1,721,067 research outputs found
Polyvalent nucleic acid aptamers and modulation of their activity: a focus on the thrombin binding aptamer
No full textNucleic acid-based aptamers can be selected from combinatorial libraries of synthetic oligonucleotides to bind, with affinity and specificity similar to antibodies, a wide range of biomedically relevant targets. Compared to protein therapeutics, aptamers exhibit significant advantages in terms of size, non-immunogenicity and wide synthetic accessibility. Various chemical modifications have been introduced in the natural oligonucleotide backbone of aptamers in order to increase their half-life, as well as their pharmacological properties. Very effective alternative approaches, devised in order to improve both the aptamer activity and stability, were based on the design of polyvalent aptamers, able to establish multivalent interactions with the target: thus, multiple copies of an aptamer can be assembled on the same molecular- or nanomaterial-based scaffold. In the present review, the thrombin binding aptamers (TBAs) are analyzed as a model system to study multiple-aptamer constructs aimed at improving their anticoagulation activity in terms of binding to the target and stability to enzymatic degradation. Indeed - even if the large number of chemically modified TBAs investigated in the last 20years has led to encouraging results - a significant progress has been obtained only recently with bivalent or engineered dendritic TBA aptamers, or assemblies of TBAs on nanoparticles and DNA nanostructures. Furthermore, the modulation of the aptamers activity by means of tailored drug-active reversal agents, especially in the field of anticoagulant aptamers, as well as the reversibility of the TBA activity through the use of antidotes, such as porphyrins, complementary oligonucleotides or of external stimuli, are discussed
Fluorine-containing nucleosides for 19F NMR-based structural studies of nucleic acids: synthesis and characterization of 8-CF3-2’-deoxyguanosine
No full textAiming at the preparation of 19F-labelled monomers, allowing to exploit 19F nuclei as probes for NMR studies on nucleic acids, and particularly G-quadruples structures, we focused our attention on the unprecedented 8-CF3 analog of 2’-deoxyguanosine. CF3 is an isostere of CH3. The presence of a CH3 group at C-8 favors the sin conformation of the guanine with respect to the N-glycosidic bond. Tagging this position with a CF3 group is expected to produce similar effects, and thus to stabilize/destabilize a G-quadruplex structure in a predictable manner, in addition providing a selective probe to detect 1H-19F correlations useful in the assignment of spatially close residues.
We here describe a synthetic study to obtain a 2’-deoxyguanosine derivative carrying a CF3 residue on the nucleobase. Key reaction to obtain this building block is the trifluoromethylation, carried out on 3’,5’-di-O-acetyl-2’-deoxyguanosine using CF3SO2Na and tert-butylhydroperoxide in a biphasic system, adapted from a recently published protocol to obtain CF3-derivatized aromatic heterocycles
Secosteroids of marine origin
No full textThis review describes the isolation from marine organisms of all secosteroids reported in the literature from 1972 to 2004. Secosteroids are highly oxidized metabolites with bond cleavage in the rings of the steroid tetracyclic nucleus. All secosteroids are grouped in accordance with their ring joined to side chain as 5,6-, 9,11-, 9,10- 8,9-, 8,14- and 13,17-secosteroids and the structures and the synthetic works, where available, are reported. Furthermore, this review gives details on the biological activities of the isolated secosteroids (e.g. antiproliferative, antifouling, antiinflammatory, antimicrobial, ichthyotoxic and antiviral)
8-CF3-2’-deoxyguanosine as a useful nucleoside analog for 19F NMR-based structural studies of G-quadruplex structures
No full textHerein, a synthetic study to obtain a 2’-deoxyguanosine derivative carrying the CF3 group on the nucleobase is reported. Key reaction to obtain this building block is the trifluoromethylation step, carried out on 3’,5’-di-O-acetyl-2’-deoxyguanosine using CF3SO2Na and tert-butylhydroperoxide in a biphasic system, adapted from a recently published protocol to obtain CF3-derivatized aromatic heterocycles
CH3ReO3-catalyzed oxidation of cholesta-5,7-dien-3beta-yl acetate with the urea-hydrogen peroxide adduct under various conditions. Synthesis of the natural epoxy sterol 9α,11α-epoxy-5α-cholest-7-en-3β,5,6β-triol
