Mini Reviews in Medicinal Chemistry - Volume 6, Issue 9, 2006

Carotenoid bioactivity, namely the quenching of reactive oxygen species (ROS) and other excited-state oxidants, suggests significant clinical potential for these natural products. However, a thorough therapeutic evaluation of the carotenoids has been hampered by limited water-solubility and/or water-dispersibility (“hydrophilicity”) as well as poor bioavailability. Hydrophilic carotenoid derivatives have been designed and prepared for parenteral administration. Synthetic methods, selected physical characteristics, and potential biological applications of these novel therapeutics will be discussed.

Catalytic RNAs, known as ribozymes, act as true enzymes and are implicated in important biological processes, such as protein synthesis, mRNA splicing, transcriptional regulation and retroviral replication. Ribozymes are capable of serving as a new molecular target for a variety of drugs and as a reliable screening system for their biological activity.

Three-dimensional structures of protein targets have proven to be extremely valuable for modern drug design and discovery. For cases where the structure of the protein is unattainable, such as G-protein coupled receptors (GPCRs), structural information on active ligands is still useful and helpful for deciphering the geometrical and chemical features of the active site. Peptides, constructed from easy-to-form amide backbones and featuring variable side-chains, have an inherent advantage in generating rapid quantitative structure-activity relationships (QSAR). Given the fact that peptides are natural ligands for many protein targets, structural investigation of a series of related peptides, typically carried out via nuclear magnetic resonance (NMR), can result in an accurate pharmacophore model. Such a model can be used for virtual screening, and to assist design of second-generation peptidomimetics with improved properties and design of non-peptidic leads. In this article, we will review examples in which a structural approach utilizing peptide ligands was employed to obtain a better understanding of the target active site. We will focus on cases where such information supplied guidance toward the discovery of small molecule ligands.

CXCR4 is the receptor for a chemokine, CXCL12 (stromal cell-derived factor-1, SDF-1). The CXCL12- CXCR4 axis has been proven to be involved in several problematic diseases, including AIDS, cancer cell metastasis, leukemia cell progression and rheumatoid arthritis (RA). Thus, CXCR4 is thought to be an important therapeutic target to overcome the above diseases. We have developed several specific CXCR4 antagonists.

Plants and invertebrates in Latin America have contributed to a great extent in the use, discovery and development of novel neuroactive tools. Significantly, these neuroactive drugs have proven to be particularly important for our current understanding of the physiology and pharmacology of the nervous system. In addition, these discoveries have helped to build the modern and successful pharmacological business that we know today. For example, curare helped to introduce the use of muscle relaxing agents into modern surgical techniques. The discovery of cocaine from the leaves of Peruvian coca plants was instrumental in the discovery of local anesthetics. The search and discovery for useful neuroactive compounds derived from Latin America has also been ongoing in other areas and new applications for quinine, capsaicin and epibatidine were recently described. Besides these organic compounds, several peptides produced by spiders and other invertebrates to hunt their prey also induce effects in channels and membrane receptors at very low concentrations, indicating their high potency and selectivity. It is likely that new pharmaceutics will be developed from these molecules. The interest to renew the search for new compounds is timely, since largely unexplored lands, such as the Amazon and Patagonia, hold an important number of plants and animals that contain exciting new active compounds. With the introduction of new techniques to isolate, identify and characterize the molecular targets and actions of chemical entities, together with the need for more potent and selective compounds to treat neurological conditions, it is necessary to broaden the current exploratory effort in order to find more beneficial uses.

Chronic inflammatory diseases are common and still remain a therapeutic challenge for both efficacy and safety reasons. Hence, novel therapeutics addressing these issues would for example improve treatment of severe diseases such as psoriasis, rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis. Inappropriate leukocyte homing to the affected compartments is a common feature of these diseases. Heparin and related polysaccharides have been shown to interfere with leukocyte homing through a variety of effects distinct from their anticoagulant properties. In this review, data on heparin as an anti-inflammatory agent are presented. In addition, structure-activity requirements for the anti-inflammatory properties of heparin are discussed, which should aid the drug development based on structurally modified heparin or other sulfated carbohydrates for treatment of inflammatory diseases.

Clan CA (papain-like) cysteine proteinases of protozoan parasites are validated targets for the rational design of new anti-parasitic chemotherapies. Peptidyl and peptidomimetic proteinase inhibitors of differing chemistries limit parasite survival in vitro and in vivo. Also, the development of activity-based affinity labels has enabled the identification and characterization of potential cysteine proteinase targets in situ. This article reviews the biology and physicochemistry of parasite proteinases and the ongoing design of peptidyl and non-peptidyl inhibitors to generate anti-parasitic compounds of greater efficacy with decreased toxicity to the host.

Apoptosis is a process that governs the elimination of unwanted, damaged, or infected cells in most organisms. Defects in its execution are associated with several diseases, including cancer. Herein, we discuss novel molecules with potential anti-tumor activity that target components of the apoptotic machinery, specifically Bcl-2 proteins, IAPs and caspases.

The combined and ordered sequential action of glycosidases and glycosyltransferases in mammalian cell compartments leads to the addition of defined glycans to proteins and lipids. Altered glycosylation patterns, neoexpression, underexpression or overexpression of glycans are a hallmark of cancer. These changes are either found in the core or the terminal structures of the carbohydrates of glycoproteins. Affected proteins can be either cellular, cell-surface or secreted proteins, and glycosylation modifications frequently result in a modified expression, metabolism, functions, properties, stability and/or cellular localization of glycoproteins in cancer cells, resulting in part in their uncontrolled growth and aggressive behavior. Therefore glycosylation pathways, and the glycosidases and glycosyltransferases of these pathways, represent potential innovative modalities for drug development in cancer therapies which are just beginning to be explored. This review proposes to summarize the published information for glycosidases and their inhibitors in cancer.

The study of the ADME features of the huge number of new chemical entities (NCEs) produced mainly by combinatorial chemistry has become a bottleneck in the drug development process. In response the pharmaceutical industry is involved in the development of new medium/high-throughput screening capabilities. The aim of this paper is to review some of the available in vitro ADME systems adapted to screening requirements together with the technological approaches which can be linked to medium/high-throughput molecular screening.