1,721,012 research outputs found
Studies on the synthesis and the biological activity of acyclonucleosides related to isopentenyladenosine
Full text linkIsopentenyladenosine analogues as potential antitumor agents : synthesis and structure-activity relationships
No full textN6-Isopentenyladenosine (1, iPA) is a member of the cytokinin family, plant hormones that regulate cell growth and differentiation. iPA is the only known cytokinin existing in animal cells in a free form, as a mononucleotide in cytoplasm, or bound to t-RNA. At present, the biological role and the mechanism of action of iPA in mammalians cells are not fully understood. It has been demonstrated that iPA is able to inhibit protein prenylation1 and competes for nucleoside transport.2 Spinola3 et al. have recently demonstrated that iPA exerts a potent in vitro anticancer activity on human epithelial cancer cell lines while it has a slight effect on tumour growth in rodents. This lack of in vivo activity could be related to the short plasma half-life of iPA, as it is well known for other nucleosides. With the aim of identifying compounds endowed with in vitro and in vivo antiproliferative activity, we have investigated structural modifications of iPA. Initially, we have synthesized a few acyclonucleosides that are characterized by the presence of an acyclic component, structurally resembling part of the ribose moiety in iPA. Proliferation, clonogenicity, and gene expression profile analysis were evaluated in human epithelial cancer cell lines derived from different tumours. The results showed that the iPA ribofuranosidic ring is pivotal for its biological activity.4 Starting from these results we have synthesized iPA analogues in which the hydroxyl group in 2′, 3′ and 5′ positions were replaced by a hydrogen group in order to verify the importance of each hydroxyl group of the furanosidic moiety for the activity of iPA. Then other analogues where the base adenine was substituted by inosine were synthesized (O-isopentenylinosine and its deoxy-derivatives). All compounds were in vitro tested using T24 cell line and the proliferation assay was carried out in the presence and absence of serum. No activity was found for the tested compounds, except 3′ deoxy-iPA, that was able to cause cell death of quiescent cultures. We have also synthesized iPA analogues in which the N6-position was differently substituted with the aim of verify the importance of the isopentenyl chain for the activity of the molecule. Preliminary results of in vitro assays using these compounds (T24 cell line, proliferation assay in presence and absence of serum) allowed us to select some compounds with cytotoxicity as high as iPA. With these molecules we have performed additional experiments in order to clarify the mechanism of action of iPA and its derivatives. We are now studying the synthesis of analogues of iPA in which the furanosidic moiety is replaced by a hydroxylated cyclopentane in order to obtain more stable compounds replacing the β-N-glycosidic bond (N-C-O) by a N-C-C bond to increase the resistance to enzymatic hydrolysis.
[1] Laezza C., Notarnicola M., Caruso M.G., Messa C., Macchia M., Bertini S., Minutolo F., Portella G., Fiorentino L., Stingo S., Bifulco M.; N6-isopentenyladenosine arrests tumor cell proliferation by inhibiting farnesyl diphosphate synthase and protein prenylation. The FASEB J. 2006, 20, 412.
[2] Hakala M.T., Slocum H.K., Gryko G.J.; N6-(Δ2-Isopentenyl)adenosine an inhibitor of cellular transport of uridine and cytidine. J.Cell Physiol. 1975, 86, 281.
[3] Spinola M., Colombo F., Falvella F.S., Dragani T.A.; N6-isopentenyladenosine: a potential therapeutic agent for a variety of epithelial cancers. Int. J. Cancer 2007, 120, 2744.
