free-radicals-chemical-biology-from-chemical-behavior-to-biomarker

Free Radicals in Chemical Biology: from Chemical Behavior to Biomarker Development

The involvement of free radicals in life sciences has constantly increased with time and has been connected to several physiological and pathological ...

Consiglio Nazionale delle Ricerche

A series of new beta-peptido sulfonamides, related to the chemotactic tripeptide fMLF-OMe, has been synthesized. The examined 1a,b-7a,b models contain the achiral -HN-(CH(2))(2)-SO(2)- taurine (Tau) residue or the chiral -HN-CH(nBu)-CH(2)-SO(2)- and -HN-CH(iBu)-CH(2)-SO(2)- residues, corresponding to the beta-aminocarboxylic acid counterparts beta(3)-HNle and beta(3)-HLeu, respectively. The biological activity of the new analogues has been determined on human neutrophils and compared with that of the reference ligand as well as that of the previously studied related models. The results are analyzed in terms of structure-activity relationships. The conformational preferences of the new tripeptides 1b and 2b, containing a central chiral beta-amino-ethanesulfonic acid residue, have also been discussed.

Beta-peptido sulfonamides: for-Met-Leu-Phe-OMe analogues containing taurine and chiral beta-amino-ethanesulfonic acid residues.

Une s&eacute;rie de nouveaux b&ecirc;ta-peptido sulfonamides, associ&eacute;s &agrave; la fMLF chimiotactique tripeptide-OMe, a &eacute;t&eacute; synth&eacute;tis&eacute;e. L&#39;examin&eacute; 1 a, b-7 a, b mod&egrave;les contiennent le r&eacute;sidu de ben jeddou - HN-(CH(2))(2)-SO(2) - taurine (Tau) ou le chiral - HN-CH(nBu)-CH(2)-SO(2) - et - HN-CH(iBu)-CH(2)-SO(2) - r&eacute;sidus, correspondant &agrave; la b&ecirc;ta-aminocarboxyliques homologues acide b&ecirc;ta 3-nccntbre et b&ecirc;ta 3-HLeu, respectivement. L&#39;activit&eacute; biologique des nouveaux analogues a &eacute;t&eacute; d&eacute;termin&eacute;e sur les neutrophiles humains et compar&eacute;e avec que du ligand de r&eacute;f&eacute;rence ainsi que celle de l&#39;&eacute;tudi&eacute;s pr&eacute;c&eacute;demment associ&eacute;s mod&egrave;les. Les r&eacute;sultats sont analys&eacute;s en termes de relations structure-activit&eacute;. Les pr&eacute;f&eacute;rences conformationnelles du nouveau tripeptides 1 b et 2 b, contenant un centre chiral b&ecirc;ta-amino-ethanesulfonic r&eacute;sidu acid, ont &eacute;galement &eacute;t&eacute; discut&eacute;es.

Sulfonamides peptido-b&ecirc;ta : pour-Met-Leu-Phe-OMe analogues contenant des r&eacute;sidus d&#39;acide b&ecirc;ta-amino-ethanesulfonic taurine et chiraux.

Una serie di nuove beta-peptido sulfamidici, imparentato con il tripeptide chemiotattica fMLF-OMe, &egrave; stata sintetizzata. La 1a esaminati, b-7a, b modelli contengono l&#39;achirali - HN-(CH(2))(2)-SO(2) - taurina (Tau) residuo o chirale - HN-CH(nBu)-CH(2)-SO(2) - e - HN-CH(iBu)-CH(2)-SO(2) - residui, corrispondente per la beta-amminocarbossilici controparti acido beta 3-HNle e beta 3-HLeu, rispettivamente. L&#39;attivit&agrave; biologica del nuova analoghi &egrave; stato determinato su neutrofili umani e confrontato con quello del ligando di riferimento cos&igrave; come quella di precedentemente studiato relativi modelli. I risultati vengono analizzati in termini di relazioni struttura-attivit&agrave;. Le preferenze conformazionali della nuova tripeptidi 1b e 2b, contenente un chirale centrale beta-ammino-ethanesulfonic residuo acido, inoltre sono stati discussi.

Beta-peptido sulfamidici: per-Met-Leu-Phe-OMe analoghi contenenti residui di acidi beta-ammino-ethanesulfonic taurina e chirali.

