Letters in Drug Design & Discovery - Volume 1, Issue 4, 2004

Both enveloped and non-enveloped viruses from different families may use heparan sulfates (HS) to bind to and / or enter into their host cells. The interactions between viruses and HS can be inhibited by a novel class of antiviral compounds, the N,N'-bisheteryl derivatives of 3,12-diaza-6,9-diazoniadispiro(5,2,5,2) hexadecane which bind to specific structural moieties of HS. By this way these compounds block adsorption of viruses that use HS as their initial interaction site with the cell, e.g. herpes simplex viruses, cytomegalovirus, respiratory syncytial virus, and human immunodeficiency viruses.

Cyclosporin A (CsA) is a fungal metabolite that has immunomodulatory and anti-inflammatory effects. Cyclosporin binds to cyclophilin, inhibiting CD4-T-cell activation. In this paper we discuss the mechanism of action of CsA and its role as a novel approach for the treatment of allergic disease.

Defects in mitochondrial function cause serious pediatric morbidity and mortality. Most mitochondrial disorders are caused by nuclear gene defects. To overcome the limitations of viral vectors for delivering gene products to mitochondria, we used protein transfection domains that cross cell membranes to deliver proteins expressed by nuclear genes to mitochondria.

Tuberculosis represents the main cause of mortality due to a single pathogen infection. Advances in anti-tuberculosis therapies are urgently required both for treatment of the 8-12 million new cases of tuberculosis leading to 2 million deaths each year, as well as for the 2 billion individuals already infected with M. tuberculosis, who are at the risk of developing disease. The present review summarizes the actually available information about currently existing therapies and perspectives for future innovative therapeutic approaches.

Natural polyphenolic compounds have attractive consideration for their cancer preventive effect. As their anti-cancer effect, inhibitory effect on angiogenesis would be important. Recently, it has been shown that quercetin has anti-angiogenic activity and is a potent anti-cancer agent. However, the activity of its glycosylated forms and related derivatives has not been investigated yet. In this study, we examined the effect of glycosylated quercetin on angiogenesis. Interestingly, quercetin 3-O-β-D-glucose (isoquercitrin) showed the strongest inhibitory effect on an ex vivo angiogenesis assay, but quercetin 3-O-β-D-glucose-[1,6]-O-α-Lrhamnose (rutin) had no effect. Inhibitory effect of quercetin 7-O-β-D-glucose (quercimeritrin) was almost similar to that of quercetin. Furthermore, we compared the activity of acylated isoquercitrins (isoquercitrin cinnamate, dihydrocinnamate, p-coumarate, and 2-naphthalate). Consequently, anti-angiogenic activity of the isoquercitrin derivatives was weaker than that of isoquercitrin. The effects of quercetin and its derivatives on human umbilical endothelial cell (HUVEC) proliferation, HUVEC tube formation and chemotaxis assays were associated with their effects on the ex vivo angiogenesis assay.

The synthesis, biochemical evaluation and molecular modelling of a series of esters based upon testosterone is described. The compounds were tested for human placental aromatase (AR) inhibition in vitro and were found, in general, to be weaker than the standard non-steroidal compound, aminoglutethimide (AG), however, one compound [testosterone 4-nitrobenzoate (15)] was found be some six times more potent than AG. The inhibitory activity of the compounds was rationalised through the use of the novel substrate-haem complex (SHC) approach and suggests that the longer alkyl chain containing compounds bind in a manner that results in steric hindrance between the active site of AR and the carboxylate moiety of the compounds, as such, reduced inhibitory activity is observed. The modelling of compound 15 suggests that an additional hydrogen-bonding group may be present at the active site, which allows this compound to possess greatly increased potency.

Osteoporosis, a common complex disease determined by multiple genetic, environmental and lifestyle factors, is mainly characterised by low bone density, leading to increased risk of low trauma fractures. Genetic factors play an important role in the etiopathogenesis of osteoporosis and may also influence its treatment. It is hoped that the ever-increasing genetics / genomics knowledge and techniques will greatly advance the research and treatment of osteoporosis.