[4] Colombo F., Favella F.S., Tortoreto M., Pratesi G., Ciuffreda P., Ottria R., Santaniello E., Cicatiello L., Weisz A. & Dragani T.A.; Pharmacogenomics and analogues of the antitumor agent N6-isopentenyladenosine. Int. J. Cancer 2009, 124, 217
Studies on the synthesis and the biological activity of nucleosides analogues related to isopentenyladenosine
Full text linkOptimized synthesis and characterization of N-acylethanolamines and O-acylethanolamines, important family of lipid-signalling molecules
No full textThe endocannabinoid anandamide (N-arachidonoylethanolamine, AEA), a physiologically occurring bioactive compound on CB1 and CB2 receptors, has multiple physiological functions. Since the discovery of AEA additional non-cannabinoid endogenous compounds such as N-palmitoylethanolamine (PEA), and N-oleoylethanolamine (OEA) have been identified from mammalian tissues. Virodhamine (O-arachidonoylethanolamine, VA) is the only identified new member of the endocannabinoid family that is characterised by an ester linkage between acylic acid and ethanolamine instead of the amide linkage found in AEA and others non-cannabinoid N-acylethanolamines. It has been reported, as a cautionary note for lipid analyses, that VA can be produced nonenzymatically from AEA (and vice versa) as consequence of O,N-acyl migrations. O,N-acyl migrations are well documented in synthetic organic chemistry literature, but are not well described or recognized with regard to methods in lipid isolation or lipid enzyme studies. We here report an economical and effective protocol for large scale synthesis and characterization of some N- and O-acylethanolamines that could be useful as reference standards in order to investigate their possible formation in biological membranes, with potentially interesting biological properties
1H, 13C and 15N NMR assignments for N- and O-acylethanolamines, important family of naturally occurring bioactive lipid mediators
No full textThe complete 1H, 13C and 15N NMR signal assignments of some N- and O-acylethanolamines, important family of naturally occurring bioactive lipid mediators, were achieved using one-dimensional and two-dimensional experiments (gs-HMQC and gs-HMBC)
17alpha- and 17beta-boldenone 17-glucuronides : synthesis and complete characterization by 1H and 13C NMR
No full textBoldenone is an androgenic anabolic steroid intensively used for growth promoting purposes in animals destined for meat production and as a performance enhancer in athletics. Therefore its use is officially banned either in animals intended for consumption or in humans. Because most anabolic steroids are completely metabolized and usually no parent steroid is excreted, metabolite identification is crucial to detect the illegal use of anabolic steroids either in humans or in livestock. 17α- and 17β-boldenone 17-glucuronides were synthesized, purified and characterized in order to provide suitable standards for the identification and quantification of these metabolites
Design, synthesis, and biological evaluation of novel N6-Isopentenyladenosine Analogues
No full textIncreases in intracellular [Ca2+] occur synchronously between cells in the neuroepithelium. If neuroepithelial cells were capable of generating action potentials synchronized by gap junctions (direct current electrical coupling), the influx of Ca2+ through voltage-activated Ca2+ channels would lead to a synchronous increase in intracellular [Ca2+]. However, no action potential is generated in neuroepithelial cells, and the [Ca2+] increase is instead produced by the release of Ca2+ from intracellular Ca2+ stores. Recently, synchronous fluctuations in the membrane potential of Ca2+ stores were recorded using an organelle-specific voltage-sensitive dye. On the basis of these recordings, a capacitative [alternating current (AC)] electrical coupling model for the synchronization of voltage fluctuations of Ca2+ store potential was proposed [Yamashita M (2006) FEBS Lett580, 4979-4983; Yamashita M (2008) FEBS J275, 4022-4032]. Ca2+ efflux from the Ca2+ store and K+ counterinflux into the store cause alternating voltage changes across the store membrane, and the voltage fluctuation induces ACs. In cases where the store membrane is closely apposed to the plasma membrane and the cells are tightly packed, which is true of neuroepithelial cells, the voltage fluctuation of the store membrane is synchronized between the cells by the AC currents through the series capacitance of these membranes. This article provides a short review of the model and its relationship to the structural organization of the Ca2+ store. This is followed by a discussion of how the mode of synchronization of [Ca2+] increase may change during central nervous system development and new molecular insights into the synchronicity of [Ca2+] increase
Synthesis of Differently Protected 1-C-Methyl-Ribofuranoses Intermediates for the Preparation of Biologically Active 1'-C-Methyl-Ribonucleosides
No full textStarting from D-ribose, differently protected 1-C-methyl-D-ribofuranoses have been prepared as intermediates for the synthesis of variously modified 1'-C-methyl-ribonucleosides, a class of compounds potentially endowed with interesting biological activity
Sintesi e attività biologica di aciclonucleosidi analoghi dell’isopenteniladenosina potenzialmente dotati di attività biologica
No full textSimultaneous ultra-high performance liquid chromathograpy-electrospray ionization-quadrupole-time of flight mass spectrometry quantification of endogenous anandamide and related N-acylethanolamides in bio-matrices
No full textWe describe and validate a sensitive UHPLC-ESI-QTOF-MS method for the simultaneous quantification of seven endocannabinoids and non-endocannabinoids related N-acylethanolamides: N-arachidonoylethanolamide, N-palmitoylethanolamide, N-stearoylethanolamide, N-oleoylethanolamide, N-linoleoylethanolamide, N-α-linolenoylethanolamide and N-eicosapentaenoylethanolamide in several bio-matrices for the purpose of research and clinical application. We examined effects of different liquid-liquid and solid phase extraction on the recovery of endocannabinoids and N-acylethanolamides. Protein precipitation with cooled acetone and extraction with acetonitrile (1% v/v formic acid) using OASIS HLB cartridge gave better results. Separation was performed on a Waters Acquity UPLC HSST3 column using a 9min elution gradient coupled with high resolution mass spectrometry (QTOF/MS). The high sensitivity of the developed method allow its application on sample with low volumes or low levels of endocannabinoids and N-acylethanolamides and make the method suitable for routine measurement in human bio-matrices, such as plasma, serum (500μL), urine (1mL) and tissues (10-30mg). Its application in clinical research could contribute to unravel pathophysiological roles of these family of lipid mediators and disclose novel diagnostic and prognostic marker
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