Leonardo Scaglioni

University of Milan, Milano, Lombardy, Italy

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Publications (51)106.25 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: G-quadruplexes have become important drug-design targets for the treatment of various human disorders such as cancer, diabetes and cardiovascular diseases. Recently, G-quadruplex structures have been visualized in the DNA of human cells and appeared to be dynamically sensitive to the cell cycle and stabilized by small molecule ligands. A small library of isoxazolo naphthoquinones (1a-h), which exhibited a strong antiproliferative activity on different cancer cell lines, was studied as potential ligands of G-quadruplex DNA. The DNA binding properties of a series of the selected compounds have been analyzed by fluorescence assays. NMR/modeling studies were performed to describe the complexes between G-quadruplex DNA sequences and two selected compounds 1a and 1b. 1a and 1b in the presence of G-quadruplexes, d(T2AG3T)4, d(TAG3T2A)4 and d(T2G3T2)4, showed good ability of intercalation and the formation of complexes with 2:1 stoichiometry. The external G-tetrads are directly involved in the interaction with the ligand, without alterations in the structure of the G-quadruplex core. The role of the adenine moieties over the G-tetrads in the stabilization of the complexes was discussed. 1a showed an important interaction with the sequence Pu22 belonging to the promoter of oncogenes c-myc. The results obtained suggested that the strong antiproliferative activity of isoxazolo naphthoquinones is not due to the Hsp90 inhibition, but mainly to the interaction at the level of telomeres and /or at the level of gene promoter. These findings can be used as a basis for the rational drug design of new anticancer agents. Copyright © 2014. Published by Elsevier B.V.
    Biochimica et Biophysica Acta (BBA) - General Subjects 12/2014; · 3.83 Impact Factor
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    ABSTRACT: Neisseria meningitidis is a Gram-negative encapsulated bacterium that is a major cause of meningitis and meningococcal septicemia. Serogroup A (MenA) is most often implicated in epidemic disease in the sub-Saharan region of Africa. However, the development and manufacture of an efficient polysaccharide-based vaccine against MenA is greatly hampered by the poor immunogenicity and instability of its capsular polisaccharide (CPS). We report the synthesis of stable MenA CPS carba analogues, and an easy strategy to access multivalent carbohydrate structures based on iron oxide nanoparticles (SPIONs). A 1-O-tetraethyleneglycol-phosphate linker attached to the carba analogues was used to attach them to the metal surface. We evaluated the positive multivalent effect of the antigen presentation by MRI analysis, which showed that the conjugated monomer and dimer analogues could be recognised by the polyclonal anti-MenA antibody.
    Annalen der Chemie und Pharmacie 08/2014; · 3.15 Impact Factor
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    ABSTRACT: The antitumor anthracycline nemorubicin is converted by human liver microsomes to a major metabolite, PNU-159682 (PNU), which was found to be much more potent than its parent drug toward cultured tumor cells and in vivo tumor models. The mechanism of action of nemorubicin appears different from other anthracyclines and until now is the object of studies. In fact PNU is deemed to play a dominant, but still unclear, role in the in vivo antitumor activity of nemorubicin. The interaction of PNU with the oligonucleotides d(CGTACG)(2), d(CGATCG)(2) and d(CGCGCG)(2) was studied with a combined use of (1)H and (31)P NMR spectroscopy and by ESI-mass experiments. The NMR studies allowed to establish that the intercalation between the base pairs of the duplex leads to very stable complexes and at the same time to exclude the formation of covalent bonds. Melting experiments monitored by NMR, allowed to observe with high accuracy the behaviour of the imine protons with temperature, and the results showed that the re-annealing occurs after melting. The formation of reversible complexes was confirmed by HPLC-tandem mass spectra, also combined with endonuclease P1digestion. The MS/MS spectra showed the loss of neutral PNU before breaking the double helix, a behaviour typical of intercalators. After digestion with the enzyme, the spectra did not show any compound with PNU bound to the bases. The evidence of a reversible process appears from both proton and phosphorus NOESY spectra of PNU bound to d(CGTACG)(2) and to d(CGATCG)(2). The dissociation rate constants (k(off)) of the slow step of the intercalation process, measured by (31)P NMR NOE-exchange experiments, showed that the kinetics of the process is slower for PNU than for doxorubicin and nemorubicin, leading to a 10- to 20-fold increase of the residence time of PNU into the intercalation sites, with respect to doxorubicin. A relevant number of NOE interactions allowed to derive a model of the complexes in solution from restrained MD calculations. The conformation of PNU bound to the oligonucleotides was also derived from the coupling constant values.