Una serie de nuevas sulfamidas peptido beta, relacionadas el trip&eacute;ptido quimiot&aacute;ctico fMLF-OMe, ha sido sintetizada. El examinado 1a, b-7a, b modelos contienen el residuo de (Tau) taurino achiral - HN-(CH(2))(2)-SO(2) - o quirales - HN-CH(nBu)-CH(2)-SO(2) - y - HN-CH(iBu)-CH(2)-SO(2) - residuos, correspondientes a la beta-aminocarbox&iacute;licos contrapartes &aacute;cido beta 3-HNle y beta 3-HLeu, respectivamente. La actividad biol&oacute;gica de los an&aacute;logos de nuevos ha sido determinada en neutr&oacute;filos humanos y Comparado con que del ligando de referencia como la de los estudiados anteriormente relacionados con modelos. Se analizan los resultados en t&eacute;rminos de relaciones estructura-actividad. Las preferencias conformacionales del nuevo trip&eacute;ptidos 1b y 2b, que contiene un centro quiral beta-amino-(n-2-hidroxietilpiperazina-N&#39;-2-&aacute;cido residuo &aacute;cido, tambi&eacute;n han sido discutidas.

Sulfonamidas peptido beta: para-Met-Leu-Phe-OMe an&aacute;logos que contengan residuos &aacute;cidos de la beta-amino-(n-2-hidroxietilpiperazina-N&#39;-2-&aacute;cido quirales y taurinos.

In order to gain information on the activity shown by alpha-peptide/beta-sulfonamidopeptide hybrid analogs of the potent chemotactic agent fMLF-OMe, a structure-activity study is reported on N-Boc- and N-formyl tripeptide models containing an aminoalkanesulfonic acid as central residue. Directed migration (chemotaxis), superoxide anion production, and lysozyme release have been measured. The biochemical functions and the conformational properties of the new compounds are discussed and related to previously studied models containing beta-residues.

Alpha-peptide/beta-sulfonamidopeptide hybrids: analogs of the chemotactic agent for-Met-Leu-Phe-OMe.

Afin d&#39;obtenir des informations sur l&#39;activit&eacute; illustr&eacute;e par des analogues d&#39;alpha-peptide/b&ecirc;ta-sulfonamidopeptide hybride de l&#39;agent chimiotactique puissante fMLF-OMe, une &eacute;tude de la structure et l&#39;activit&eacute; est signal&eacute;e sur les mod&egrave;les de tripeptide N-Boc - et N-formyl contenant un acide aminoalkanesulfonic comme r&eacute;sidu central. Ont a mesur&eacute; les migrations dirig&eacute;e (chimiotactisme), production d&#39;anions superoxyde et lysozyme release. Les fonctions biochimiques et les propri&eacute;t&eacute;s conformationnelles des nouveaux compos&eacute;s sont discut&eacute;es et associ&eacute;es &agrave; des mod&egrave;les &eacute;tudi&eacute;s pr&eacute;c&eacute;demment contenant des r&eacute;sidus de b&ecirc;ta.

Alpha-peptide/b&ecirc;ta-sulfonamidopeptide hybrides : analogues de l&#39;agent chimiotactique pour-Met-Leu-Phe-OMe.

Al fine di ottenere informazioni sull&#39;attivit&agrave; mostrata da analoghi alfa-peptide/beta-sulfonamidopeptide ibrida del potente agente chemiotattico fMLF-OMe, uno studio di struttura-attivit&agrave; &egrave; riportato sui modelli di tripeptide Boc-N - e N-formil contenente un acido aminoalkanesulfonic come residuo centrale. Regia migrazione (chemiotassi), produzione di anione superossido e lisozima release sono stati misurati. Le funzioni biochimiche e le propriet&agrave; conformazionali di nuovi composti sono discusse e relative ai modelli precedentemente studiati contenenti residui di beta.

Alfa-peptide/beta-sulfonamidopeptide ibridi: analoghi dell&#39;agente chemiotattico per-Met-Leu-Phe-OMe.

Para obtener informaci&oacute;n sobre la actividad mostrada por an&aacute;logos de alfa-p&eacute;ptido/beta-sulfonamidopeptide h&iacute;brido de la potente agente quimiot&aacute;ctico fMLF-OMe, un estudio de la estructura y actividad se divulga en modelos de trip&eacute;ptido N-Boc - y N-formil que contiene un &aacute;cido aminoalkanesulfonic como residuo central. Se han medido migraci&oacute;n dirigida (quimiotaxis), la producci&oacute;n de ani&oacute;n super&oacute;xido y la liberaci&oacute;n de la lisozima. Las funciones bioqu&iacute;micas y las propiedades conformacionales de los nuevos compuestos se discute y se relaciona con modelos previamente estudiados que contengan residuos de beta.

Alfa-p&eacute;ptido/beta-sulfonamidopeptide h&iacute;bridos: an&aacute;logos de la agente quimiot&aacute;ctico para-Met-Leu-Phe-OMe.