No full textThis article describes the oxidation of cholesta-5,7-dien-3β-yl acetate (4) with the urea-hydrogen peroxide adduct (UHP) using methyltrioxorhenium (MTO) as catalyst, under various conditions. Specifically, the effects of using different solvents (CHCl3 and ethers) and additives (EtOH and pyridine) on the course of the MTO-catalyzed oxidation of 4 were investigated. Some new steroids (6, 9, 10 and 11), obtained from this oxidation, were isolated and characterized on the basis of chemical evidence and interpretation of spectroscopic data including H-H COSY and HMBC experiments. The optimal solvent for the oxidation of 4 with MTO/UHP oxidizing system was diethyl ether. In this solvent the reaction is clean and gave as the main product 5,6β-dihydroxy-5α-cholest-7-en-3β-yl acetate (8, 65% yield), obtained with a more simple procedure and with a higher yield than that reported in literature. Sterol 8 is a key intermediate compound in the synthesis of many steroids of marine origin, biologically active, oxygenated at the B/C rings. In fact, starting from diol 8, we performed the synthesis of the natural cytotoxic epoxy sterol 9α,11α-epoxy-5α-cholest-7-en-3β,5,6β-triol (15, 21% yield) with an improvement in yield and number of steps over a synthesis of the same natural product previously reported. When the oxidation of 4 with the MTO/UHP system in diethyl ether was performed in the presence of pyridine as ligand, the unsaturated epoxide 5,6α-epoxy-5α-cholest-7-en-3β-yl acetate (10, 90% yield) was obtained after only 5 min in good yield. In fact, pyridine, besides having beneficial effect on the reaction rate, shuts down the ring opening reactions, as reported in literature
Synthetic approaches to nucleopeptides containing all four nucleobases, and nucleic acid-binding studies on a mixed-sequence nucleo-oligolysine
No full textIn this article we describe two solid-phase synthetic routes to obtain a nucleo-oligolysine α-peptide containing all four natural nucleobases. The first one is based on the oligomerization of the nucleobase-containing monomers, easily synthesized as herein described. The second strategy has the advantage of avoiding the solution synthesis of the monomeric building blocks, leading to the final nucleopeptide by direct solid-phase couplings of the suitably protected nucleobases with the free amino groups on the growing peptide chain still anchored to the resin. Both strategies are general and can be applied to the synthesis of nucleopeptides having backbones formed by any other diamino acid moiety decorated with the four nucleobases. We also report the CD and UV studies on the hybridization properties of the obtained nucleopeptide, containing all four nucleobases on alternate lysines in the sequence, towards complementary DNA and RNA strands. The nucleo-oligolysine with a mixed-base sequence did not prove to bind complementary DNA, but was able to recognize the complementary RNA forming a complex with a higher melting temperature than that of the corresponding RNA/RNA natural duplex and comparable with that of the analogous PNA/RNA system
Inhibition of HMGB1 cytokine activity by use of DNA-based strategy
No full textA review of oligonucleotidic systems, designed and realized in our laboratories, as inhibitors of HMGB1 cytokine activity were presente
Synthesis of a Cholesteryl-HEG Phosphoramidite Derivative and Its Application to Lipid-conjugates of the Anti-HIV 5'TGGGAG3' Hotoda’s Sequence
No full textA novel phosphoramidite derivative of cholesterol, with an ether-linked hexaethylene glycol (HEG) spacer arm, has been obtained through simple and reproducible solid phase modified oligonucleotide synthesis manipulations. This building block and the known phosphoramidite derivative of 3b-(2-hydroxyethoxy)cholesterol have been exploited in standard oligonucleotide synthesis protocols for the preparation of 5'- conjugates of the G-quadruplex-forming 5'TGGGAG3' oligomer, known as the Hotoda’s sequence, to produce new potential anti-HIV agents
Cationic peptides as RNA compaction agents: A study on the polyA compaction activity of a linear alpha,epsilon-oligo-l-lysine
No full textIn this work, we investigate the compaction activity of a sequential alpha,epsilon-peptide composed of l-lysines towards two RNA targets, in view of its possible pharmaceutical application in RNA-targeting and RNA delivery. The basic oligolysine, object of the present study, proved not only to be efficient in compacting the single-stranded polyA RNA, but also to strongly interact with the polyA·polyU complex, as evidenced by CD-binding and UV-melting experiments. In particular, the marked differences in the CD spectra of the RNA targets upon addition of the peptide, as well as the different UV melting behaviour for the polyA·polyU complex in the presence and absence of the peptide, sustain the hypothesis of a strong RNA compaction capacity of the alpha,epsilon-oligolysine. Finally, by using HPLC analysis, we found a good resistance of the peptide against the lytic action of human serum, an important requirement in view of in vitro/in vivo biological assays
The oxidation of Delta2, Delta2,4 and Delta4,6 steroids with RuO4
No full textIn order to find new ways for the functionalization of the A and B rings of the steroid nucleus, the reaction of 5α-androst-2-en-17β-ol 17-acetate (1), cholesta-2,4-diene (4) and cholesta-4,6-dien-3β-ol 3-acetate (7) was examined using stoichiometric amounts of ruthenium tetraoxide to yield 1,2-cis diols and/or α-hydroxy ketones. The reaction of 5α-cholest-2-en-3-ol 3-acetate (9) with ruthenium tetraoxide was also carried out and afforded, apart from an α-hydroxy ketone, also a diketone and a seco-dicarboxylic acid. The structures of all new steroids, including stereochemical details, were deduced by analysis of spectral data
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