Design, synthesis, biophysical and biological studies of trisubstitutednaphthalimides as G-quadruplex ligands

A series of trisubstituted naphthalimides have been synthesized and evaluated as telomeric G-quadruplex ligands by biophysical methods. Affinity for telomeric G-quadruplex AGGG(TTAGGG)3 binding was first screened by fluorescence titrations. Subsequently, the interaction of the telomeric G-quadruplex with compounds showing the best affinity has been studied by isothermal titration calorimetry and UVmelting experiments. The two best compounds of the series tightly bind the telomeric quadruplex with a 2:1 drug/DNA stoichiometry. These derivatives have been further evaluated for their ability to inhibit telomerase by a TRAP assay and their pharmacological properties by treating melanoma (M14) and human lung cancer (A549) cell lines with increasing drug concentrations. A dose-dependent inhibition of cell proliferation was observed for all cellular lines during short-term treatment

Design, synthesis and biological evaluation of novel bicyclo[1.1.1]pentane-basedx-acidic amino acids as glutamate receptors ligands

A novel series of bicyclo[1.1.1]pentane-based x-acidic amino acids, including (2S)- and (2R)-3-(30-carboxybicyclo[ 1.1.1]pentyl)alanines (8 and 9), (2S)- and (2R)-2-(30-carboxymethylbicyclo[1.1.1]pentyl)glycines (10 and 11), and (2S)- and (2R)-3-(30-phosphonomethylbicyclo[1.1.1]pentyl)glycines (12 and 13), were synthesized and evaluated as glutamate receptor ligands. Among them, (2R)-3-(30-phosphonomethylbicyclo[ 1.1.1]pentyl)glycine (13) showed relatively high affinity and selectivity at the NMDA receptor. The results are also discussed in light of pharmacophoric modelling studies of NMDA agonists and antagonists

The aldol addition of readily enolizable 1,3-dicarbonyl compounds to 2-cyanobenzaldehyde in the synthesis of novel 3-substituted isoindolinones

The aldol addition of readily enolizable 1,3-dicarbonyl compounds to 2-cyanobenzaldehyde in the presence of a tertiary amine led to a series of new 3-substituted isoindolinones. Despite the instability of the related aldols, this synthesis was possible because of the intramolecular trapping of the adducts with the cyano group due to a tandem process of cyclization-rearrangement. Simple decarboxylation of some derivatives gave access to some very useful compounds

Metabolic acidosis as Food Protein Induced Enterocolitis Syndrome (FPIES) onset in a newborn

Abstract Background FPIES (Food Protein Induced Eneterolitis Syndrome) is a rare non IgE- mediated food allergy, usually affecting infants and children after first months of life. Clinical presentation is heterogeneous, usually characterised by repetitive vomiting and diarrhoea, lethargy, failure to thrive until to dehydration with hypotension and shock. The diagnosis is based on clinical criteria, after excludind other hypothetical conditions. Early recognition of FPIES is essential to set a correct dietatay management that is resolving for the patient. Case report We present the case of a 12 days old child who was admitted to the hospital for poor feeding, failure to thrive and severe metabolic acidosis. Conclusions The early onset of this case is peculiar and rember us to consider FPIES in differential diagnosis of newborn metabolica acidosis

Natural Compounds in Anti-Leukaemic Therapy: A Review

Human leukemia results from multiple mutations that lead to abnormalities in the expressions and functions of genes that maintain the delicate balance between proliferation, differentiation and apoptosis. Continued research on the molecular aspects of leukemia cells has resulted in the developments of several potentially useful therapeutic agents. Discovery of new cellular and/or molecular pathways enabling innate or acquired resistance of cancers to current chemotherapeutics to be overcome is therefore of crucial importance if one wants to efficiently combat those cancers associated with dismal prognoses. In this concern, natural compounds are regarded as new chemical entities for the development of drugs against various pharmacological targets, including cancer, and, above all, leukemia

A New Approach to Di- and Tetrasubstituted 2,3-Dihydropyridin-4(1H)-ones through Aza-Diels–Alder Reaction Promoted by Silicon Tetrachloride

Silicon tetrachloride promotes an aza-Diels Alder reaction with a range of imines and Danishefsky's diene or an alkylated derivative, giving the desired products in good to excellent yields

1-Methoxy-Canthin-6-One and Related b-Carbolines: From Natural Compound to Synthesis and Biological Activities