The aim of this pilot study was to analyze the effects of glucosamine (GlcN) and its N-acetyl-phenylalanine derivative (NAPA) in Vitamin A model of osteoarthritis (OA) in rabbits. GlcN or NAPA or saline solution was intra-articularly administered in rabbit OA knees. Histological analysis revealed that treatment with GlcN or NAPA was associated with more homogeneous chondrocyte cellularity, absence of fissures and fragmentation and more intense staining of the matrix with Alcian Blue compared to the articular surfaces of the knees treated with saline solution. Comparative in vitro study performed on rabbit primary chondrocytes revealed that GlcN and NAPA were also able to counteract the IL-1beta-upregulation of genes coding for metalloproteases and inflammatory cytokines. Our preliminary in vivo and in vitro studies suggest that GlcN and NAPA could play a disease-modifying protective role in OA by an anti-catabolic effect and an anti-inflammatory activity on chondrocytes.

Effects of intra-articular administration of glucosamine and a peptidyl-glucosamine derivative in a rabbit model of experimental osteoarthritis: a pilot study.

Le but de cette &eacute;tude pilote a &eacute;t&eacute; d&#39;analyser les effets de la glucosamine (GlcN) et son d&eacute;riv&eacute; N-ac&eacute;tyl-ph&eacute;nylalanine (NAPA) dans le mod&egrave;le de la vitamine A de l&#39;arthrose (OA) chez le lapin. GlcN ou NAPA ou une solution saline a &eacute;t&eacute; administr&eacute;e quatre chez lapin genoux OA. L&#39;analyse histologique a r&eacute;v&eacute;l&eacute; que le traitement avec GlcN ou NAPA a &eacute;t&eacute; associ&eacute; &agrave; la cellularit&eacute; plus homog&egrave;ne de chondrocytes, absence de fissures et de la fragmentation et une coloration plus intense de la matrice au bleu Alcian par rapport aux surfaces articulaires des genoux trait&eacute;s avec une solution saline. Une &eacute;tude in vitro comparative effectu&eacute;e sur lapin chondrocytes primaires r&eacute;v&egrave;le que GlcN et NAPA sont &eacute;galement en mesure de contrecarrer le IL-1beta-stimulation de l&#39;expression des g&egrave;nes codant pour les m&eacute;talloprot&eacute;ases et des cytokines inflammatoires. Nos &eacute;tudes in vivo et in vitro pr&eacute;liminaires sugg&egrave;rent que GlcN et NAPA pourraient jouer un r&ocirc;le de protecteur de modificateurs de la maladie dans l&#39;arthrose par un effet anti-catabolique et une activit&eacute; anti-inflammatoire sur les chondrocytes.

Effets de l&#39;administration intra-articulaire de glucosamine et d&#39;un d&eacute;riv&eacute; de la peptidyl-glucosamine dans un mod&egrave;le de lapin d&#39;arthrose exp&eacute;rimentale : une &eacute;tude pilote.

Lo scopo di questo studio pilota &egrave; stato di analizzare gli effetti della glucosammina (GlcN) e suoi derivati N-acetil-fenilalanina (NAPA) in vitamina A modello di osteoartrite (OA) nei conigli. GlcN o NAPA o soluzione salina intrarticolare &egrave; stato somministrato in coniglio ginocchia OA. L&#39;analisi istologica ha rivelato che il trattamento con GlcN o NAPA &egrave; stato associato con cellularit&agrave; condrociti pi&ugrave; omogenea, assenza di fessure e di frammentazione e una colorazione pi&ugrave; intensa della matrice con Alcian Blue rispetto alle superfici articolari delle ginocchia trattate con soluzione salina. Studio comparativo in vitro eseguiti su coniglio condrociti primari ha rivelato che GlcN e NAPA erano anche in grado di contrastare IL-1beta-sovraregolazione di geni codificanti per metalloproteases e citochine infiammatorie. I nostri studi preliminari in vivo e in vitro suggeriscono che GlcN e NAPA potrebbe svolgere un ruolo protettivo modificanti la malattia in OA da un effetto anti-catabolico e un&#39;attivit&agrave; antinfiammatoria su condrociti.

Effetti della somministrazione intraarticolare di glucosamina e un derivato di peptidilica-Glucosamina in un modello di coniglio di osteoartrite sperimentale: uno studio pilota.

