Mini Reviews in Medicinal Chemistry - Volume 5, Issue 3, 2005

Enzyme electrodes for biosensors are discussed. Different methods to increase electron transfer between enzymes and electrodes are described. Results of encasing the enzymes in conducting polymers as well as in hydrogels are presented. The environment of the enzyme in the biosensor is compared to the natural environment of enzymes.

Endotoxemia and endotoxin shock are common problems in the intensive care unit and carry a very high mortality rate. Endotoxemia increases production of endogenous cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), IL-6, and IL-8. Not only endotoxin but also cytokines have been implicated as important factors in the pathophysiology of endotoxic shock and the development of cardiovascular dysfunction in endotoxemia. Recently, it has been shown both in vitro and in vivo that several intravenous anesthetics have anti-inflammatory effects. Thiopental and ketamine inhibit the endotoxininduced TNF-alpha, IL-1 and IL-8 responses and increase IL-10 release in vitro. Ketamine prevent the proinflammatory cytokine (TNF-alpha, IL-1, and IL-6) responses to endotoxemia in vivo. Moreover, thiopental and ketamine suppress the activation of nuclear factor-kappa B induced by endotoxin. Propofol have been proven its anti-inflammatory effects on endotoxemia both in vitro and in vivo, but several studies have shown that propofol does not have any anti-inflammatory effects and deteriorates the inflammatory response to endotoxemia. This article reviews the anti-inflammatory effects of intravenous anesthetics on endotoxemia and endotoxic shock.

Drugs which release nitric oxide (NO) have great therapeutic potential. The organic nitrates and sodium nitroprusside have been used in cardiovascular therapeutics for many years, but several drawbacks limit their usefulness. In this review, we consider novel and potential future developments in NO-donor drugs, and the possible clinical usefulness of such compounds.

Bacterial strains isolated from clinical specimens have become more and more resistant to many antimicrobials. This is because we have consumed large amounts of strong antimicrobials over long periods of time and thus bacterial cells are able to survive by altering the target(s) of antimicrobial agents. A good example of this phenomenon is methicillin-resistant Staphylococcus aureus (MRSA). One of the cell wallsynthesizing enzymes (known as PBP2;) of this pathogen has low affinity to βlactams, and therefore the bacterial cells continue to grow even under high concentrations of the agents. However, this drug resistance does not seem to be total. They seem to have some weak spots and several substances are known to sensitize strains of MRSA to βlactams. This review discusses the ability of polyoxotungstates (POTs) to sensitize MRSA to βlactams by reducing the expression of PBP2;. It is also possible that the sensitization is a type of stress response of MRSA to POTs. This idea may provide a hint for the development of a new antimicrobial agent.

Type 2 diabetes mellitus (NIDDM) is a complex metabolic disease that occurs when insulin secretion can no longer compensate insulin resistance in peripheral tissues. At the molecular level, insulin resistance correlates with impaired insulin signaling. This review provides new insights into the molecular mechanisms of insulin action and resistance in brown adipose tissue (BAT) and pinpoints the role of BAT in the control of glucose homeostasis.

Transglutaminases (TGases), a family of enzymes that catalyze the formation of ε-(γ-glutamyl)lysine isopeptide linkage, play an important physiological role in hemostasis, wound healing, assembly and remodeling of the extracellular matrix, cell signaling and apoptosis. Although many members of this class of enzymes have been known for decades, their role in various physiological and pathological processes is still a subject of substantial research and debate. Convincing evidence exists that TGases are involved in formation of cytotoxic proteinatious aggregates in Alzheimer's, Huntington's and other neurodegenerative diseases. However, it is not clear if elevated levels of TGases play a causative or protective role in several of these processes. Increased or defective TGase activity is a factor in cortical cataract formation, lamellar ichtyosis and fibrosis. TGase creates epitopes for the production of autoantibodies in celiac disease and possibly other autoimmune diseases. Another TGase, Factor XIIIa, is involved in the etiology of vascular diseases. Modulation of TGase activity through its selective inhibition may have therapeutic benefit in a wide variety of diseases. This paper will examine TGases as targets for the development of new therapeutics and review the progress in discovery of selective inhibitors of these enzymes.

Albumin nanoparticles (NP) were proved to be effective and safe carriers for delivering anticytomegaloviral compounds in the vitreous. NP improved the antiviral activity of both ganciclovir and the phosphodiester oligonucleotide analog to formivirsen. NP appeared to be fusogenic carriers able to target the nucleus of cells. In addition, these drug carriers were well tolerated when administered by the intravitreal route and did not induce autoimmune reactions.

The interaction of taxol with DNA has major biological importance since it is shown the presence of higher concentration of taxol in the nucleus, than in the human lung tumor cell. Therefore, in this report we examine the interaction of taxol with calf-thymus DNA in aqueous solution at physiological pH, using constant DNA concentration (25 or 1.25 mM phosphate) and various taxol / DNA (phosphate) ratios 1 / 200 to 1 / 2. Capillary electrophoresis and Fourier transform infrared (FTIR) difference spectroscopic methods are used to characterize the nature of drug-DNA interaction and to determine the taxol binding site, the binding constant, sequence selectivity, helix stability and biopolymer secondary structure in the taxol-DNA complexes in vitro. Structural analysis showed that taxol is an external DNA binder with no affinity towards DNA intercalation. The major target of taxol is A-T, G-C bases and the backbone PO2 groups. Two bindings were observed for taxol-DNA complexes with K1= 1.4 x 104 M-1 and K2=3.5 X 103 M-1. The taxol-DNA interaction is associated with a partial helix stabilization and no major alterations of B-DNA structures.

Many tumors are not curable because current treatments primarily target the tumor cells. Intratumoral endothelial cells, on the other hand, proliferate rapidly and are sensitive to the cytotoxic effects of chemotherapeutic agents. This review summarizes the literature concerning the antiangiogenic effects of these agents when administered alone or in combination with other angiogenesis inhibitors.

Present review describes research on novel natural antitumor agents isolated from marine sponges. More than 90 novel cytotoxic antitumor compounds and their synthetic analogs have shown confirmed activity in vitro tumor cell lines bioassay and are of current interest to NCI for further in vivo evaluation. A great problem, to use directly the reservoir of marine organisms for therapy is the very low availability and the isolation of only very small amounts of the biologically active substances from the natural materials. Thus, the synthetic chemistry is required to develop high yield synthetic methods, which are able to produce sufficient marine alkaloids for a broad biological screening. This review will present some of the aspects of the medicinal chemistry developed recently to introduce such modifications. The structures, origins, synthesis and biological activity of a selection of N-heterocyclic marine sponge alkaloids are reviewed. The emphasis is on compounds poised as potential anticancer drugs: pyrroles, pyrazines, imidazole, and other structural families. With computer program PASS some additional biological activities are also predicted, which point toward new possible applications of these compounds. This review emphasizes the role of marine sponge alkaloids as an important source of leads for drug discovery.