Current Medicinal Chemistry - Volume 12, Issue 26, 2005

In human solid cancer, the lymph node status is the most important prognostic indicator for the clinical outcome of patients. Follow-up data has shown that about 80% of metastasis follows an orderly pattern of progression via the lymphatic network while about 20% systemic metastasis occurs, bypassing the lymphatic system. Over the past few years, advances have been made in understanding the cellular and molecular aspects of physiological lymphangiogenesis and tumour-induced lymphangiogenesis, and the majority of studies point out to a positive correlation between tumour-induced lymphangiogenesis and lymphatic metastasis. However, the impact of intra- and peritumoural lymphatics on the tumour biology and the first steps of lymphatic metastasis, i.e. the invasion of tumour cells into the lymphatic vessels, are not well understood. We will give an outline of i. the physiological process of lymphangiogenesis, ii. tumour-induced lymphangiogenesis and lymphatic metastasis, iii. lymphatic invasion and the common pathways of tumourlymphangiogenesis and lymphatic invasion. The growing interest in this topic has brought up a number of new molecular players in the field, which may provide the basis for a rational therapy against the process of lymphatic dissemination of tumour cells.

Since the beginning of the 20th century, important medicinal progress has led medical doctors to think that the end of devastating epidemics has arrived. In 1930, the discovery of sulfamides and penicillin opened a wide area of applications able to fight against bacterial infections. However, almost all antibiotics were baffled by the great ability to adaptation of bacteria (1) and the emergence of new bacterial agents, discovered with up-dated technologies. The living world is perpetually in co-evolution and since more than 3 billion years, bacteria have developed resistance mechanisms to overcome external aggressions. Thus, in the middle of the 80th century, multi-resistant bacteria appeared and disseminated out from hospitals. In this context, researches have been developed in order to find new antimicrobial substances to destroy such new types of bacteria. Thus, several groups have turned their focus on invertebrates, which co-evoluad with human and have appeared on the planet since a long time. Evidence of new families of antimicrobial substances isolated from invertebrates different to the classical cationic peptide family i.e. dipeptides and anionic peptides been given. Moreover, these molecules are also present in human and may serve in the innate immune response as an important survival strategy.

This review is intended to give a short summary of the developments in the field of natural and synthetic alicyclic and heterocyclic hydroxylated β-amino acids and to focus on the main strategies that have been reported for their synthesis. Given the medicinal and biological significance of the hydroxylated β-amino acids, an increasing volume of research is currently being directed toward regio-, stereo- and enantioselective access to this class of compounds.

It was reported that angiotensin-converting enzyme (ACE) plays an important role in increasing blood pressure. Recently, it was reported that several food hydrolysates have ACE inhibitory effects in the spontaneous hypertensive rat (SHR) model and mildly hypertensive subjects. Therefore, the anti-hypertensive effects of brewer's yeast BY-G were investigated, which contains many kinds of beneficial nutrients (vitamins, minerals, nucleic acids, glutathione, amino acids, etc.). The aim of this study was to evaluate the anti-hypertensive effects of BY-G and i ts component peptides obtained by enzymatic treatment. The peptide fraction KRF814 was obtained by the hydrolysate of BY-G with alkaline protease and then treated with Amberlite XAD-2. The KRF814, which has an inhibitory effect on ACE in vitro, was obtained. BY-G and KRF814 were fed to male SHR and showed significantly anti-hypertensive effects. KRF814 contained alanyl-phenylalanine (AF) and glycyl-phenylalanine (GF), which significantly decreased systolic BP in the SHR model. The active ingredients of KRF814, AF, and GF had about 60% of the potency of the positive control, which was captopril. It i s considered that intake of BY-G or its component peptides as a functional food stuff might be beneficial for improving BP in people with hypertension.

Telomerase is a ribonucleoprotein polymerase that maintains the length of telomeric DNA by adding hexameric units (TTAGGG) to the ends of the chromosomes. This mechanism prevents replicative senescence, thus conferring unlimited proliferative potential to cells. Telomerase reactivation has been detected in most human tumour tissue, indicating that the enzyme may be useful as a specific tumour marker. The inhibition of telomerase causes a progressive and critical reduction of telomeres, leading to a potent signal for the blockage of cell proliferation and the induction of apoptosis. Since normal somatic cells lack telomerase activity, the anti-telomerase approach is highly specific for tumour cells and metastases. Prolonged treatment is required before enzyme deactivation causes the telomeres to be shortened enough to induce senescence and apoptosis. Therefore, the drugs employed in anti-telomerase therapy should be of only moderate non-specific cytotoxicity. Certain cis-Pt(II)-complexes have recently been shown to be effective inhibitors of telomerase in both cell-free and in vitro assays, most likely by targeting the nucleobases of the RNA component of the enzyme.

Quorum sensing (QS) systems comprise a new therapeutic target potentially substitutive or complementary to traditional antibiotic treatment of chronic diseases. One route to disrupt the previously established interrelationship between pathogenesis and QS is by blocking the dual functioning signal/receptor transcriptional regulator in some clinically relevant Gram-negative bacteria. The present review contains all reported compound types that are currently known to inhibit the QS transcriptional regulator in Gram-negative bacteria. These compounds are sub-divided into two main groups, one comprising structural analogs of the native signaling molecules and the other compounds lacking structural resemblance. Biological activity is rationalized on the basis of structure-activity relationships and structural insight into the target protein.