Different mouse models have been generated to understand the molecular mechanisms involved in human tumorigenesis. Some of these models are produced by gene-targeting procedures, whereas others use the normal mouse as an experimental animal. The pathogenetic relevance of these mouse models has generated optimism for the development of effective targeted therapies, advances in rational drug design and has provided valuable information about human cancer disease. By combining genetic analysis and molecule screening techniques, the mouse is emerging as a powerful system for identifying novel cancer genes and for cancer drug discovery. However, there are both parallelisms and discrepancies between mouse and human carcinogenesis important for elucidating the human disease process.

Conjugates containing nigrin b (two-chain RIP) linked to a new lectin (SELld) from Sambucus ebulus L. have been designed. They retain the anti-ribosomal inhibitory activity of nigrin b but, in contrast to nigrin b, they exerted strong cytotoxicity on COLO 320 and HeLa cells, which ran in parallel with DNA fragmentation.

Discoid lupus erythematosus (DLE) is a skin disorder characterised by an active inflammatory phase that leads to the formation of atrophic scars. The molecular basis underlying the development of atrophic scars is not yet known. In this study we investigated the expression of the extra-cellular matrix (ECM) components of the BM, Laminin-1 (Ln-1), Laminin-5 (Ln-5), Collagen IV (Coll IV) and the expression of their integrin receptors α2β1, α3β1 and α6β4. In active DLE lesions expression of the ECM BM components is discontinuous and uneven and the integrins are largely absent or present with an altered polarity. In established lesions both ECM BM components and their integrin receptors are absent. In conclusion, altered expression of ECM BM components together with altered expression of their integrin receptors is responsible for the lack of cross-talk between keratinocytes and the surrounding microenvironment and this could lead to the development of atrophic scars.

Pharmacophore hypotheses were generated for a series of isoxazolylpiperazine inhibitors selectively acting on the dopamine D4 receptor. HypoGen and HipHop programs in the CATALYST software were used to get insight into the structural features required for the inhibition activity. The HypoGen-generated pharmacophore model, with four features, which include HBAl, HBAl, HpAr, RA, showed high correlation (r = 0.950) and predictive power. It also rationalized the relationships between structure and biological activity of these inhibitors of dopamine D4 receptor. This successful prediction was further validated on several structurally diverse compounds active against dopamine D4 receptor using HipHop method.

The aim of the study was to investigate the effect of fenofibrate on the concentration and relative distribution of low density lipoprotein (LDL) subfractions in patients with combined dyslipidemia. Micronised fenofibrate was administered in a single daily dose of 200 mg. Serum lipid parameters and LDL subfraction concentrations were determined at baseline as well as after 16 weeks of treatment. Fenofibrate administration resulted in a significant decrease in total LDL mass. This decrease was due to the reduction in all LDL subfractions. As a consequence, the relative distribution of LDL subfractions was not affected by fenofibrate administration.

The naturally-occurring alkaloid ibogaine, found in the West African shrub Tabernanthe iboga, possesses the ability to diminish self-administration of substances of abuse, such as cocaine, heroin and alcohol. This was the lead structure for the design of a 16-member library of N-substituted isoquinuclidines. A solution-phase method for their synthesis is described.

Roxatidine acetate hydrochloride is a widely prescribed H2-receptor antagonist for peptic ulcers. Its conformation has been studied using 1H, 13C, and 15N NMR spectroscopy in DMSO-d6 and H2O:D2O (90:10) solvents coupled with AM1 calculations. The results show a folded conformation in DMSO-d6 as opposed to an extended structure in water. Its conformation in DMSO has been constructed with AM1 calculations and closely resembles the structures seen for cimetidine, ranitidine and famotidine in the solid state and in solution. Its structure in water is comparable to its crystallographic state. The interaction of roxatidine with model membranes prepared from DPPC has also been investigated by 31P NMR. Roxatidine is seen to induce the formation of lipid structures (cubic or rhombic or tetragonal) not normally seen for pure DPPC. The formation of such structures is seen to occur in a narrow dose regimen.