Targeting kinases with anilinopyrimidines: Discovery of N-phenyl-N'-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives as selective inhibitors of class III receptor tyrosine kinase subfamily

Kinase inhibitors are attractive drugs/drug candidates for the treatment of cancer. The most recent literature has highlighted the importance of multi target kinase inhibitors, although a correct balance between specificity and non-specificity is required. In this view, the discovery of multityrosine kinase inhibitors with subfamily selectivity is a challenging goal. Herein we present the synthesis and the preliminary kinase profiling of a set of novel 4-anilinopyrimidines. Among the synthesized compounds, the N-phenyl-N\u2019-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives selectively targeted some members of class III receptor tyrosine kinase family. Starting from the structure of hit compound 19 we synthesized a further compound with an improved affinity toward the class III receptor tyrosine kinase members and endowed with a promising antitumor activity both in vitro and in vivo in a murine solid tumor model. Molecular modeling simulations were used in order to rationalize the behavior of the title compounds

Corilagin Induces High Levels of Apoptosis in the Temozolomide-Resistant T98G Glioma Cell Line

Glioblastoma multiforme (GBM), a malignant tumor of the central nervous system, has a high mortality rate; no curativetreatment is presently available and the most commonly used chemiotherapeutic drug, the alkylating agent temozolomide (TMZ), is only able to increase life expectancy and is often associated with drugresistance. Therefore, an urgent need does exist for novel drugs aimed at treating gliomas. In the present study we obtained three major results using corliagin: (a) demonstrate that it inhibits the growth of U251 glioma cells through activation of the apoptotic pathway; (b) demonstrate that it is also active on temozolomideresistant T98G glioma cells; (c) demonstrate that when used in combination with temozolomide on T98G glioma cells a higher level of pro-apototic and antiproliferative effects are observed. Our study indicates that corilagin should be investigated in more detail in order to determine if it can be developed as a potential therapeutic agent. In addition, our results suggest that corilagin could be used in combination with low dosages of other standard anticancer chemotherapeutic drugs against gliomas (such as temozolomide) with the aim of obtaining enhanced anticancer effects

The Moss Macromitrium Richardii (Orthotrichaceae) with Sporophyte and Calyptra Enclosed in Hymenaea Resin from the Dominican Republic

Abstract Dominican amber is an important source for Early Miocene bryophytes. We report the moss Macromitrium richardii Schwägr., an extant representative of the Orthotrichaceae, from the Dominican amber collection of the American Museum of Natural History. This species is currently a widespread Neotropical epiphyte. The specimen includes several gametophytes and sporophytes, and represents the first fossil record of Orthotrichaceae. Alongside the Macromitrium shoots we observed several fragments of the liverworts Cheilolejeunea antiqua and Frullania sp. The unusual thermal behavior of the resin sample initially led to doubts about the Miocene age of the specimen, but chemical analyses of the Hymenaea resin provides evidence that the specimen represents a highly oxidized sample of Miocene Dominican amber rather than an artificially thermally-treated subfossil resin (copal). Our inclusion demonstrates the exceptional preservation potential of tree resin, but our observations also suggest that provenance (including any possibility that a modern resin has been thermally treated to make it appear older) should be scrutinized when single pieces with atypical thermal behavior and exceptionally well-preserved extant morphotypes come to light

Early Evaluation of Copper Radioisotope Production at ISOLPHARM

The ISOLPHARM (ISOL technique for radioPHARMaceuticals) project is dedicated to the development of high purity radiopharmaceuticals exploiting the radionuclides producible with the future Selective Production of Exotic Species (SPES) Isotope Separation On-Line (ISOL) facility at the Legnaro National Laboratories of the Italian National Institute for Nuclear Physics (INFN-LNL). At SPES, a proton beam (up to 70 MeV) extracted from a cyclotron will directly impinge a primary target, where the produced isotopes are released thanks to the high working temperatures (2000 \ub0C), ionized, extracted and accelerated, and finally, after mass separation, only the desired nuclei are collected on a secondary target, free from isotopic contaminants that decrease their specific activity. A case study for such project is the evaluation of the feasibility of the ISOL production of 64Cu and 67Cu using a zirconium germanide target, currently under development. The producible activities of 64Cu and 67Cu were calculated by means of the Monte Carlo code FLUKA, whereas dedicated off-line tests with stable beams were performed at LNL to evaluate the capability to ionize and recover isotopically pure copper

Molecular mechanism of action of trimethylangelicin derivatives as CFTR modulators

The psoralen-related compound, 4,6,40-trimethylangelicin (TMA) potentiates the cAMP/PKA-dependent activation of WT-CFTR and rescues F508del-CFTR-dependent chloride secretion in both primary and secondary airway cells homozygous for the F508del mutation. We recently demonstrated that TMA, like lumacaftor (VX-809), stabilizes the first membrane-spanning domain (MSD1) and enhances the interface between NBD1 and ICL4 (MSD2). TMA also demonstrated anti-inflammatory properties, via reduction of IL-8 expression, thus making TMA a promising agent for treatment of cystic fibrosis. Unfortunately, TMA was also found to display potential phototoxicity and mutagenicity, despite the fact that photo-reactivity is absent when the compound is not directly irradiated with UVA light. Due to concerns about these toxic effects, new TMA analogs, characterized by identical or better activity profiles and minimized or reduced side effects, were synthesized by modifying specific structural features on the TMA scaffold, thus generating compounds with no mutagenicity and phototoxicity. Among these compounds, we found TMA analogs which maintained the potentiation activity of CFTR in FRT-YFP-G551D cells. Nanomolar concentrations of these analogs significantly rescued F508del CFTR-dependent chloride efflux in FRT-YFP-F508del, HEK-293 and CF bronchial epithelial cells. We then investigated the ability of TMA analogs to enhance the stable expression of varying CFTR truncation mutants in HEK-293 cells, with the aim of studying the mechanism of their corrector activity. Not surprisingly, MSD1 was the smallest domain stabilized by TMA analogs, as previously observed for TMA. Moreover, we found that TMA analogs were not effective on F508del-CFTR protein which was already stabilized by a second-site mutation at the NBD1-ICL4 interface. Altogether, our findings demonstrate that these TMA analogs mediate correction by modifying MSD1 and indirectly stabilizing the interface between NBD1 and CL4

Guidelines of the Italian Society of Videosurgery in Infancy for the minimally invasive treatment of the esophageal atresia

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Guidelines of the Italian Society of Videosurgery in Infancy for the minimally invasive treatment of the ureteropelvic-junction obstruction

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Guidelines of the Italian Society of Videosurgery in Infancy (SIVI) for the minimally invasive treatment of fetal and neonatal ovarian cysts

In the last three decades, fetal ovarian cysts were diagnosed more frequently, due to technological improvement and the increasing use of prenatal screening ultrasound. Nonetheless, treatment uncertainties are still present, either prenatally or postnatally. Recently, significant innovations on diagnosis and treatment have been proposed and a more conservative, minimally invasive approach may be offered to the Pediatrician or the Surgeon who face with this condition during prenatal or neonatal age. (...

Guidelines of the Italian Society of Videosurgery (SIVI) in Infancy for the minimally invasive treatment of Hypertrophic Pyloric Stenosis in neonates and infants

The most appropriate treatment for the infantile Hypertrophic Pyloric Stenosis (HPS) is still debated. The non-surgical conservative treatment with oral or intravenous administration of atropine does not enjoy a widespread appreciation for several factors (...