    Bioorganic & medicinal chemistry 11/2012; · 2.82 Impact Factor
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    ABSTRACT: 5-Carboxymethylene hydantoins have been synthesized in high yield and under very mild conditions (20 °C, dichloromethane) through a highly (often totally) regio- and diastereoselective domino process involving readily accessible carbodiimides and acetylenedicarboxylic acid monoesters. Such compounds could be considered very intriguing intermediates for the preparation of spirohydantoins and other hydantoin derivatives. For instance, they react smoothly with either acyclic and cyclic nitrones to form spiroisoxazolidinohydantoins in high yield and with total control of the regio- and diastereoselectivity. Starting from an enantiomerically pure chiral pyrroline nitrone, the reaction was also enantiospecific. Both processes have been studied in detail and the diastereoselectivities seen have been rationalized upon examination of the alternative transition states and by density functional theory calculations of the cycloaddition step.
    RSC Advances 11/2011; 1(7):1250-1264. · 3.71 Impact Factor
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    ABSTRACT: Two novel metabolites have been isolated from the aerial parts of Stachys ehrenberiigii. Their structures and stereochemistry were elucidated using a combination of 13C and 1H homo and heteronuclear 2D NMR experiments and mass analysis. The development of an enantioselective synthesis of 3-(2′-acetoxy-4-phenylbut-3′-enoylamino)propionic acid allowed to confirm the structure and assign the (R) absolute configuration at C-2′ of the natural product.
    Tetrahedron Letters 11/2011; 52(45):5972-5975. · 2.39 Impact Factor
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    ABSTRACT: An understanding of the integrated relationships among the principal cellular functions that govern the bioenergetic reactions of an organism is necessary to determine how cells remain viable and optimise their fitness in the environment. Urease is a complex enzyme that catalyzes the hydrolysis of urea to ammonia and carbonic acid. While the induction of urease activity by several microorganisms has been predominantly considered a stress-response that is initiated to generate a nitrogen source in response to a low environmental pH, here we demonstrate a new role of urease in the optimisation of cellular bioenergetics. We show that urea hydrolysis increases the catabolic efficiency of Streptococcus thermophilus, a lactic acid bacterium that is widely used in the industrial manufacture of dairy products. By modulating the intracellular pH and thereby increasing the activity of β-galactosidase, glycolytic enzymes and lactate dehydrogenase, urease increases the overall change in enthalpy generated by the bioenergetic reactions. A cooperative altruistic behaviour of urease-positive microorganisms on the urease-negative microorganisms within the same environment was also observed. The physiological role of a single enzymatic activity demonstrates a novel and unexpected view of the non-transcriptional regulatory mechanisms that govern the bioenergetics of a bacterial cell, highlighting a new role for cytosol-alkalizing biochemical pathways in acidogenic microorganisms.
    PLoS ONE 11/2010; 5(11):e15520. · 3.53 Impact Factor
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    ABSTRACT: A short and efficient synthesis of the novel cytotoxic natural product berkeleyamide A, isolated from a deep-water Penicillium rubrum, has been accomplished. L-Leucinol was used as the only chiral starting material. A diastereoselective aldol condensation is the key step in the synthesis.
    European Journal of Organic Chemistry 09/2010; 2010(32):6217 - 6223. · 3.15 Impact Factor
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 07/2010; 31(30).
  • ChemInform 05/2010; 32(22).
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    ABSTRACT: Among the disaccharide derivatives of the antitumor anthracycline doxorubicin, sabarubicin (Men10755) is more active and less cytotoxic than doxorubicin. It showed a strong in vivo antitumor activity in all preclinical models examined, in conjunction with a better tolerability, and is now in phase II clinical trials. The interaction of sabarubicin and Men10749 (a similar disaccharide with a different configuration at C-4' of the proximal sugar) with the hexanucleotides d(CGTACG)(2) and d(CGATCG)(2) was studied by a combined use of 2D-(1)H and (31)P NMR techniques. Both (1)H and (31)P chemical shifts of imino protons and phosphates allowed to established the intercalation sites between the CG base pairs, as it occurs for other anthracyclines of the series. The dissociation rate constants (k(off)) of the slow step of the intercalation process were measured for Men10755 and Men10749, by NMR NOE-exchange experiments. The increase of k(off) , with respect of doxorubicin, showed that the intercalation process is significantly faster for both drugs, leading to an average residence time for sabarubicin into d(CGTACG)(2) sixfold shorter than for doxorubicin. This could give account of both higher cytoplasmic/nuclear ratio and lower cellular uptake of sabarubicin in comparison with doxorubicin and accordingly of the lower cytotoxicity of these disaccharide analogues. A relevant number of NOE interactions allowed the structure of the complexes in solution to be derived through restrained MD calculations. NMR-DOSY experiments were performed with several drug/oligonucleotide mixtures in order to determine the structure and the dimension of the aggregates.
