"Scientia", rivista di scienza. Rivista internazionale di sintesi scientifica.

Vol. 1, no. 2, v. 2: "Ed. per l'Italia." Issued also in an international ed.

Elementi di fisica,

"Il Melzi ... dice che l' analisi dei Problemi di Diofanto è del Crivelli, e la traduzione è del p. Jacopo Paitoni."--Riccardi, Bibl. math. ital.

Antiproliferative and phenotype-transforming antitumor agents derived from cysteine

Selective destruction of malignant tumor cells without damaging normal cells is an important goal for cancer chemotherapy in the 21st century. Differentiating agents that transform cancer cells to either a nonproliferating or normal phenotype could potentially be tissue-specific and avoid side effects of current drugs. However, most compounds that are presently known to differentiate cancer cells are histone deacetylase inhibitors that are of low potency or suffer from low bioavailability, rapid metabolism, reversible differentiation, and nonselectivity for cancer cells over normal cells. Here we describe 36 nonpeptidic compounds derived from a simple cysteine scaffold, fused at the C-terminus to benzylamine, at the N-terminus to a small library of carboxylic acids, and at the S-terminus to 4-butanoyl hydroxamate. Six compounds were cytotoxic at nanomolar concentrations against a particularly aggressive human melanoma cell line (MM96L), four compounds showed selectivities of greater than or equal to5:1 for human melanoma over normal human cells (NFF), and four of the most potent compounds were further tested and found to be cytotoxic for six other human cancer cell lines (melanomas SK-MEL-28, DO4; prostate DU145; breast MCF-7; ovarian JAM, CI80-13S). The most active compounds typically caused hyperacetylation of histones, induced p21 expression, and reverted phenotype of surviving tumor cells to a normal morphology. Only one compound was given orally at 5 mg/kg to healthy rats to look for bioavailaiblity, and it showed reasonably high levels in plasma (C-max 6 mug/mL, T-max 15 min) for at least 4 h. Results are sufficiently promising to support further work on refining this and related classes of compounds to an orally active, more tumor-selective, antitumor drug.

Synthesis, biological activity, and preliminary pharmacokinetic evaluation of analogues of a phosphosulfomannan angiogenesis inhibitor (PI-88)

The phosphosulfomannan 1 (PI-88) is a mixture of highly sulfated oligosaccharides that is currently undergoing clinical evaluation in cancer patients. As well as it's anticancer properties, 1 displays a number of other interesting biological activities. A series of analogues of 1 were synthesized with a single carbon (pentasaccharide) backbone to facilitate structural characterization and interpretation of biological results. In a fashion similar to 1, all compounds were able to inhibit heparanase and to bind tightly to the proangiogenic growth factors FGF-1, FGF-2, and VEGF. The compounds also inhibited the infection of cells and cell-to-cell spread of herpes simplex virus (HSV-1). Preliminary pharmacokinetic data indicated that the compounds displayed different pharmacokinetic behavior compared with 1. Of particular note was the n-octyl derivative, which was cleared 3 times less rapidly than 1 and may provide increased systemic exposure.

Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase

3-Fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines (14, 16, and 18-22) are highly potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT). Molecular modeling studies with 3-fluoromethyl-7-(N-alkyl aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines, such as 16, suggested that the sulfonamide -NH-could form a hydrogen bond with the side chain of Lys57. However, SAR studies and analysis of the crystal structure of human PNMT (hPNMT) in complex with 7 indicated that the sulfonamide oxygens, and not the sulfonamide -NH-, formed favorable interactions with the enzyme. Thus, we hypothesized that replacement of the sulfonamide -NH-with a methylene group could result in compounds that would retain potency at PNMT and that would have increased lipophilicity, thus increasing the likelihood they will cross the blood brain barrier. A series of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines (23-30) were synthesized and evaluated for their PNMT inhibitory potency and affinity for the R2-adrenoceptor. A comparison of these compounds with their isosteric sulfonamides (14, 16, and 18-22) showed that the sulfones were more lipophilic but less potent than their corresponding sulfonamides. Sulfone 24 (hPNMT K-i = 1.3 mu M) is the most potent compound in this series and is quite selective for PNMT versus the R2-adrenoceptor, but 24 is less potent than the corresponding sulfonamide, 16 (hPNMT K-i = 0.13 mu M). We also report the crystal structure of hPNMT in complex with sulfonamide 15, from which a potential hydrogen bond acceptor within the hPNMT active site has been identified, the main chain carbonyl oxygen of Asn39. The interaction of this residue with the sulfonamide -NH-is likely responsible for much of the enhanced inhibitory potency of the sulfonamides versus the sulfones.

