A century of thioxanthones: through synthesis and biological applications.

The interest in the synthesis and applications of thioxanthones, dibenzo-gamma-thiopyrones, started in the beginning of the 20th century. Thioxanthones are traditionally synthesized via benzophenone, diarylthioether or diarylthioester intermediates. In recent years, more efficient and cleaner synthetic methodologies are being applied to obtain thioxanthone derivatives, especially for photochemical applications. Considering biological activities, the first thioxanthone introduced in therapy in 1945 was Miracil D, as an antischistosomal agent. Since then, the variety of studies of biological/ pharmacological activities of thioxanthones led to the discovery of new agents and to the disclosure of their mechanisms of action. Moreover, the ability to sensitize cancer cells suggested new and promising applications in chemotherapy. New antitumor derivatives are being developed by molecular modifications such as isosterism (aza-thioxanthones and aminoethylthioxanthones) or hybridation (psorospermine and acronycin analogues). The last generation of antitumor thioxanthones rendered a derivative, SR271425, with an excellent preclinical antitumor efficacy. The last decade has been excited in the research of thioxanthones with important achievements in both synthesis and biochemical applications, especially in order to dissociate the antitumor activity from the toxicity of drug candidates. Recently, thioxanthones emerged as dual inhibitors of P-glycoprotein and tumor cell growth. It is expected that in the following years new analogues with the thioxanthone scaffold emerge in the field of anticancer therapy, with enhanced antitumor activity and without serious side effects.

Metformin inhibits inflammatory angiogenesis in a murine sponge model.

To investigate the effects of metformin on angiogenesis, on inflammatory cell accumulation and on production of endogenous cytokines in sponge implant in mice. Polyester-polyurethane sponges were implanted in Swiss mice and metformin (40 or 400mg/kg/day) was given orally for six days. The implants collected at day 7 postimplantation were processed for the assessment of hemoglobin (Hb), myeloperoxidase (MPO), N-acetylglucosaminidase (NAG) e collagen used as indexes for angiogenesis, neutrophil and macrophage accumulation and extracellular matrix deposition, respectively. Relevant inflammatory, angiogenic and fibrogenic cytokines were also determined. Metformin treatment attenuated the main components of the fibrovascular tissue, wet weight, vascularization (Hb content), macrophage recruitment (NAG activity), collagen deposition and the levels of transforming growth factor (TGF-beta1) intraimplant. A regulatory function of metformin on multiple parameters of main components of inflammatory angiogenesis has been revealed giving insight into the potential therapeutic underlying the actions of metformin.

Zinc, magnesium and copper profiles in three experimental models of epilepsy.

Trace metals are involved in the mechanisms of CNS excitability, including epilepsy. In this study, atomic absorption spectrophotometry was used to determine concentrations of Mg(2+), Cu(2+) and Zn(2+) in plasma (microg/ml) and hair (microg/g) samples. Differential profiles of trace metals were detected in rats displaying three different kinds of seizures, i.e. acute audiogenic seizures (generalized tonic-clonic type GTC) and audiogenic kindling (limbic type; LS) in Wistar Audiogenic Rats (WARs) and electroshock-induced seizures (ES) in Wistar non-epileptic rats (resistant). Significantly lower Zn(2+) concentrations were observed in the plasma of WARs (0.80+/-0.02) compared with resistants (0.89+/-0.03) in the basal (non-seizing) condition. After GTC, WARs showed lower Zn(2+) levels (0.64+/-0.12) while both Mg(2+) (12.56+/-1.51) and Cu(2+) (0.81+/-0.14) were higher than in non-seizing WARs. After ES-induced seizures only Mg(2+) changed, being higher than in the basal condition (11.78+/-2.25 and 8.90+/-0.95). In hair, basal levels of Mg(2+) and Cu(2+) (192.49+/-36.73 and 13.33+/-1.76) were higher whereas Zn(2+) (136.53+/-15.67) was lower in WARs than in resistants. WARs submitted to 0, 3 and 25 stimuli presented higher Mg(2+) concentrations as the number of stimuli increased. In animals receiving the same number of stimuli, Zn(2+) levels were higher for animals displaying GTC (151.09+/-5.53) than those displaying LS (128.07+/-8.51). In conclusion, seizure type (limbic or generalized tonic-clonic) and number of stimuli seem to be the determinant factors for changes in Zn(2+) and Mg(2+) levels, respectively.

Inhibitors of dihydrodipicolinate reductase, a key enzyme of the diaminopimelate pathway of Mycobacterium tuberculosis.

Tuberculosis (TB) remains a leading cause of infectious disease in the world today and therapies developed over the last forty years are becoming increasingly ineffective against resistant strains of Mycobacterium tuberculosis. In an effort to explore new mechanisms for drug development, we have investigated the enzymes of the diaminopimelate biosynthetic pathway as potential targets. Specifically, dihydrodipicolinate reductase, the essential gene product of dapB, was screened for novel inhibitors. Inhibitors were identified both by a molecular modeling approach which utilized the available crystal structure of the enzyme with an inhibitor bound at the active site as well as by more conventional screening strategies. The resulting compounds contain a number of structural motifs and were all found to be competitive with respect to the DHDP substrate. The K(i) values for the inhibitors range from 10 to 90 microM. The molecular modeling approach was very effective in identifying novel inhibitors of the enzyme. These compounds were obtained at a higher frequency based on the number of compounds analyzed than those inhibitors discovered via conventional screening. However, conventional screening proved beneficial in identifying compounds with greater structural diversity.

Assay for recombinant hepatitis B surface antigen using reversed-phase high-performance liquid chromatography.

Several HPLC assays are reported for monitoring the mass of recombinant hepatitis B surface antigen (rHBsAg) in yeast cell lysates. The assays utilized either a polymeric resin column containing a phenyl ligate or a silica-based octadecyl micropellicular column. Prior to chromatography on the polymeric column, the samples were derivatized with the thiol-specific fluorescent probe monobromobimane to discriminate the rHBsAg from nonfluorescent cellular components. Using a dual gradient of acetic acid and acetonitrile the derivatized rHBsAg eluted with a retention time equal to 17 min. Chromatography on the micropellicular column did not require prederivatization and utilized an isopropanol gradient with increasing amounts of acetonitrile. Operating this column at elevated temperature with a high flow rate resolved the rHBsAg from yeast components within 5 min and allowed a new sample injection every 10 min. All the assays displayed useful linear ranges for analyzing rHBsAg in cell lysates and had detection limits for rHBsAg between 10 and 50 ng per injection.

Lipomatose difusa e congenita de extremidades. / Congenital and diffuse lipomatosis of extremities

Sao apresentados cinco casos de lipomatose difusa e congenita de extremidades cursando com gigantismo de dedos e aumento de volume de mao e pe correspondentes. O estudo radiologico mostrou aumento de volume das falanges dos dedos envolvidos, ao lado de rarefacao ossea e de lesoes osteoliticas. Histologicamente, documentou-se infiltracao difusa de plano muscular, de pele e de osso pelo tumor