    Bioorganic & medicinal chemistry 02/2010; 18(4):1497-506. · 2.82 Impact Factor
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    ABSTRACT: Acid treatment of indole-2-carboxylic acid β- and γ-oxoamides causes Friedel–Crafts intramolecular cyclization to β-carbolinones and dihydro-2H-azepino[3,4-b]indol-1-ones, in contrast to secondary δ-,ɛ-, and ζ-oxoamides, which cyclize to the novel heterocyclic rings pyrrolizino[2,1-b]indole, indolizino[2,1-b]indole, and 9a,11-diaza-indeno[1,2-a]azulene, via an intermediate N-acyliminium ion. Tertiary amides lead only the Friedel–Crafts ring closure, thus allowing the synthesis of larger fused rings
    Tetrahedron 04/2009; 65(17):3465-3472. · 2.82 Impact Factor
  • Anna Arnoldi, Lucio Merlini, Leonardo Scaglioni
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    ABSTRACT: The synthesis of some 8-hydroxy-2,3-benzo-l-oxaoctems is reported. The imide 7, a potential β-lactamase inhibitor, was also synthesized.
    Journal of Heterocyclic Chemistry 04/2009; 24(1):75 - 77. · 1.22 Impact Factor
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    ABSTRACT: Perilla frutescens is a food plant widely used in Asian cuisine. This plant was investigated for its interesting taste and somatosensory properties. Perillaldehyde and perillaketone are among the components of the aromatic extracts from P. Frutescens. These compounds were shown here to activate the cloned TRPA1 channel when expressed in an heterologous cell system and are therefore suggested to be responsible for the chemesthetic properties of this plant.
    Bioorganic & medicinal chemistry 02/2009; 17(4):1636-9. · 2.82 Impact Factor
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    ABSTRACT: A water soluble derivative (2) of topopyrones was selected for NMR studies directed to elucidate the mode of binding with specific oligonucleotides. Topopyrone 2 can intercalate into the CG base pairs, but the residence time into the double helix is very short and a fast chemical exchange averaging occurs at room temperature between the free and bound species. The equilibria involved become slow below room temperature, thus allowing to measure a mean lifetime of the complex of ca. 7 ms at 15 degrees C. Structural models of the complex with d(CGTACG)(2) were developed on the basis of DOSY, 2D NOESY and (31)P NMR experiments. Topopyrone 2 presents a strong tendency to self-associate. In the presence of oligonucleotide a certain number of ligand molecules are found to externally stack to the double-helix, in addition to a small fraction of the same ligand intercalated. The external binding to the ionic surface of the phosphoribose chains may thus represents the first step of the intercalation process.
    Bioorganic & medicinal chemistry 01/2009; 17(2):484-91. · 2.82 Impact Factor
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    ABSTRACT: Nature is a rich source of taste-active compounds, in particular of plant origin, many of which have unusual tastes. Many of these are found in traditional food, where spontaneous plants are used as ingredients. Some taste-active compounds were identified in the bulbs of Muscari comosum, a spontaneous plant belonging to the family of the Liliaceae, very common in the Mediterranean area, and used in traditional gastronomy (called 'lampascioni' in South Italy). The bulbs were extracted with a series of solvents of different polarity. The different fractions were submitted to a preliminary sensory evaluation, and the most interesting ones, characterized by a strong bitter taste and some chemestetic properties, were submitted to further purification and structural analysis. From the ethereal extract, several 3-benzyl-4-chromanones and one stilbene derivative were isolated. Pure compounds were examined for their taste activity by means of sensory evaluation, and proved to be responsible for the characteristic taste of this food. Some of these compounds have been synthesized de novo to confirm their structure.