El objetivo de este estudio piloto fue analizar los efectos de la glucosamina (GlcN) y su derivado N-acetil-fenilalanina (NAPA) en el modelo de la vitamina A de la osteoartritis (OA) en conejos. GlcN o NAPA o soluci&oacute;n salina se administr&oacute; intra-articularly en conejo rodillas OA. El an&aacute;lisis histol&oacute;gico revel&oacute; que el tratamiento con GlcN o NAPA se asoci&oacute; con celularidad de condrocitos m&aacute;s homog&eacute;nea, ausencia de fisuras y la fragmentaci&oacute;n y la coloraci&oacute;n m&aacute;s intensa de la matriz con azul Alciano en comparaci&oacute;n con las superficies articulares de las rodillas tratadas con soluci&oacute;n salina. Estudio comparativo in vitro realizada en conejo condrocitos primaria revelaron que GlcN y NAPA tambi&eacute;n fueron capaces de contrarrestar la IL-1beta-regulaci&oacute;n al alza de genes codificantes de metaloproteasas y citoquinas inflamatorias. Nuestros estudios preliminares in vivo e in vitro sugieren que GlcN y NAPA podr&iacute;an desempe&ntilde;ar un papel protector de modificador de la enfermedad en OA un efecto anticatab&oacute;lico y una actividad antiinflamatoria en condrocitos.

Efectos de la administraci&oacute;n intra-articular de glucosamina y un derivado de la peptidil-glucosamina en un modelo en conejo de osteoartritis experimental: un estudio piloto.

Derivati del peptide 1-5, che incorporano gli aminoacidi sintetici non proteinogenici, correlati a beta-amiloide frammento 17-21 di amiloidogeniche Abeta(1-40) e il decapeptide protetto N 6, corrispondente a una sequenza dimerica dello stesso frammento, sono stati sintetizzati. Questi composti sono stati progettati utilizzando pentapeptide di Soto Ac-LPFFD-NH(2) (iAbeta5p) come composto di piombo. Loro attivit&agrave; come inibitori di fibrillogenesis e stabilit&agrave; contro degradazione enzimatica sono stati determinati. Composti di 1, 5 e 6 sono potenti inibitori rispetto ai composto del piombo. L&#39;esposizione a chimotripsina dei derivati del peptide 1-5, tutti contenenti amminoacidi innaturali, mostra maggiore stabilit&agrave; rispetto ai iAbeta5p e 6. Propriet&agrave; conformazionali di nuovi composti sono stati determinati dalla spettroscopia CD e FT-IR.

Sintesi e l&#39;attivit&agrave; degli inibitori del peptide fibrillogenesis legato alla sequenza di beta-amiloide 17-21.

Peptide derivatives 1-5, incorporating synthetic non-proteinogenic amino acids, related to the beta-amyloid 17-21 fragment of the amyloidogenic Abeta(1-40), and the N-protected decapeptide 6, corresponding to a dimeric sequence of the same fragment, have been synthesized. These compounds were designed by using Soto's pentapeptide Ac-LPFFD-NH(2) (iAbeta5p) as lead compound. Their activity as inhibitors of fibrillogenesis and stability against enzymatic degradation have been determined. Compounds 1, 5 and 6 are potent inhibitors in comparison to the lead compound. Exposure to chymotrypsin of peptide derivatives 1-5, all containing unnatural amino acids, shows increased stability as compared with iAbeta5p and 6. Conformational properties of the new compounds have been determined by CD and FT-IR spectroscopies.

Synthesis and activity of fibrillogenesis peptide inhibitors related to the 17-21 beta-amyloid sequence.

D&eacute;riv&eacute;s de peptide 1-5, incorporant synth&eacute;tique non-acide amin&eacute;, associ&eacute;s &agrave; la prot&eacute;ine b&ecirc;ta-amylo&iuml;de, 17-21 fragments de l&#39;amylo&iuml;dog&egrave;ne Abeta(1-40) et le d&eacute;capeptide prot&eacute;g&eacute; N 6, correspondant &agrave; une s&eacute;quence dim&egrave;re du m&ecirc;me fragment, ont &eacute;t&eacute; synth&eacute;tis&eacute;s. Ces compos&eacute;s ont &eacute;t&eacute; con&ccedil;us en utilisant le pentapeptide de Soto Ac-LPFFD-NH(2) (iAbeta5p) comme principal compos&eacute;. Leur activit&eacute; en tant qu&#39;inhibiteurs de FIBRILLOGENESE et de la stabilit&eacute; contre la d&eacute;gradation enzymatique ont &eacute;t&eacute; d&eacute;termin&eacute;es. Compos&eacute;s de 1, 5 et 6 sont de puissants inhibiteurs en comparaison avec le compos&eacute; principal. Exposition &agrave; la chymotrypsine, de d&eacute;riv&eacute;s de peptide 1-5, tous contenant des acides amin&eacute;s non naturels, montre une stabilit&eacute; accrue par rapport aux iAbeta5p et 6. Propri&eacute;t&eacute;s conformationnelles des nouveaux compos&eacute;s ont &eacute;t&eacute; d&eacute;termin&eacute;es par spectroscopie FT-IR et CD.

