Medicinal Chemistry Reviews - Online (Discontinued) - Volume 1, Issue 3, 2004

Chronic and age-related neurodegenerative diseases are characterised by a selective loss of specific subsets of neurons over a period of years. The underlying causes of these diseases are not clear, however, the death of neurons and the loss of cell-cell contacts seem to be key features. Understanding molecular mechanisms that control neuronal cell death and survival and identification of factors involved in these processes is crucial for the development of preventing strategies and further treatment of neurodegenerative disorders. In the present review accumulated evidence is presented that members of a ubiquitous family of annexins, homologous Ca2+- and membrane-binding proteins expressed in the central nervous system (CNS), are playing a role in regulation of neuron life span, as either potent neuroprotective or proapoptotic agents. It was also found that annexins might be related to some CNS pathologies and disorders. In addition, annexins are important partners in many vital neuronal processes, as they exhibit neurotransmitter precursor- and nucleotide-binding properties in vitro, interact with nucleotide-binding proteins in brain, as well as are involved in the cellular response to inflammation and oxidative stress. These properties suggest that some annexins may couple calcium homeostasis and cellular metabolism in neurons and neuroendocrine cells.

This update focuses on recent advances in the knowledge of roles which chemokines play in the biology of a tumor, and on ways of exploiting this knowledge to achieve therapeutic advances in the treatment of non-small cell lung cancer (NSCLC). Chemokines were once thought to play important roles only in the trafficking of leukocytes in the immune response. That this large family of proteins can play a role in homeostasis, cancer, and many chronic diseases is now widely recognized by many investigators in these diverse fields. In the filed of cancer in particular, recent findings indicate that chemokines function in; 1) Directing organ-specific patterns of metastatic disease that characterize solid tumors 2) Providing prognostic information for patients undergoing surgery for NSCLC by means of their angiogenic properties, and 3) Initiation and control of tumor-specific immune responses, such that chemokines may actually be used therapeutically to augment cytotoxic T-cell responses to tumors. Recent findings in three areas, as well as their implications for therapeutic advances in NSCLC, will be the focal point of this update.

Acridine derivatives show a broad range of biological activities. They have primarily been explored as chemotherapeutic agents (anticancer, antibacterial, antiprotozoal), because of the ability of the acridine chromophore to intercalate DNA and inhibit topoisomerase and telomerase enzymes. Research continues to be focussed primarily in these areas, but recent work shows they are active also as anticholinesterase agents.

In the field of antitomour DNA-binding agents, the class of acridine derivatives plays an important role both in terms of number of compounds and their anticancer activities. We have synthesised a number of acridine derivatives as potential antitomour drugs, in which the chromophore is fully or partially constituted either by an acridine or by a 9- acridone ring system: pyrimido[5,6,1-de]acridines, pyrimido[4,5,6-kl]acridines, bis(amine-functionalised) 9-acridone-4- carboxamides, bis(amine-functionalised) acridine-4-carboxamides, pyrazolo[3,4,5-kl]acridine-5-carboxamides, pyrazolo [3,4,5-mn]pyrimido[5,6,1-de]acridines, [1,2,6]thiadiazino[3,4,5-kl]acridines and bis(acridine-4-carboxamides). In the present review we will describe the rational design, the synthesis and the salient biological characteristics of these classes of acridine derivatives.

A growing body of research reveals that malignant cells can induce cyclooxygenase-2 (COX-2) and prostaglandin expression. Induction of COX-2 has been reported not only in isolated hepatic cells, but also in cancer cells. Both proteins are part of complex hormonal cycles involving the production of estrogen. Imbalance of hormone secretion can generate alteration at the cellular level. COX-2 inhibitors have been shown to mediate signal transduction and consequently prevent specific cancer in man. In this review, we focus on the recent study of COX-2 inhibitors for cancer prevention. The biologic action of COX-2 inhibitor on key pathway in signal transduction was discussed. The signal transduction pathway culminates with the ultimate target hepatic cells. The study provides information on the roles of COX-2 and its inhibitors. The mode of action of COX-2 inhibitor may lead to development of potential chemopreventive agents for cancer in humans. Information on the expression of COX-2 may reveal modulation of cellular functions by COX-2 inhibitors.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate lipid and carbohydrate metabolism. In addition, in the last few years it has been highlighted that these receptors play a role in regulating inflammatory processes. Here, we update, in a concise way, the latest advances concerning the antiinflammatory effects of PPARs, previously reported in Current Drug Targets-Inflammation and Allergy, I, 243-248, 2002.

