Cannabinoid derivatives exert a potent anti-myeloma activity both in vitro and in vivo.

Although hematopoietic and immune system show high levels of the cannabinoid receptor CB2, the potential effect of cannabinoids on hematologic malignancies has been poorly determined. Here we have investigated their anti-tumor effect in multiple myeloma (MM). We demonstrate that cannabinoids induce a selective apoptosis in MM cell lines and in primary plasma cells of MM patients, while sparing normal cells from healthy donors, including hematopoietic stem cells. This effect was mediated by caspase activation, mainly caspase-2, and was partially prevented by a pan-caspase inhibitor. Their pro-apoptotic effect was correlated with an increased expression of Bax and Bak, a decrease of Bcl-xL and Mcl-1, a biphasic response of Akt/PKB and an increase in the levels of ceramide in MM cells. Inhibition of ceramide synthesis partially prevented apoptosis, indicating that these sphingolipids play a key role in the pro-apoptotic effect of cannabinoids in MM cells. Remarkably, blockage of the CB2 receptor also inhibited cannabinoid-induced apoptosis. Cannabinoid derivative WIN-55 enhanced the anti-myeloma activity of dexamethasone and melphalan overcoming resistance to melphalan in vitro. Finally, administration of cannabinoid WIN-55 to plasmacytoma-bearing mice significantly suppressed tumor growth in vivo. Together, our data suggest that cannabinoids may be considered as potential therapeutic agents in the treatment of MM.

Presente y Futuro en el Descubrimiento de Fármacos para la Enfermedad de Chagas / The Present and Future of Drug Discovery for Chagas Disease

La enfermedad de Chagas, también conocida como Tripanosomiasis Americana es una enfermedad parasitaria causada por el Trypanosoma cruzi. Se estima que alrededor de 7,7 millones de personas se encuentran infectadas y padecen la enfermedad de Chagas. Esta enfermedad silenciosa que esta estrechamente relacionada con la pobreza, es transmitida a los humanos por unos insectos que se encuentran exclusivamente en el continente americano, principalmente en áreas rurales con muy deficientes condiciones de salubridad. Los fármacos existentes (nifurtimox y benznidazol), no siempre disponibles, constituyen un tratamiento paliativo, pero no curan la enfermedad y no son aceptables desde un punto de vista terapéutico debido a sus efectos secundarios indeseables y a su falta de eficacia. Por tanto, es necesario el desarrollo urgente de nuevos tratamientos y por tanto, sería muy conveniente la utilización del diseño racional en todas las etapas. El diseño de fármacos es una tarea compleja que requiere la colaboración interdisciplinar de muchos especialistas en diferentes campos de la ciencia. El presente trabajo describe de manera estructurada las diferentes estrategias que se han utilizado y las que se pueden utilizar en el futuro para el descubrimiento de nuevos fármacos para la enfermedad de Chagas. Se recogen las estrategias más clásicas como el diseño de análogos, el cribado sistemático o el basado en la información biológica y los métodos más novedosos basados en lo que se conoce como quimioinformática(AU)

The Present and Future of Drug Discovery for Chagas DiseaseChagas disease, also known as American trypanosomiasis, is caused by infection with the Trypanosoma cruzi. The Pan American Health Organization (PAHO) estimates that 7.7 million persons currently have T. cruzi infection in the 21 endemic countries. This disease can be transmitted to humans by insect vectors that are found only in the American continent, mainly, in rural areas with unhealthy housing conditions where poverty is a general concern. Nifurtimox and benznidazole are the only drugs used against this disease, but sometimes they are not available. The treatment of Chagas disease with nifurtimox or benznidazole is unsatisfactory because of their limited efficacy on the prevalent chronic stage of the disease and their toxic side effects. It is, therefore, necessary the development of new effective antichagasic drugs for the suitable treatment of this disease. The development of new drugs for Chagas disease requires a multidisciplinary approach involving diverse disciplines such as molecular and cellular biology, chemistry, bioinformatics, biochemistry, pharmacology and toxicology. This revision describes the different strategies used for drug discovery on Chagas disease treatment. The most classic strategies as the design of analogous, the systematic screening or that one based on the biological information, together the most recent methods based on chemiinformatics, are presented(AU)

Synthesis and pharmacological evaluation of sulfamide-based analogues of anandamide.

Arachidonyl and linoleyl sulfamide derivatives have been synthesized and their potential cannabimimetic properties evaluated in in vitro functional and binding assays. Replacement of the ethanolamide moiety of anandamide by -CH(2)NHSO(2)NH-R considerably reduces the CB1 receptor activity and only some of the compounds showed modest cannabinoid properties in binding assays. The new compounds were also tested as inhibitors of the FAAH enzyme but were inactive.

Tacrine-melatonin hybrids as multifunctional agents for Alzheimer's disease, with cholinergic, antioxidant, and neuroprotective properties.