La synth&egrave;se et l&#39;activit&eacute; des inhibiteurs de peptide FIBRILLOGENESE associ&eacute;s &agrave; la s&eacute;quence de prot&eacute;ines b&ecirc;ta-amylo&iuml;des 17-21.

Derivados del p&eacute;ptido 1-5, incorporaci&oacute;n de amino&aacute;cidos sint&eacute;ticos no-proteinogenic, relacionado con el beta-amiloide fragmento 17-21 de la amyloidogenic Abeta(1-40) y el decap&eacute;ptido protegido N 6, correspondiente a una secuencia dim&eacute;rica del mismo fragmento, han sido sintetizados. Estos compuestos fueron dise&ntilde;ados usando pentap&eacute;ptido de Soto Ac-LPFFD-NH(2) (iAbeta5p) como compuesto de plomo. Se ha determinado su actividad como inhibidores de fibrilog&eacute;nesis y estabilidad contra la degradaci&oacute;n enzim&aacute;tica. Los compuestos 1, 5 y 6 son inhibidores potentes en comparaci&oacute;n con el compuesto de plomo. Exposici&oacute;n a la quimotripsina de derivados del p&eacute;ptido 1-5, todos conteniendo amino&aacute;cidos antinaturales, muestra mayor estabilidad en comparaci&oacute;n con iAbeta5p y 6. Propiedades conformacionales de los nuevos compuestos han sido determinadas por espectroscop&iacute;as de CD y FT-IR.

S&iacute;ntesis y actividad de fibrilog&eacute;nesis inhibidores de p&eacute;ptido relacionado con la secuencia de la prote&iacute;na beta-amiloide de 17-21.

A small library of N-For and N-Boc tetrapeptidic analogues of the chemotactic tripeptide For-Met-Leu-Phe-OMe (fMLF-OMe), obtained by incorporating three different spacer aminoacids (Gly, betaAla and Pro) between the native residues of Met and Leu (N-For- and N-Boc-Met-Xaa-Leu-Phe-OMe; Xaa2 series) and Leu and Phe (N-For- and N-Boc-Met-Leu-Xaa-Phe-OMe; Xaa3 series), have been synthesized and examined for their biological activity as agonists and antagonists. Chemotaxis, lysozyme release and superoxide anion production have been measured. All the N-For analogues maintain good to moderate chemotactic activity with the betaAla3 15 model reaching the maximum value. All the N-Boc tetrapeptides are efficient chemotactic antagonists. Conversely, with the exception of the moderate antagonistic activity exhibited by the N-Boc Xaa2 models against lysozyme release, all the other N-Boc analogues do not show significant activity against both superoxide anion and lysozyme release.

Synthesis and bioactivity of chemotactic tetrapeptides: fMLF-OMe analogues incorporating spacer aminoacids at the lateral positions.

Une petite biblioth&egrave;que de N-pour et N-Boc tetrapeptidic analogues du tripeptide chimiotactique pour-Met-Leu-Phe-OMe (fMLF-OMe), obtenues par l&#39;incorporation de trois acides amin&eacute;s de diff&eacute;rentes entretoise (Gly, betaAla et Pro) entre les r&eacute;sidus natifs de Met et Leu (N-pour- et N-Boc-Met-Xaa-Leu-Phe-OMe ; Xaa2 series) et Leu et Phe (N-pour- et N-Boc-Met-Leu-Xaa-Phe-OMe ; Xaa3 s&eacute;rie), ont &eacute;t&eacute; synth&eacute;tis&eacute;s et examin&eacute;s pour leur activit&eacute; biologique comme agonistes et antagonistes. La chimiotaxie, lysozyme lib&eacute;rer et production d&#39;anions superoxyde ont &eacute;t&eacute; mesur&eacute;s. Tous le N-pour analogues maintiennent bons d&#39;activit&eacute; chimiotactique mod&eacute;r&eacute;e avec le mod&egrave;le 15 betaAla3 pour atteindre la valeur maximale. Tous les tetrapeptides N-Boc sont antagonistes chimiotactiques efficaces. &Agrave; l&#39;inverse, &agrave; l&#39;exception de l&#39;activit&eacute; antagoniste mod&eacute;r&eacute;e expos&eacute;e par les mod&egrave;les N-Boc Xaa2 contre la lib&eacute;ration de lysozyme, tous les autres analogues N-Boc ne montrent pas une activit&eacute; significative contre anion superoxyde et le lysozyme de sortie.

Synth&egrave;se et bioactivit&eacute; des tetrapeptides chimiotactique : fMLF-OMe analogues incorporant entretoise acides amin&eacute;s aux positions lat&eacute;rales.