The introduction in clinical practice of new antipsychotic drugs neurologically safer and with a broader spectrum of efficacy than “classical” neuroleptics has brought about significant improvement in the therapy of schizophrenic patients. These second-generation antipsychotics usually called “atypical” antipsychotics, have several therapeutical features in common, such as their effectiveness against the negative symptoms of schizophrenia and the advantage of not causing severe extrapyramidal symptoms and hyperprolactinemia. The therapeutic drug monitoring of patients treated with atypical antipsychotics is however, still advisable. In many cases, it can avoid the onset of side and toxic effects due to high plasma levels of the drug caused by overdose or interactions with other drugs. Furthermore, monitoring can significantly improve the patient's compliance, thus leading to higher treatment efficacy. The pharmacological properties of the most widely used atypical antipsychotics (clozapine, olanzapine, risperidone and quetiapine) will be treated herein with particular attention paid to metabolism, side effects and pharmacokinetics. The analytical methods suitable for the therapeutical drug monitoring of these drugs will also be discussed, in terms of sensitivity, selectivity and usefulness in clinical settings. Other recent atypical agents (ziprasidone, aripiprazole, iloperidone, sertindole and zotepine) will be described as well.

The growth and maintenance of tissue is impossible without the formation, growth and remodeling of functional vascular networks. The understanding of mechanisms of vessel development becomes increasingly important in the successful treatment of many vascular diseases. Angiogenesis and arteriogenesis play an important role in these processes. Whether angiogenesis or arteriogenesis predominate may depend on several factors: the pre-existing collateral vessel network, the type and location of occlusion and the different developmental origin of arteries. Further investigation of signaling pathways within vascular cells may lead to better understanding of the role of angiogenic factors in angiogenesis and / or arteriogenesis. This may allow for better control of each of these processes for the development of efficient therapy. Often, the treatment of vascular disorders using the administration of single angiogenic factor does not achieve the desired therapeutic effect. Therefore, new therapeutic strategies need to be developed, which may include the use of combined gene therapy, including site-specific angiogenic factors optimized not only for various vascular diseases but also for different blood vessels regarding the developmental origin of vascular tree.

Since the first description of phage surface display in 1985, more than 2500 publications report the use of this technology in different fields of life science. Phage display is based on presenting recombinant proteins or peptides fused to a phage coat protein by using appropriately designed phage surface-display vectors in combination with in vitro selection procedures. These technologies have now revolutionized the way in which we can generate and manipulate ligands. The ability to create and survey large molecular libraries for the presence of specific clones using the discriminative power of affinity selection has strongly contributed to a rapid progress in life science. However, the potential of phage display applications to directly select genes from phage surface-displayed cDNA libraries has lagged behind the impressive progress of phage display technology achieved during the last years. Here we present an update of our earlier review (1) devoted to this promising field of research.

Receptors for the constant fragment (Fc) of IgGs (FcgRs) are largely involved in the pathogenesis of haematological and rheumatic autoimmune disorders, triggering a wide variety of effector functions including phagocytosis, antibody-dependent cellular cytotoxicity, and release of inflammatory mediators, as well as immune complex clearance and regulation of antibody production. The availability of single and multiple Fc-receptor-deficient mice has allowed to get considerable progresses on the in vivo regulation of these responses, through the appreciation of the importance of balancing activation responses with inhibitory signalling. These new insights have a profound impact on our understanding of inflammation in autoimmune diseases, and might lead to new therapeutic approaches for human disorders including Systemic Lupus Erythematosus (SLE) and rheumatoid arthritis.

Mast cells play a central role in allergic reactions and inflammation. Successful anti-allergic therapies have typically targeted mast cell mediators, particularly histamine. Antihistaminic compounds interact with the various histamine receptors found on many cells, whereas other compounds are referred to as mast cell stabilizers, as they inhibit degranulation. Some of the most successful compounds developed recently are dual-action, in that they have both anti-histaminic and mast cell stabilizing activities. Recent trends in pharmaceutical intervention, however, have been focused on the secondary effects of mast cell mediators on epithelial cell adhesion molecule expression and mediator release in the process of allergic inflammation. Since, the ocular mucosa is highly exposed to environmental allergens it is commonly involved in allergic reactions and, as such, has been a useful and accessible model in which to test new therapies in vivo. These ocular allergen provocation studies permit analysis of ocular surface cells and evaluation of tear film mediators. Furthermore, techniques to purify conjunctival mast cells have facilitated the study of the effects of mast cell stabilizing compounds on other mast cell mediators, such as cytokines, and the direct effects of mast cell mediators on epithelial cells in vitro. This review discusses current understanding of how anti-histamines and mast cell stabilizers work, particularly in the context of molecular mechanisms of ocular allergic inflammation.