Tacrine-melatonin hybrids were designed and synthesized as new multifunctional drug candidates for Alzheimer's disease. These compounds may simultaneously palliate intellectual deficits and protect the brain against both beta-amyloid (A beta) peptide and oxidative stress. They show improved cholinergic and antioxidant properties, and are more potent and selective inhibitors of human acetylcholinesterase (hAChE) than tacrine. They also capture free radicals better than melatonin. Molecular modeling studies show that these hybrids target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. At sub-micromolar concentrations they efficiently displace the binding of propidium iodide from the PAS and could thus inhibit A beta peptide aggregation promoted by AChE. Moreover, they also inhibit A beta self-aggregation and display neuroprotective properties in a human neuroblastoma line against cell death induced by various toxic insults, such as A beta(25-35), H(2)O(2), and rotenone. Finally, they exhibit low toxicity and may be able to penetrate the central nervous system according to an in vitro parallel artificial membrane permeability assay for the blood-brain barrier (PAMPA-BBB).

Genotipo cag A+ en cepas de Helicobacter pylori asociadas a úlcera péptica, gastritis crónica y cáncer gástrico / Cag A+ genotype in Helicobacter pylori strains associated with peptic ulcer, chronic gastritis and gastric cancer

Se estudiaron 171 pacientes con úlcera duodenal, úlcera gástrica, gastritis crónica y cáncer gástrico; los 3 últimos confirmados histológicamente. Se analizaron 56 casos con úlcera duodenal, 48 con úlcera gástrica, 47 con gastritis crónica y 20 con cáncer gástrico. Se detectó la presencia de Helicobacter pylori mediante PCR en el 98,2 por ciento de las úlceras duodenales; en el 95,8 por ciento de las úlceras gástricas; en el 95,0 por ciento de los cánceres gástricos y en el 93,6 por ciento de las gastritis crónicas, para una prevalencia total del 95,9 por ciento. El genotipaje cag A de las cepas detectadas reportó positividad en el 80,0 por ciento de las úlceras duodenales; en el 72,7 por ciento de las gastritis crónicas; en el 69,6 por ciento de las úlceras gástricas y en el 42,1 por ciento de los cáncer gástricos, para una prevalencia total del 70,7 por ciento. Tanto las úlceras en su conjunto, como la gastritis crónica presentaron una prevalencia de cepas Helicobacter pylori cag A+ significativamente superior al cáncer gástrico (p = 0,19).

171 patients with duodenal ulcer, gastric ulcer, chronic gastritis and gastric cancer were studied. The last 3 were histologically confirmed. 56 cases with duodenal ulcer, 48 with gastric ulcer, 47 with chronic gastritis and 20 with gastric cancer were analyzed. The presence of Helicobacter pylori was detected by PCR in 98.2 percent of the duodenal ulcers; in 95.8 percent of the gastric ulcers; in 95.0 percent of the gastric cancers; and in 93.6 percent of the chronic gastritis. The cag A genotyping of the strains found proved to be positive in 80.0 percent of the duodenal ulcers; in 72.7 percent of the chronic gastritis; in 69.6 percent of the gastric ulcers; and in 42.1 percent of the gastric cancers, for a total prevalence of 70.7 percent. Both, the ulcers as a whole and the chronic gastritis showed a prevalence of cag A+ strains of Helicobacter pylori significantly higher than gastric cancer (p = 0,19).

Genotipo cag A+ en cepas de Helicobacter pylori asociadas a úlcera péptica, gastritis crónica y cáncer gástrico / Cag A+ genotype in Helicobacter pylori strains associated with peptic ulcer, chronic gastritis and gastric cancer

Se estudiaron 171 pacientes con úlcera duodenal, úlcera gástrica, gastritis crónica y cáncer gástrico; los 3 últimos confirmados histológicamente. Se analizaron 56 casos con úlcera duodenal, 48 con úlcera gástrica, 47 con gastritis crónica y 20 con cáncer gástrico. Se detectó la presencia de Helicobacter pylori mediante PCR en el 98,2 por ciento de las úlceras duodenales; en el 95,8 por ciento de las úlceras gástricas; en el 95,0 por ciento de los cánceres gástricos y en el 93,6 por ciento de las gastritis crónicas, para una prevalencia total del 95,9 por ciento. El genotipaje cag A de las cepas detectadas reportó positividad en el 80,0 por ciento de las úlceras duodenales; en el 72,7 por ciento de las gastritis crónicas; en el 69,6 por ciento de las úlceras gástricas y en el 42,1 por ciento de los cáncer gástricos, para una prevalencia total del 70,7 por ciento. Tanto las úlceras en su conjunto, como la gastritis crónica presentaron una prevalencia de cepas Helicobacter pylori cag A+ significativamente superior al cáncer gástrico (p = 0,19)(AU)

171 patients with duodenal ulcer, gastric ulcer, chronic gastritis and gastric cancer were studied. The last 3 were histologically confirmed. 56 cases with duodenal ulcer, 48 with gastric ulcer, 47 with chronic gastritis and 20 with gastric cancer were analyzed. The presence of Helicobacter pylori was detected by PCR in 98.2 percent of the duodenal ulcers; in 95.8 percent of the gastric ulcers; in 95.0 percent of the gastric cancers; and in 93.6 percent of the chronic gastritis. The cag A genotyping of the strains found proved to be positive in 80.0 percent of the duodenal ulcers; in 72.7 percent of the chronic gastritis; in 69.6 percent of the gastric ulcers; and in 42.1 percent of the gastric cancers, for a total prevalence of 70.7 percent. Both, the ulcers as a whole and the chronic gastritis showed a prevalence of cag A+ strains of Helicobacter pylori significantly higher than gastric cancer (p = 0,19)(AU)

Discovery of 1,1-dioxo-1,2,6-thiadiazine-5-carboxamide derivatives as cannabinoid-like molecules with agonist and antagonist activity.