Una piccola biblioteca di N-per e N-Boc tetrapeptidic analoghi del tripeptide chemiotattica per-Met-Leu-Phe-OMe (fMLF-OMe), ottenuti incorporando tre distanziale diversi aminoacidi (glicina, betaAla e Pro) tra i residui nativi di Met e Leu (N-per- e N-Boc-Met-Xaa-Leu-Phe-OMe; Serie di Xaa2) e Leu e Phe (N-per- e N-Boc-Met-Leu-Xaa-Phe-OMe; Xaa3 serie), sono stati sintetizzati ed esaminati per la loro attivit&agrave; biologica come agonisti e antagonisti. Rilascio di chemiotassi, lisozima e produzione di anione superossido sono stati misurati. Tutte le N-per analoghi mantengono buone a moderata attivit&agrave; chemiotattica con il modello 15 betaAla3 raggiungendo il valore massimo. Tutti i Tetra N Boc &egrave; antagonisti chemiotattici efficienti. Al contrario, con l&#39;eccezione della moderata attivit&agrave; antagonistica esposte dai modelli N-Boc Xaa2 contro il rilascio di lisozima, altre analoghi N-Boc non mostrano un&#39;attivit&agrave; significativa sia contro l&#39;anione superossido e lisozima rilasciare.

Sintesi e bioattivit&agrave; di Tetra chemiotattica: fMLF-OMe analoghi che incorporano distanziale aminoacidi nelle posizioni laterali.

Una peque&ntilde;a biblioteca de N-para y N-Boc tetrapeptidic an&aacute;logos del trip&eacute;ptido quimiot&aacute;ctico para-Met-Leu-Phe-OMe (fMLF-OMe), obtenidos mediante la incorporaci&oacute;n de tres amino&aacute;cidos diferentes espaciador (Gly, betaAla y Pro) entre los residuos nativos del Met y Leu (N-para- y N-Boc-Met-Xaa-Leu-Phe-OMe; Serie de Xaa2) y Leu y Phe (N-para- y N-Boc-Met-Leu-Xaa-Phe-OMe; Serie de Xaa3), han sido sintetizados y examinado para su actividad biol&oacute;gica como agonistas y antagonistas. Quimiotaxis, lisozima suelte y se han medido la producci&oacute;n de ani&oacute;n super&oacute;xido. Todos los N-para an&aacute;logos mantienen buenos a moderada actividad quimiot&aacute;ctica con el modelo 15 betaAla3 alcanzar el valor m&aacute;ximo. Todos los tetrapeptides de N-Boc son antagonistas quimiot&aacute;cticos eficientes. Por el contrario, con la excepci&oacute;n de la moderada actividad antagonista exhibida por los modelos N-Boc Xaa2 contra liberaci&oacute;n de lisozima, todos los an&aacute;logos de la N-Boc no muestran una actividad significativa contra el ani&oacute;n super&oacute;xido y la lisozima liberar.

S&iacute;ntesis y bioactividad de tetrapeptides quimiot&aacute;cticos: fMLF OMe an&aacute;logos con amino&aacute;cidos de espaciador en las posiciones laterales.

New potent indolylarylsulfone (IAS) HIV-1 NNRTIs were obtained by coupling natural and unnatural amino acids to the 2-carboxamide and introducing different electron-withdrawing substituents at position 4 and 5 of the indole nucleus. The new IASs inhibited the HIV-1 replication in human T-lymphocyte (CEM) cells at low/subnanomolar concentration and were weakly cytostatic. Against the mutant L100I, K103N, and Y181C RT HIV-1 strains in CEM cells, sulfones 3, 4, 19, 27, and 31 were comparable to EFV. The new IASs were inhibitors to Coxsackie B4 virus at low micromolar (2-9 microM) concentrations. Superimposition of PLANTS docked conformations of IASs 19 and 9 revealed different hydrophobic interactions of the 3,5-dimethylphenyl group, for which a staking interaction with Tyr181 aromatic side chain was observed. The binding mode of 19 was not affected by the L100I mutation and was consistent with the interactions reported for the WT strain.

Indolylarylsulfones bearing natural and unnatural amino acids. Discovery of potent inhibitors of HIV-1 non-nucleoside wild type and resistant mutant strains reverse transcriptase and coxsackie B4 virus.