The following “;updates” re-stresses upon the importance of the hydrophobic and steric properties of the molecules in their CCK antagonist action. In the case of benzodiazepines, some importance of electronic properties is also indicated, which however needs further verification.

Cells of macrophage lineage contribute to the pathogenesis of HIV-1 infection throughout the course of disease. Blood monocytes and tissue macrophages can be infected with HIV-1 in vivo and in vitro. In contrast to tissue macrophages, which are highly susceptible to HIV-1 infection, blood monocytes are relatively resistant to HIV-1, with the possible exception of their CD14lo / CD16hi subset. Cells of macrophage lineage can be infected mainly with macrophage (M)-tropic strains, although infection with some T cell line (T)-tropic strains or dual-tropic isolates of HIV-1 also occurs. Following HIV-1 infection, monocyte / macrophages are resistant to cytopathic effects of the virus. The assembly of HIV-1 in macrophage subcellular vesicles rather than budding from the plasma membrane may help to preserve long-term cell viability. Macrophages can therefore persist throughout the course of infection as long-term stable reservoirs for HIV-1 capable of disseminating the virus to tissues. These cells contribute to the development of HIV-induced dementia via production of proinflammatory cytokines and neurotoxins. Following HIV-1 infection, monocyte / macrophages also display impaired effector functions such as phagocytosis, intracellular killing and cytokine production, contributing to the development of opportunistic infections. This review provides insights into the most recent studies on the role of monocyte / macrophages in the pathogenesis of HIV-1 infection by serving as viral targets and reservoirs, contributing to neuropathogenesis and opportunistic infections.

Tumour necrosis factor has been found to play a central role in the pathogenesis of rheumatoid arthritis, leading to development of novel drug therapies that neutralise the deleterious effects of this cytokine. This new concept of immunological treatment of rheumatoid arthritis has yielded successful results. Several studies have shown that the 3 available TNF-α blockers: infliximab, etanercept and adalimumab, though differ in structure and mechanism of action, have provided similar positive benefits both in clinical improvement and in slowing down the progression of radiographic damage. However, despite these successes, a significant proportion of patients with RA as well as other inflammatory conditions do not show definite improvement with this therapy. Therefore, the next major advance might be the identification of predictors of treatment response, such as genetic polymorphism that may enhance the efficiency by which these expensive therapies are used in clinical practice. This article discusses the positive response of TNF-α therapy as evidenced from the several clinical trials published, the differences between the different TNF-α blocking agents, the parameters useful in the identification of non-responders and the way to manage such patients.

Replicative senescence is a programmed cellular response in normal cells, the induction of which depends on the accumulated number of cell divisions. Recently, senescent-like growth arrest has been observed in many types of human tumour cell lines after exposure to a number of chemotherapeutic drugs. These senescent-like cancer cells show similar morphology, growth arrest and β-gal expression to normal cells undergoing replicative senescence. However, unlike replicative senescence during the aging process, the chemodrug-induced senescent-like growth arrest is not entirely dependent of cell cycle distribution, telomere length or cell cycle inhibitors. These observations suggest that induction of senescent-like response may provide a novel strategy leading to permanent growth arrest in cancer cells. So far cell lines derived from more than 20 types of cancers have shown senescent-like growth arrest by either introduction of tumour suppressor genes or treatment with chemotherapeutic drugs, and increased β-gal expression has been correlated with cancer cells undergoing terminal senescent-like growth arrest. In addition, the recent demonstration that cancer cell senescence was observed in both animal models and human frozen specimens after exposure to anticancer drugs, which was also associated with β-gal expression and treatment outcome, indicates that tumour senescence may not only provide an alternative target for the treatment of human cancer but also a prognostic indicator. This review will describe the evidence on senescent-like growth arrest in human cancer cells and the molecular changes that differ between chemodruginduced senescent-like growth arrest and apoptosis. In addition, the possible factors and mechanisms involved in this process are also discussed. Finally, the implications on how senescent-like growth arrest might be exploited as a possible new target for the development of new anti-cancer drugs are addressed.