    Chemistry & Biodiversity 07/2008; 5(6):1184-94. · 1.81 Impact Factor
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    ABSTRACT: A series of structurally simple analogues of natural topopyrone C were synthesized and tested for cytotoxic and topoisomerase I inhibitory activities. The removal of the hydroxyl groups at the 5 and 9 positions resulted in an increased cytotoxic potency and ability to stabilize topoisomerase-mediated cleavage. In addition, the results suggest that some structural features, such as the pyrone ring and a polar group in position 11, are fundamental for topoisomerase I inhibitory effect. These structural requirements are also consistent with the cytotoxic activity.
    Bioorganic & medicinal chemistry letters 03/2008; 18(4):1484-9. · 2.65 Impact Factor
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    ABSTRACT: The photochemical reactivity, in methanol at λ = 254 nm, of two 6α-hydroxy-7-keto neoclerodane, isoeriocephalin (1) and teucrolivin B (2) was evaluated. From the first compound, two new products were obtained: the 6β-hydroxy epimer (3) and the ɛ-lactone (4). The second one yielded exclusively the new spiro γ-lactone (5). The formation of these new products can be explained by the well-known radical mechanism Norrish type I.
    Journal of Photochemistry and Photobiology A Chemistry 05/2006; · 2.29 Impact Factor
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    ABSTRACT: Seeds of the water plant Trapa natans L. (water chestnut) can germinate in strict anoxia. The seedlings show seminal roots growing upwards while shoot buds remain quiescent until O2 becomes available. Trapa seedlings are highly tolerant to anoxia. The rate of ethanol fermentation was 21.2 μmol (g FW)−1 h−1, while production of lactate was negligible and lower than that of succinate. The seminal root of Trapa compares better to the rice coleoptile rather than to the rice root, both functionally and as to the metabolic response to anoxia. The anaerobic germination of Nuphar luteum L. and Scirpus mucronatus L. was also characterized by a limited developmental program.
    Physiologia Plantarum 04/2006; 86(1):168 - 172. · 3.26 Impact Factor
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    ABSTRACT: A series of 1-(3-pyridyl)-1-substituted-but-3-yn-1-ols and some related compounds were synthesised and tested for antifungal activity against eight phytopathogenic fungi of different taxonomic classes. High activity was shown in particular against Sphaerotheca fuliginea on Cucumis sativus. The compounds containing aromatic substituents gave the best results, not only in protectant but also in systemic and eradicant tests. The quantitative structure-activity relationship suggests that steric effects play an important role in determining fungicidal activity.
    Pesticide Science 04/2006; 14(6):576 - 586.
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    ABSTRACT: The conformational properties of the homo oligomers of increasing chain length Boc-(Asn)(n)-NHMe (n = 2, 4, 5), (GlcNAc-beta-Asn)(n)-NHMe (n = 2, 4, 5, 8) and Boc-[GlcNAc(Ac)(3)-beta-Asn](n)-NHMe (n = 2, 4, 5) were studied by using NOE experiments and molecular dynamic calculations (MD). Sequential NOEs and medium range NOEs, including (i,i+2) interactions, were detected by ROESY experiments and quantified. The calculated inter-proton distances are longer than those characteristic of beta-turn secondary structures. Owing to the large conformational motions expected for linear peptides, MD simulations were performed without NMR constraints, with explicit water and by applying different treatments of the electrostatic interactions. In agreement with the NOE results, the simulations showed, for all peptides, the presence of both folded and unfolded structures. The existence of significant populations of beta-turn structures can be excluded for all the examined compounds, but two families of structures were more often recognized. The first one with sinusoidal or S-shaped forms, and another family of large turns together with some more extended conformations. Only the glycosylated pentapeptide shows in vacuo a large amount of structures with helical shaped form. The results achieved in water and in DMSO are compared and discussed, together with the effect of the glycosylation.
    Journal of Peptide Science 08/2005; 11(8):452-62. · 1.86 Impact Factor

Publication Stats

202 Citations
106.25 Total Impact Points


  • 1993–2014
    • University of Milan
      • Department of AgriFood Molecular Sciences
      Milano, Lombardy, Italy
  • 2006
    • Università degli Studi di Palermo
      • Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche
      Palermo, Sicily, Italy
  • 2004
    • National Research Council
      Roma, Latium, Italy