Nouveau indolylarylsulfone puissant (IAS) VIH-1 INNTI ont &eacute;t&eacute; obtenus par couplage des acides amin&eacute;s naturels et contre naturels pour le 2-carboxamide et pr&eacute;sentant diff&eacute;rents substituants &eacute;lectroattracteurs en position 4 et 5 du noyau indole. Le NCI nouveau inhibe la r&eacute;plication du VIH-1 dans les cellules humaines de lymphocytes T (CEM) &agrave; concentration faible/subnanomolar et ont &eacute;t&eacute; faiblement cytostatique. Contre les souches mutantes de L100I et K103N Y181C RT HIV-1 dans les cellules CEM, sulfones, 3, 4, 19, 27 et 31 &eacute;taient comparables aux EFV. Les nouveau IAS sont des inhibiteurs au virus Coxsackie B4 &agrave; faible micromolaire (2-9 microM) les concentrations. La superposition des plantes ancr&eacute; conformations de l&#39;IAS 19 et 9 a r&eacute;v&eacute;l&eacute; diff&eacute;rentes interactions hydrophobes du groupe 3, 5-dimethylphenyl, pour lequel une interaction jalonnement avec cha&icirc;ne lat&eacute;rale aromatique Tyr181 a &eacute;t&eacute; observ&eacute;e. Le mode de liaison de 19 n&#39;a pas &eacute;t&eacute; affect&eacute; par la mutation L100I et correspondait &agrave; des interactions rapport&eacute;es pour la souche WT.

Indolylarylsulfones portant des acides amin&eacute;s naturels et contre nature. D&eacute;couverte de puissants inhibiteurs du VIH-1 non nucl&eacute;osidiques sauvage et virus de souches mutantes r&eacute;sistantes &agrave; la transcriptase inverse et coxsackie B4.

Nuovo potente indolylarylsulfone NNRTIs HIV-1 (IAS) sono stati ottenuti accoppiamento naturale e innaturale di aminoacidi per il 2-carbossamide e introducendo diversi sostituenti elettrone-ritirarsi in posizione 4 e 5 del nucleo di indolo. Il nuovo IAS inibito la replicazione dell&#39;HIV-1 nelle cellule umane T-linfociti (CEM) a concentrazione bassa/subnanomolar ed erano debolmente citostatica. Contro i ceppi mutanti L100I, K103N e Y181C RT HIV-1 in cellule di CEM, solfoni, 3, 4, 19, 27 e 31 erano paragonabili a EFV. Il nuovo IAS sono stati gli inibitori al virus Coxsackie B4 a basso micromolare (2-9 microM) concentrazioni. Sovrapposizione di piante ancorato conformazioni di IAS 19 e 9 ha rivelato diverse interazioni idrofobiche del gruppo 3,5-dimethylphenyl, per cui &egrave; stata osservata un&#39;interazione picchettamento con catena laterale aromatico Tyr181. La modalit&agrave; di associazione del 19 non &egrave; stata influenzata dalla mutazione L100I ed &egrave; stato coerenza con le interazioni segnalate per il ceppo WT.

Indolylarylsulfones cuscinetto aminoacidi naturali e innaturali. Scoperta dei potenti inibitori di HIV-1 non nucleosidici wild type e virus di ceppi mutanti resistenti trascrittasi inversa e coxsackie B4.

Nuevo indolylarylsulfone potente (IAS) VIH-1 INNTR se obtuvieron amino&aacute;cidos naturales y no naturales de acoplamiento para el 2-carboxamida e introduciendo diversos sustitutos electr&oacute;n retirar en la posici&oacute;n 4 y 5 del n&uacute;cleo indol. Las nuevas NIC inhibici&oacute;n la replicaci&oacute;n del VIH-1 en c&eacute;lulas humanas de linfocitos T (CEM) en concentraci&oacute;n baja/subnanomolar y fueron citost&aacute;ticos d&eacute;bil. Frente a las cepas mutantes L100I, K103N y Y181C RT HIV-1 en las c&eacute;lulas de la CEM, Sulfonas, 3, 4, 19, 27 y 31 fueron comparables a EFV. Las nuevas NIC fueron inhibidores virus Coxsackie B4 en baja micromolar (2-9 microM) concentraciones. Superposici&oacute;n de plantas hab&iacute;a acoplado conformaciones de las NIC 19 y 9 revel&oacute; diferentes interacciones hidrof&oacute;bicas del grupo 3,5-dimethylphenyl, para lo cual se observ&oacute; una interacci&oacute;n entutorada con cadena de arom&aacute;ticos lateral de Tyr181. El modo de enlace de 19 no fue afectado por la mutaci&oacute;n de L100I y era constante con las interacciones de la cepa WT.

Indolylarylsulfones con amino&aacute;cidos naturales y no naturales. Descubrimiento de inhibidores potentes de tipo salvaje de VIH-1 no nucle&oacute;sido y virus de cepas mutantes resistentes de la transcriptasa reversa y coxsackie B4.