Platelet activation plays an important role in a wide range of pathological conditions. For example, platelet activation has been shown to be involved in the defence against parasitic infection, the pathogenesis of atherosclerotic disease, and various arterial and venous thrombotic diseases. Indeed, there is considerable interest in the manipulation of platelet function for therapeutic gain. It is for these reasons that there is considerable interest in developing assays measuring in vivo platelet activation. Current modalities in the measurement of platelet activation include Enzyme-linked Immunosorbent Assays (ELISA), platelet flow cytometry and electron microscopy. It is proposed that methods in measuring platelet activation can also be classified into 'direct' and 'indirect' modalities, both of which have their distinct advantages and disadvantages. Unfortunately, there is at present no consensus on the ideal method of measuring platelet activation. Thus, studies on platelet activation should ideally include at least one of each of direct and indirect modality of studying platelet activation. This review provides an overview of basic platelet biology and the various methods of measuring platelet activation, with an emphasis on their role in drug development.

The phosphate group is at the heart of an enormous number of biological processes. The simple phosphorylation or dephosphorylation of a protein can have a wide range of consequences, including effects on its biological activity, its interaction with other proteins, and on its subcellular location. Abnormal levels of protein phosphorylation have been linked to a wide range of diseases including cancer and diabetes. Consequently, proteins that recognise the phosphate moiety have become an attractive target for therapeutic development. The most prevalent medicinal chemistry research examines the interactions of phosphorylated tyrosine residues; however, the role of phosphate groups on serine or threonine residues, in nucleotides, DNA and RNA, on sugars, and lipid mediators such as lysophosphatidic acid should not be overlooked. Investigations have focused on the non-catalytic phosphotyrosine-recognising domains such as Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains, as well as catalytic proteins such as protein tyrosine phosphatase 1B (PTP1B). The utilisation of the phosphate moiety as part of an inhibitor is severely limited by the enzymatic lability and poor cellular bioavailability of this highly charged recognition element. The development of phosphate isosteres attempts to address these issues by introducing a non-scissile bond and utilizing groups with less charge that are still able to interact favourably with the target protein in much the same way as the phosphate group does. Many phosphate mimics retain the phosphorus atom such as in the highly successful fluoromethylenephosphonates, whereas others have lost the tetrahedral phosphate geometry and are based on the combination of one or more carboxylate groups that generally reduce the overall charge of the molecule. This review focuses on the recent developments and the use of phosphate isosteres in medicinal chemistry, covering roughly the past four years.

The discovery of RNA interference (RNAi) in eukaryotic cells has been the major recent breakthrough in molecular and cell biology. RNAi machineries exert biological functions in gene regulation, genome defense and chromatin architecture and dynamics. The potential of RNAi to silence any gene of interest in a highly specific and efficient manner via double-stranded RNA (dsRNA) has literally revolutionized modern genetics. RNAi-based functional genomics now permits, for the first time, to evaluate the cellular role of individual gene products on a genome-wide scale in higher organisms like mammals, presenting an alternative to the generation of animal knockouts often doomed to failure because of a lethal phenotype. RNAi has had an enormous impact on the development of novel disease models in animals, and it is likely that small interfering RNAs (siRNAs), which are the trigger molecules for RNA silencing, will become an invaluable tool for the treatment of genetic diseases. First clinical trials, using siRNAs directed against the vascular endothelial growth factor (VEGF) or one of its receptors, have been initiated recently for the treatment of age-related macular degeneration. Improving guidelines for the rational design of siRNAs, based on recent progress in understanding the mechanisms underlying RNAi, as well as the introduction of chemical modifications into siRNAs are expected to improve their pharmacokinetic and pharmacodynamic properties for in vivo applications. Finally, successful therapeutic application of RNAi will depend on the development of improved siRNA delivery strategies that combine high specificity and efficiency with a low immunostimulatory and tumorigenic potential.

Due to an overlook on the part of the authors in Current Medicinal Chemistry, 2005, 12(7), 877-85 of article "2(3H)- Benzoxazolone and Bioisosters as 'Privileged Scaffold' in the Design of Pharmacological Probes" by Jacques Poupaert, Pascal Carato, Evelina Colacino and Saïd Yous. Two mistakes were unfortunately encountered: The affiliation of Dr Pascal Carato was not mentioned and the authorship of Prof. Saïd Yous had been lost. The list of authors should therefore read: Jacques H. Poupaerta, Pascal Caratob, Evelina Colcinoa and Saïd Yousb. and the affiliations should read as following: aUnite de Chimie Pharmaceutique et Radiopharmacie, Ecole de Pharmacie, Universite Catholique de Louvain, (UCL-CMFA 7340), Brussels B-1200, Belgium. [email protected] bLaboratoire de Chimie Thérapeutique, EA 1043, Faculté des Sciences Pharmaceutiques et Biologiques de Lille, 3, rue du, Professeur Laguesse, BP 83, 59006 LILLE Cedex FRANCE