A series of new 2-substituted 1,1-dioxo-1,2,6-thiadiazine-5-carboxylate derivatives have been prepared from monosubstituted sulfamides in order to obtain N-substituted 1,1-dioxo-1,2,6-thiadiazine-5-carboxamides as novel cannabinoid derivatives, analogues of Rimonabant (SR141716A). Their potential functional activity on cannabinoid receptors has been evaluated in vitro and in vivo in mice, showing that two compounds (37 and 39) behave as cannabinoid agonists in vitro. Their potency is lower than that of the reference compound, WIN 55,212-2, but their efficacy is similar to that of this cannabinoid agonist, although no in vivo activity is observed. Another derivative (38) behaves as a cannabinoid antagonist both in vitro and in vivo, being its efficacy and potency similar to that of the well-known antagonist SR141716A.

Novel sulfamide analogs of oleoylethanolamide showing in vivo satiety inducing actions and PPARalpha activation.

Long chain saturated and unsaturated alkyl sulfamide and propyl sulfamide derivatives, analogs of oleoylethanolamide, have been synthesized and evaluated in vivo and in vitro as peroxisome proliferator activated receptor alpha (PPARalpha) activators. Additionally, the anorexic effects of the new compounds have been studied in vivo in food-deprived rats. Among the active compounds N-octadecyl-N'-propylsulfamide (7) has been identified as a potent hypolipidemic compound, a potent feeding suppressant, and a concentration-dependent activator of PPARalpha.

Homology modelling and active-site-mutagenesis study of the catalytic domain of the pneumococcal phosphorylcholine esterase.

Streptococcus pneumoniae is among the major human pathogens. Several interactions of this bacterium with its host appear to have been mediated by bacterial cell wall components. Specifically, phosphorylcholine residues covalently attached to teichoic and lipoteichoic acids serve as anchors for many surface-located proteins (choline-binding proteins CBPs), including cell-adhesion and virulence factors, and are also recognized by host response components through choline-binding receptors. In this study, we have performed modelling of the catalytic domain of pneumococcal phosphorylcholine esterase (Pce), a modular enzyme that is capable of removing phosphorycholine residues from teichoic and lipoteichoic acids, remodelling their distribution on the bacterial envelope. We wish to contribute to the structural knowledge of Pce. In this pursuit, 3D models of Pce have been established by homology modelling, using the X-ray structure of enzymes from the alpha/beta metallo-lactamase family fold as templates. Theoretical models of pneumococcal phosphorylcholine esterase (Pce) catalytic modules obtained by homology modelling, and corresponding docking studies employed to find out the residues involved in the binding of Zn ions, are discussed according to mutational studies and ab initio calculations. The presence of a binuclear Zn cluster in the catalytic domain of Pce and a likely coordination model are proposed.

Homology models of the cannabinoid CB1 and CB2 receptors. A docking analysis study.

The 3D models of both CB1 and CB2 human receptors have been established by homology modeling using as template the X-ray structure of bovine Rhodopsin (code pdb: 1F88) a G-protein-coupled receptor (GPCR). A recursive approach comprising sequence alignment and model building was used to build both models, followed by the refinement of non-conserved regions. The cannabinoid system has been studied by means of docking techniques, using the 3D models of both CB1 and CB2 and well known reference inverse agonist/antagonist compounds. An approach based on the flexibility of the structures has been used to model the receptor-ligand complexes. The structural effects of ligand binding were studied and analyzed on the basis of hydrogen bond interactions, and binding energy calculations. Potential interaction sites of the receptor were determined from analysis of the difference accessible surface area (DASA) study of the protein with and without ligand.

Synthesis and nematocide activity of S-glycopyranosyl-6,7-diarylthiolumazines.

6,7-Diaryl derivatives of mono and di-S-glycopyranosylthiolumazine derivatives 5-8 were prepared to test their nematocide activity. In vitro tests against Caenorhabditis elegans were performed and it was found that monosubstituted derivatives 5-7 showed higher activity than the corresponding unsubstituted 2-thiolumazines 1-3, whilst 2-S,4-S-di-glycopyranosylpteridine derivative 8 was inactive in contrast to unsubstituted derivative 4. In order to check whether the lack of activity of 8 was due to the two bulky substituents of the pteridine nucleus, 2-S,4-S-dimethyl derivative 9 was synthesized and assayed showing also lack of activity. A theoretical study on the stability of the different possible tautomers of compound 4 was carried out in an attempt to explain some, in appearance, anomalous (13)C NMR data of this compound.