Cyclic MrIA: A stable and potent cyclic conotoxin with a novel topological fold that targets the norepinephrine transporter

Conotoxins, disulfide-rich peptides from the venom of cone snails, have created much excitement over recent years due to their potency and specificity for ion channels and their therapeutic potential. One recently identified conotoxin, MrIA, a 13-residue member of the chi-conotoxin family, inhibits the human norepinephrine transporter (NET) and has potential applications in the treatment of pain. In the current study, we show that the, beta-hairpin structure of native MrIA is retained in a synthetic cyclic version, as is biological activity at the NET. Furthermore, the cyclic version has increased resistance to trypsin digestion relative to the native peptide, an intriguing result because the cleavage site for the trypsin is not close to the cyclization site. The use of peptides as drugs is generally hampered by susceptibility to proteolysis, and so, the increase in enzymatic stability against trypsin observed in the current study may be useful in improving the therapeutic potential of MrIA. Furthermore, the structure reported here for cyclic MrIA represents a new topology among a growing number of circular disulfide-rich peptides.

Design, Synthesis, Potency and Cytoselectivity of Anticancer Agents Derived by Parallel Synthesis from alpha-Aminosuberic Acid

Chemotherapy in the last century was characterized by cytotoxic drugs that did not discriminate between cancerous and normal cell types and were consequently accompanied by toxic side effects that were often dose limiting. The ability of differentiating agents to selectively kill cancer cells or transform them to a nonproliferating or normal phenotype could lead to cell- and tissue-specific drugs without the side effects of current cancer chemotherapeutics. This may be possible for a new generation of histone deacetylase inhibitors derived from amino acids. Structure-activity relationships are now reported for 43 compounds derived from 2-aminosuberic acid that kill a range of cancer cells, 26 being potent cytotoxins against MM96L melanoma cells (IC50 20 nM-1 mu M), while 17 were between 5- and 60-fold more selective in killing MM96L melanoma cells versus normal (neonatal foreskin fibroblasts, NFF) cells. This represents a 10- to 100-fold increase in potency and up to a 10-fold higher selectivity over previously reported compounds derived from cysteine (J. Med. Chem. 2004, 47, 2984). Selectivity is also an underestimate, because the normal cells, NFF, are rarely all killed by the drugs that also induce selective blockade of the cell cycle for normal but not cancer cells. Selected compounds were tested against a panel of human cancer cell lines (melanomas, prostate, breast, ovarian, cervical, lung, and colon) and found to be both selective and potent cytotoxins (IC50 20 nM-1 mu M). Compounds in this class typically inhibit human histone deacetylases, as evidenced by hyperacetylation of histones in both normal and cancer cells, induce expression of p21, and differentiate surviving cancer cells to a nonproliferating phenotype. These compounds may be valuable leads for the development of new chemotherapeutic agents.

Edizione critica del volgarizzamento fiorentino dell'Estoire d'Eracles (Biblioteca Medicea Laurenziana, ms. Plut. LXI.45)

Edizione critica del volgarizzamento fiorentino trecentesco dell'"Estoire d'Eracles", contenuto nel ms. Plut. LXI.45 della Biblioteca Medicea Laurenziana, ancora inedito. Si tratta della traduzione in antico francese dell'opera di Guglielmo di Tiro "Historia rerum in partibus transamarinis gestarum", corredata di continuazioni svincolate all'opera latina e in stretto legame con la "Chronique d'Ernoul et de Bernard le Trésorier", che proseguono la narrazione degli eventi in Terrasanta. Il testo fiorentino riporta i fatti d'Oltremare dalla Prima Crociata a circa il 1231. La sua edizione è preceduta da una introduzione letterario-filologica, dalla descrizione del manoscritto e dall'analisi linguistica; seguono un glossario, l'indice dei nomi e dei luoghi.

