Current Medicinal Chemistry - Volume 11, Issue 18, 2004

The brain remains an area where little corrective surgery can be performed and the reversal of damage is almost impossible. Recently, reports of agents offering neuroprotection have begun to appear in the literature. The concept of neuroprotection is the administration of some agent, which should reverse some of the damage or prevent further damage. Some agents offer protection against cell degeneration to the neuronal cells. Still other agents specifically protect the dopamine neurons and the retina. The majority of neuroprotective agents are antioxidants. An immunosuppressive calcineurin inhibitor, NOS inhibitor, σ-1 modulator, AMPA antagonist and Ca2+ channel blocker have all shown neuroprotective activity. An estrogen agonist and two glycoprotein IIb / IIIa antagonists also exhibit neuroprotective activity.Most of the synthetic compounds presented were not originally designed as neuroprotective agents but were found to possess neuroprotective activity in later studies. Many of these compounds are biologically active natural products, either plant extracts or endogenous peptides / proteins. This review will present the most recent reports on these agents.

Several sulfated seaweed polysaccharides show high antiviral activity against enveloped viruses, including important human patogens such as human immunodeficiency virus, herpes simplex virus, human citomegalovirus, dengue virus and respiratory syncytial virus. They can be obtained in major amounts and at low costs, have low toxicity and in some cases, lack anticoagulant effects. Even if the systemic applications have many drawbacks, their structure and mode of action indicate potential for topical uses to prevent virus infection. The herpes simplex viruses attach to cells by an interaction between the envelope glycoprotein C and the cell surface heparan sulfate (HS). The virus-cell complex is formed by ionic interactions between the anionic (mainly sulfate) groups in the polysaccharide and basic amino acids of the glycoprotein, and non-ionic ones depending on hydrophobic amino acids interspersed between the basic ones in the glycoprotein-binding zone. Hypothesis are advanced of the corresponding hydrophobic structures in the polysaccharides. The antiviral activity of the sulfated seaweed polysaccharides is based on the formation of formally similar complexes that block the interaction of the viruses with the cells. Correlations are established between different structural parameters and antiviral activity. The minimal, ionic and hydrophobic, structures in the seaweed polysaccharides were hypothesized by comparison of the polysaccharides with the known minimal binding structure in HS / heparin, together with a correlation between those structures of the polysaccharides and their antiviral activity.

Membrane and membrane-active peptides and proteins play a crucial role in numerous cell processes, such as signaling, ion conductance, fusion, and others. Many of them act as highly specific and efficient drugs or drug targets, and, therefore, attract growing interest of medicinal chemists. Because of experimental difficulties with characterization of their spatial structure and mode of membrane binding, essential attention is given now to molecular modeling techniques. During the last years an important progress has been achieved in molecular dynamics (MD) and Monte Carlo (MC) simulations of peptides and proteins with explicit and / or implicit theoretical models of membranes. The first ones allow atomic-resolution studies of peptides behavior on the membrane-water interfaces. Models with implicit consideration of membrane are of a special interest because of their computational efficiency and ability to account for principal trends in protein-lipid interactions. In this approximation, the bilayer is usually treated as continuum whose properties vary along the membrane thickness, and membrane insertion is simulated using either MC or MD methods. This review surveys recent applications of both types of lipid bilayer models in computer simulations of a wide variety of peptides and proteins with different biological activities. Theoretical background of the membrane models is considered with examples of their applications to biologically relevant problems. The emphasis of the review is made on recent MC and MD computations, on structural and / or functional information, which may be obtained via molecular modeling. The approximations and shortcomings of the models, along with their perspectives in design of new membrane active drugs, are discussed.

Etoposide is an antitumor agent currently in clinical use for the treatment of small cell lung cancer, testicular cancer and lymphomas. Since the introduction of etoposide in 1971, its mechanism of action and potent antineoplastic activity has served as the impetus for intensive research activities in chemistry and biology. This drug acts by stabilizing a normally transient DNA-topoisomerase II complex, thus increasing the concentration of double-stranded DNA breaks. This phenomenon triggers mutagenic and cell death pathways. The function of topoisomerase II is understood in some detail, as is the mechanism of inhibition of etoposide at a molecular level. Etoposide has shortcomings of limited neoplastic activity against several solid tumors such as non-small cell lung cancer, cross-resistance to MDR tumor cell lines and low bioavailability. The design and synthesis of etoposide analogs is an activity of fundamental interest to the field of cancer chemotherapy. In the first part, this article is a survey of the discovery of etoposide, the DNA topoisomerase II structure and mechanism, and the models for drug-enzyme interaction. The last part is concerned with the search for new etoposide analogs based upon an empirical design.

Insulin resistance is the major cause in Non Insulin Dependent Diabetes Mellitus (NIDDM). In this review insulin production from α-cells and action of insulin is briefly described. Any intervention either in the production or action of insulin has been the leading cause of NIDDM. Therapeutic intervention to deal with the defective action of insulin at various receptor or target tissues has been outlined. Structure-activity relationship of a large number of thiazolidinediones, oxazolidinediones, isoxazolidinediones, biguanides, tetrazole derivatives, pyrazoles and pyrazolones, oxathiadiazole oxide, hydroxyurea and carboxylic acid derivatives have been described. The probable mechanism of action of these novel compounds through Peroxisome Proliferator - Activated Receptors that ameliorate the insulin resistance, has been described. Finally the clinical candidates at various stages of clinical evaluation have been compiled.

In the overall scheme of the future development of new drugs for the treatment of breast cancer, specially tamoxifen resistant tumours, we have explored the unprecedented use of organometallic SERMs. The initial idea is to enhance the efficacy of the current standard, i.e. tamoxifen, by modifying the structure through judicious incorporation of an organometallic moiety possessing novel properties. Results have been varied, justifying a systematic approach that has proved to be full of surprised. The following differing situations were observed (a) the anti-proliferative effect is due to the vector and the organometallic moiety does not improve the effects of the SERM, no matter what concentration is used. In particular, this is the case for the hydroxytamoxifen derivative bearing a CpRe(CO)3 group, which behaves almost identically to hydroxytamoxifen. These stable species have future promise for use with radionucleides of Re and Tc (b) the effect of the organometallic moiety counteracts the anti-estrogenic behaviour of the vector and leads to species with proliferative activity; this is the case with Cp2TiCl2 entity, which when attached to tamoxifen behaves as a powerful estrogen, probably due to in situ release of Ti(IV) (c) a synergy exists between the cytotoxic organometallic moiety and its organic vector, leading to unique anti-proliferative effects on breast cancer cells classed ER+ and ER-. This result opens a new window on organometallic oncology. It is also clear that the range of possibilities is broad, varied and currently unpredictable. A systematic study combining organometallic chemistry and biology is the only option in the search for new SERMs with novel properties.