyamine moiety for biological activity, photolabeling studies using polyamine toxins as templates, as well as use of solid phase methods for the synthesis of polyamine toxins. The review is mainly concerned with effects of polyamine toxins on nicotinic acetylcholine receptors and ionotropic glutamate receptors.

During the past years a number of potent and selective antagonists for the human A3 adenosine receptor (AR) have been developed, including tricyclic compounds, such as triazoloquinazoline, pyrazolo-triazolopyridine, imidazopurinone, triazoloquinoxaline and pyrazoloquinoline derivatives. Bicyclic compounds include isoquinoline and related quinazoline derivatives. Monocyclic dihydropyridine and pyridine derivatives also proved to be potent selective A3 AR antagonists. So far, no potent, selective antagonist is available for rodent A3 ARs. Most of the A3 AR antagonists are highly lipophilic and exhibit very poor water-solubility. Potential therapeutic applications for A3 AR antagonists include inflammatory diseases, asthma, stroke, and glaucoma.

The isolation and preparation ten years ago of the fullerenes in bulk quantities, sparked off a truly remarkable interdisciplinary research activity, encompassing diverse fields of chemistry, physics, materials science and medicinal chemistry. Pharmaceutical and biological studies have revealed that fullerene-based compounds exhibit various types of biological activity either in vitro or in vivo and are discussed in this review.

Enzymatic carbohydrate synthesis using glycosyltransferases is highly regio- and stereospecific and does not require extensive protecting group designs. Naturally occurring carbohydrates have been prepared by this biomimetic pathway successfully. As more and more transferases are isolated and get cloned and overexpressed, non-natural substrates were probed with these biocatalysts. Key-polar groups and non-essential residues of the substrates have been determined. Consequently, this technique was employed to generate natural and non-natural carbohydrate libraries for pharmaceutical purposes.The synthesis of sialyl-Lewis a- and sialyl-Lewis x libraries and non-natural Linear-B derivatives applying glycosyltransferases is presented in this article. The respective transferases investigated are α(1-3)galactosyltransferase, β(1-3)galactosyltransferase, β(1-4)galactosyltransferase, α(2-3)sialyltransferase, α(1-3)fucosyltransferase III and α(1-3)fucosyltransferase VI. With respect to the natural acceptors, the aglycon part and the N-acetyl group of the glucosamide have been varied. All enzymes tolerate an unexpected wide range of non-natural acceptors, which is not yet exploited in its full scale. In addition, fucosyltransferase III and VI can be employed to convert also non-natural donors with non-natural acceptors at the same time. Thus sialyl-Lewis a- and sialyl-Lewis x-libraries which differ in three positions compared to the natural tetrasaccharides are generated very efficiently. Also a library of linear-B trisaccharides, a reactive xenoantigen, has been prepared enzymatically. The aglycon part and the natural N-acetyl group of the glucosamine, which is a part of the acceptor substrate, have been altered widely.This convenient methodology is compared with the evolving solid-phase carbohydrate synthesis using conventional chemistry. The potential use of transferases in solid-phase carbohydrate chemistry is discussed together with the possibility to use these biocatalysts to synthesize carbohydrate mimetics. The presented findings may also be useful to design potential glycosyltransferase inhibitors.

Opioid receptor like-1 (ORL-1) has recently been indicated as a potentially useful target for the treatment of a number of central disorders and several other diseases.This review deals with non-peptidic ligands at the ORL-1 receptor, focusing on their structural and binding properties. Agonism or antagonism evidenced from functional experiments is also commented. For some compounds, possible therapeutic applications are considered.

Given their clinical importance for the treatment of acute and chronic neurodegenerative diseases in humans including nerve injuries (e.g. Alzheimer's disease, Parkinson's disease, diabetic neuropathy) a number of different approaches were pursued to obtain selectively acting FK506-binding protein (FKBP) ligands: computational methods and target-oriented screening of natural compound and synthetic product libraries. The resulting monofunctional ligands, which inhibit the peptidyl prolyl cis / trans isomerase activity of FKBPs, highlight the role of these enzymes in neuronal signaling. The exploration of the mechanisms of neuroregenerative and neuroprotective action of some of these compounds is the main focus of ongoing neuropharmaceutical research.

In antibody directed enzyme prodrug therapy (ADEPT) an antibody bound enzyme is targeted to tumor cells. This allows for selective activation of a nontoxic prodrug to a cytotoxic agent at the tumor site for cancer therapy. Site-selective prodrug activation results in reduced side effects in remote tissue. This article reviews ADEPT with emphasis on the chemical viewpoint and recent developments.

Lipopolysaccharide (LPS) induced Gram-negative sepsis and septic shock remain lethal in up to 60 percent of cases, and LPS antagonists that neutralize its endotoxic action are the subject of intensive research. In the last decade peptidic antagonists have become increasingly important in providing leads for treatment of LPS-mediated diseases. In this review an overview of the sources, functions and structures of antiseptic and antibacterial peptides that interact with LPS is presented.

Significant advances have been made in the field of peptide chemistry, especially in the design of synthetic peptide immunogens which has led to new concepts and strategies for human vaccine development. This article reviews some of these technological advances and approaches to vaccine design including the multiple antigenic peptide system, the lipid polylysine core peptide system, the polymerization of peptides into multivalent immunogens and self adjuvanting synthetic peptide-based immunogens.