1,721,162 research outputs found
Tetra-end-linked G-rich oligonucleotides: design, synthesis and application in aptamers technology
No full textThe word aptamer, which stems from the Latin "aptus" (to fit) and the Greek "meros" (region or part), indicates DNA or RNA oligonucleotides (ONs) selected for their ability to bind with high affinity and specificity to a given target, and as such suitable for therapeutics or diagnostics applications. The ability of DNA and RNA aptamers to self-assemble into ordered structural motifs (e.g. hairpins, pseudoknots, G-quadruplexes) according to their ON sequence, accounts for their striking binding affinity and specificity. However, the development of aptamer technology is affected by two main drawbacks: i) the requirement of synthesizing 25 to 90 bases-long ONs (to allow the proper folding) and ii) the necessity of protecting the ON aptamers from the action of ubiquitous nucleases by post-selection chemical modifications. In 2004 we presented a new class of G-quadruplex forming ONs obtained by linking four short G-rich ON strands to the four arms of a tetra branched linker (TEL linker). This strategy allows the obtainment of parallel-stranded G-quadruplexes endowed with enhanced thermodynamic and kinetics parameters, as well as with improved resistance to nucleases starting from ON strands as short as 4 nucleobases. In this talk, I will comment on the optimization of the TEL strategy and on its exploitation for the development of new aptamers capable of protecting human CEM cells from HIV infection at submicromolar concentrations
Ruthenium-catalyzed oxidative cyclization of 1,7-dienes. A novel diasteroselective synthesis of 2,7-disubstituted trans-oxepane diols
No full textThe ruthenium-catalyzed oxidation of some representative 1,7-dienes has been investigated. Tetrasubstituted 1,7-dienes are transformed into the corresponding trans-2,7-bis-hydroxyalkyl-oxepanes through an oxidative cyclization process. The process proceeds with an excellent stereoselectivity level
RuO4-catalyzed oxidative polycyclization of the Cs-symmetric isoprenoid polyene digeranyl. An unexpected stereochemical outcome.
No full textThe RuO4-catalyzed oxidative polycyclization of digeranyl, a Cs-symmetric tetraene possessing a repetitive 1,5-diene structural motif, has been studied. The required substrate has been synthesized by Ti(III)-mediated tail-to-tail homocoupling of geranyl bromide. The process afforded two hitherto unknown isomeric tris-tetrahydrofuran products possessing unexpected all-threo cis–trans–cis and cis–trans–trans relative configuration. The new stereochemical outcome is explained based on previously formulated chelation or steric control models on the basis of structural differences between digeranyl and previously studied isoprenoid polyenes farnesyl acetate, geranylgeranyl acetate and squalene
AN EFFICIENT SYNTHETIC STRATEGY FOR THE FUNCTIONALIZATION OF 9-RIBOSYL PURINE (NEBULARINE)
Full text linkIn the last decades, many research groups have focused their attention to the preparation of new modified nucleosides and nucleotides to expand the pool of molecules with potential antineoplastic, antihypertensive and antiviral activities. In this context, efforts have been directed to the synthesis of sugar and/or base-modified nucleosides. Many nucleobase analogues exist and several nucleoside analogues have been employed against cancer and viral diseases. In addition, base modified nucleosides often show fluorescent properties, and can be used as fluorescent probes for the analysis of DNA and RNA structures as well as for analysing the interaction of DNA and RNA with binding proteins. Purine bases and nucleosides bearing a C or N-substituent at C2 and C6 positions represent an important class of compounds possessing a broad spectrum of biological effects including cytostatic, antiviral, antibacterial as well as receptor modulation activity. The reactivity imparted to purines and related nucleosides by halogenation at C6 and C2 positions has opened the way to the construction of new libraries of C6 and C2 modified nucleosides generally through direct aromatic nucleophilic substitution (SNAr), or metal-mediated cross-coupling processes. We have recently reported on the reactivity of 9-ribosyl purine (nebularine) N1-oxide demonstrating that its C6(C2)-N1-O- nitrone moiety can react with dipolarophiles and with Grignard reagents leading to their addition on the C6 or C2 carbons of the purine base. In particular, we observed that the sugar-protected nebularine N1-oxide can regioselectively react with Grignard reagents at the more electrophilic C6 position leading to an adduct, which re-aromatized by treatment with Ac2O/pyridine, furnishing the C6-substituted purine nucleoside in high yields. We have also shown that a second alkyl/aryl substituent can be introduced at C2 by a similar strategy, that is, by the addition of a Grignard reagent to the C6- substituted nebularine N1-oxides through the opening/reclosing of the pyrimidine ring induced by the Grignard reagent itself. Through this approach, we have synthesized new collections of 2,6-dialkyl(aryl)purine nucleosides. A slightly modified synthetic procedure allowed us also to insert pyridinyl residues at the C6 purine position to obtain the few explored C6-pyridinyl nucleosides. The last are appealing nucleoside analogues because the presence of a nitrogen atom in the C6 residue can potentially alter the hydrogen-bonding capabilities of the nucleoside as well as promote its coordination to biologically important metals, such as platinum and ruthenium. We have discovered that they can be easily accessed after bromine-magnesium exchange between bromopyridines and iPrMgCl
Synthesis of a New N1-Pentyl Analogue of Cyclic Inosine Diphosphate Ribose (cIDPR) as a Stable Potential Mimic of Cyclic ADP Ribose (cADPR)
No full textThe new analogue 7 of cADPR (1), a cyclic nucleotide bis(phosphate) involved in Ca2+ metabolism, was prepared starting from 2',3'-isopropylideneinosine (8) which was alkylated at N-1, leading to the intermediate 11. Bis(phosphorylation) of 11 through two alternative procedures, followed by phosphate deprotection steps, afforded derivatives 15 and 16, the substrates for the intramolecular pyrophosphate bond formation. Both 15 and 16 were converted into derivative 17 in high yields, which was finally deprotected to give the target compound 7
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