Studio e sviluppo di un framework per il riconoscimento vocale nell'ambito di sistemi Hands-Free

Negli ultimi anni, l'avanzamento incredibilmente rapido della tecnologia ha portato allo sviluppo e alla diffusione di dispositivi elettronici portatili aventi dimensioni estremamente ridotte e, allo stesso tempo, capacità computazionali molto notevoli. Più nello specifico, una particolare categoria di dispositivi, attualmente in forte sviluppo, che ha già fatto la propria comparsa sul mercato mondiale è sicuramente la categoria dei dispositivi Wearable. Come suggerisce il nome, questi sono progettati per essere letteralmente indossati, pensati per fornire continuo supporto, in diversi ambiti, a chi li utilizza. Se per interagire con essi l’utente non deve ricorrere obbligatoriamente all'utilizzo delle mani, allora si parla di dispositivi Wearable Hands Free. Questi sono generalmente in grado di percepire e catture l’input dell'utente seguendo tecniche e metodologie diverse, non basate sul tatto. Una di queste è sicuramente quella che prevede di modellare l’input dell’utente stesso attraverso la sua voce, appoggiandosi alla disciplina dell’ASR (Automatic Speech Recognition), che si occupa della traduzione del linguaggio parlato in testo, mediante l’utilizzo di dispositivi computerizzati. Si giunge quindi all’obiettivo della tesi, che è quello di sviluppare un framework, utilizzabile nell’ambito dei dispositivi Wearable, che fornisca un servizio di riconoscimento vocale appoggiandosi ad uno già esistente, in modo che presenti un certo livello di efficienza e facilità di utilizzo. Più in generale, in questo documento si punta a fornire una descrizione approfondita di quelli che sono i dispositivi Wearable e Wearable Hands-Free, definendone caratteristiche, criticità e ambiti di utilizzo. Inoltre, l’intento è quello di illustrare i principi di funzionamento dell’Automatic Speech Recognition per passare poi ad analisi, progettazione e sviluppo del framework appena citato.

La ciencia de los principios y de las causas primeras en el libro primero de la Metafísica

En este trabajo se presenta la concepción aristotélica de la filosofía primera como ciencia de los principios y de las causas primeras según el libro primero de la Metafísica. Para ello, se distinguen tres momentos sucesivos que constituyen el análisis de la naturaleza y la meta que debe alcanzar esta ciencia: 1) la concepción de la sabiduría como ciencia que se ocupa de ciertos principios y causas; 2) la sabiduría como ciencia de los primeros principios y de las causas; 3) la determinación de las cuatro causas primeras como tarea de la filosofía primera. De este modo, se pretende mostrar que la Metafísica de Aristóteles es un intento para explicar las últimas cuestiones, el último porqué, indicando cuatro géneros diferentes de respuesta.

Notas críticas y exegéticas sobre el capítulo 166 (Antonio Diógenes, Las maravillas de más allá de Tule) de la "Biblioteca" de Focio.

Notas críticas y exegéticas sobre el capítulo 166 (Antonio Diógenes, Las maravillas de más allá de Tule) de la Biblioteca de Focio.

Ausonius’ Caesares

Ausonio de Burdigala (Burdeos) escribe entre los años 379-383 su obra poética titulada Caesares. Esta colección es una biografía de la vida de los emperadores en verso (hexámetro y dístico elegíaco). Caesares no está completa; la obra acaba de repente en el cuarteto dedicado a Heliogábalo. En este trabajo abordamos el género de la colección, examinamos el estilo de Ausonio en varias partes (monósticos y tetrásticos) y destacamos las fuentes (Suetonio, Tácito, Kaisergeschichte, Mario Máximo). Asimismo valoramos las diferentes opiniones que los estudiosos de Ausonio han expresado sobre la parte perdida de esta colección.

El dinero fuente de pecados en el Inferno de Dante y en la traducción de Pedro Fernández de Villegas (Burgos, 1515)

El trabajo se centra en el análisis de los pecados relacionados con el dinero en el Inferno de Dante y en la primera traducción castellana de la primera cantiga de la Commedia, obra del arcediano de Burgos Pedro Fernández de Villegas. La traducción, compuesta en coplas de arte mayor y acompañada de un enciclopédico comentario, se publicó en 1515. Particular atención se dedica a la reflexión sobre el problema del mal uso del dinero que Villegas desarrolla en la glosa de los cantos en que con más vigor se levanta la voz de Dante para denunciar la gravedad del pecado de la sed de riquezas. Se analiza la postura del traductor español ante el tema comparándola no sólo con la de Dante sino también con la de Cristoforo Landino, autor del Comento sopra la Comedia, obra exégetica que se publicó por primera vez en Florencia en 1481 y que representó el punto de referencia privilegiado de Villegas.