Ailanthus altissima Swingle (Simaroubaceae) is a medicinal plant used in traditional medicine as an antiviral and an antitumoral drug. Its roots have been successively extracted, at room temperature, with solvents of increasing polarity. The extracts were tested for their antiproliferative activity on HeLa (human cervical carcinoma cell line), at a dose of 10 μg/mL. The chloroform extract, the most active in biological assays, was fractionated on a silica-gel column: the fractions obtained were assayed on the proliferation of the same cellular line, at a dose of 10 mg/mL. The most active fraction (100 of cytotoxic activity) demonstrated to contain a single substance. The identification of this active substance, recognized as 1-methoxy-canthin-6-one, was performed by NMR methods. This indole alkaloid has shown antiproliferative and proapoptotic effects on several tumoral cell lines. In particular, it provoked mitochondrial membrane depolarization, mitochondrial release of cytochrome c and Smac/DIABLO, and caspase 3 activation on Jurkat cells (human leukemia cell line). The compound was active also on other tumor cell lines, HuH7 (hepatocellular carcinoma), NPA (human papillary carcinoma), and ARO (anaplastic thyroid cell line): the apoptosis-inducing activity was evident at a concentration of < 10 μmol/L until half maximal at about 40 μmol/L. Peripheral blood mononuclear cells (PBMC) from healthy subjects have been used as control; in these cells, the alkaloid showed no proapoptotic activity. The effects of 1-methoxy-canthin-6-one, in combination with TRAIL (human recombinant tumor necrosis factor-related apoptosis-inducing ligand), has also been investigated on Jurkat cells using suboptimal concentrations of both agents, showing 45 apoptosis. Also, the TMRE (tetramethylrhodamine ethyl ester) bioassay resulted in a definite mitochondrial membrane depolarization, when alkaloid and TRAIL are used together, always using their suboptimal concentrations. The study of the possible synergism has shown that the alkaloid increases TRAIL R1 receptors, inducing JNK activation and c-Jun phosphorylation. JNK inhibition reduces only partly the synergism between alkaloid and TRAIL; therefore, other factors take part in TRAIL-induced apoptosis, besides TRAIL R1 upregulation. In order to obtain more information about biological properties of 1-methoxy-canthin-6-one and to investigate on chemical requirements responsible for its biological activity, a series of novel 1,4-disubstituted and 1,4,9-trisubstituted β-carbolines and tetracyclic derivatives were designed and synthesized. In vitro cytotoxic activities of these compounds were studied in a human tumor cell line panel. Almost all compounds demonstrated antiproliferative effects, in particular against prostate cancer cells PC-3, with an IC 50 values ranging between 60 and 8 μM. The most active derivatives were tested to evaluate the possible interaction with DNA and inhibition of topoisomerase I. None of these compounds were observed to stabilize the DNA-Topo I complex, thereby poisoning the reaction. In particular, 3-benzyl-1-methoxy-canthin-6- onium bromide exhibited strong inhibition of Topo I, with IC 50 of 17.77 μM

Synthesis, Physicochemical Propertiesand In Vitro Permeation Studies of New Ketorolac Ester Derivatives

Six new 1-alkylazacycloalkan-2-one esters of ketorolac (1-6) were synthesized and evaluated as potential dermal prodrugs. In vitro experiments were carried out to evaluate their chemical and enzymatic stability and permeation through excised human skin. Furthermore, partition coefficients n-octanol-water of ketorolac and its esters were determined to obtain information about their lipophilicity. Esters 1-6 showed increased lipophilicity compared to the parent drug, good stability in phosphate buffer pH 7.4, and were readily hydrolyzed in human plasma. Results from in vitro percutaneous absorption studies showed that, among all esters synthesized, only for esters 2 and 4 did a higher cumulative amount of drug penetrate through the skin, compared with that obtained after topical application of ketorolac

Molecular modelling studies, synthesis and biological activity of a series of novelbisnaphthalimides and their development as new DNA topoisomeraseII inhibitors

A series of bisnaphthalimide derivatives were synthesized and evaluated for growth-inhibitory property against HT-29 human colon carcinoma. The N,N'-bis[2-(5-nitro-1,3-dioxo-2,3-dihydro-1H-benz[de]-isoquinolin-2-yl)]propane-2-ethanediamine (9) and the N,N'-Bis[2-(5-nitro-1,3-dioxo-2,3-dihydro-1H-benz[de]-isoquinolin-2-yl)]butylaminoethyl]-2-propanediamine (12) derivatives emerged as the most potent compounds of this series. Molecular modelling studies indicated that the high potency of 12, the most cytotoxic compound of the whole series, could be due to larger number of intermolecular interactions and to the best position of the naphthalimido rings, which favours pi-pi stacking interactions with purine and pyrimidine bases in the DNA active site. Moreover, 12 was designed as a DNA topoisomerase II poison and biochemical studies showed its effect on human DNA topoisomerase II. We then selected the compounds with a significant cytotoxicity for apoptosis assay. Derivative 9 was able to induce significantly apoptosis (40%) at 0.1 microM concentration, and we demonstrated that the effect on apoptosis in HT-29 cells is mediated by caspases activation

Synthesis, physicochemical properties and <i>in vitro</i> permeation studies of new ketorolac ester derivatives

Six new 1-alkylazacycloalkan-2-one esters of ketorolac (1-6) were synthesized and evaluated as potential dermal prodrugs. In vitro experiments were carried out to evaluate their chemical and enzymatic stability and permeation through excised human skin. Furthermore, partition coefficients n-octanol-water of ketorolac and its esters were determined to obtain information about their lipophilicity. Esters 1-6 showed increased lipophilicity compared to the parent drug, good stability in phosphate buffer pH 7.4, and were readily hydrolyzed in human plasma. Results from in vitro percutaneous absorption studies showed that, among all esters synthesized, only for esters 2 and 4 did a higher cumulative amount of drug penetrate through the skin, compared with that obtained after topical application of ketorolac