The opioid agonists endomorphins (Tyr-Pro-Trp-Phe-NH(2); EM1 and Tyr-Pro-Phe-Phe-NH(2); EM2) and morphiceptin (Tyr-Pro-Phe-Pro-NH(2)) exhibit an extremely high selectivity for mu-opioid receptor. Here a series of novel EM2 and morphiceptin analogues containing in place of the proline at position 2 the S and R residues of beta-homologues of proline (HPro), of 2-pyrrolidinemethanesulphonic acid (HPrs) and of 3-pyrrolidinesulphonic acid (betaPrs) have been synthesized and their binding affinity and functional activity have been investigated. The highest micro-receptor affinity is shown by [(S)betaPrs(2)]EM2 analogue (6e) which represents the first example of a beta-sulphonamido analogue in the field of opioid peptides.

Synthesis and activity of endomorphin-2 and morphiceptin analogues with proline surrogates in position 2.

Les endomorphines agonistes opio&iuml;des (Tyr-Pro-Trp-Phe-NH(2) ; EM1 et Tyr-Pro-Phe-Phe-NH(2) ; EM2) et morphiceptin (Tyr-Pro-Phe-Pro-NH(2)) pi&egrave;ce une s&eacute;lectivit&eacute; tr&egrave;s &eacute;lev&eacute;e pour le r&eacute;cepteur mu-opio&iuml;de. Ici, une s&eacute;rie de roman EM2 et morphiceptin analogues contenant en lieu et place de la proline &agrave; la position 2 de la S et R les r&eacute;sidus de b&ecirc;ta-homologues de la proline (HPro), de l&#39;acide 2-pyrrolidinemethanesulphonic (HPR) et de l&#39;acide 3-pyrrolidinesulphonic (betaPrs) ont &eacute;t&eacute; synth&eacute;tis&eacute;s et leur affinit&eacute; de liaison et l&#39;activit&eacute; fonctionnelle ont &eacute;t&eacute; &eacute;tudi&eacute;s. L&#39;affinit&eacute; du r&eacute;cepteur micro plus haute t&eacute;moignent [(S)betaPrs(2)] EM2 analogique (6e), qui repr&eacute;sente le premier exemple d&#39;un analogue de la b&ecirc;ta-sulphonamido dans le domaine des peptides opio&iuml;des.

Synth&egrave;se et activit&eacute; d&#39;endomorphine-2 et morphiceptin analogues des substituts de la proline en position 2.

Gli oppioidi agonisti endomorphins (Tyr-Pro-Trp-Phe-NH(2); EM1 e Tyr-Pro-Phe-Phe-NH(2); EM2) e morphiceptin (Tyr-Pro-Phe-Pro-NH(2)) Mostra un&#39;elevatissima selettivit&agrave; per il recettore mu-oppioide. Qui una serie di romanzo EM2 e morphiceptin analoghi contenenti al posto della prolina in posizione 2 S e R residui di beta-omologhi di prolina (HPro), dell&#39;acido 2-pyrrolidinemethanesulphonic (HPrs) e di acido 3-pyrrolidinesulphonic (betaPrs) sono stati sintetizzati e loro affinit&agrave; di legame e l&#39;attivit&agrave; funzionale sono stati indagati. il pi&ugrave; alta affinit&agrave; di micro-recettore &egrave; mostrato da EM2 [(S)betaPrs(2)] analogico (6e) che rappresenta il primo esempio di un analogo beta-sulphonamido nel campo dei peptidi oppioidi.

Sintesi e attivit&agrave; di endomorphin-2 e morphiceptin analoghi con surrogati di prolina in posizione 2.

El endomorphins de agonistas opi&aacute;ceos (Tyr-Pro-Trp-Phe-NH(2); EM1 y Tyr-Pro-Phe-Phe-NH(2); EM2) y morphiceptin (Tyr-Pro-Phe-Pro-NH(2)) muestra una extremadamente alta selectividad para los receptores mu-opioides. Aqu&iacute; una serie de novela EM2 y an&aacute;logos de morphiceptin que contiene en lugar de la prolina en la posici&oacute;n 2 de los residuos S y R de beta-hom&oacute;logos de prolina (HPro), del &aacute;cido 2-pyrrolidinemethanesulphonic (HPR) y del &aacute;cido 3-pyrrolidinesulphonic (betaPrs) han sido sintetizados y su afinidad y actividad funcional han sido investigados. La mayor afinidad de micro receptor se muestra por [(S)betaPrs(2)] EM2 an&aacute;logo (6e) que representa el primer ejemplo de un an&aacute;logo de la beta-sulphonamido en el campo de los p&eacute;ptidos opioides.

S&iacute;ntesis y actividad de endomorphin-2 y morphiceptin an&aacute;logos con sustitutos de la prolina en la posici&oacute;n 2.

Detection of enzyme activity through catalytic signal amplification with functionalized gold nanoparticles.

D&eacute;tection de l&#39;activit&eacute; enzymatique gr&acirc;ce &agrave; l&#39;amplification du signal catalytique avec des nanoparticules d&#39;or.

Rilevamento dell&#39;attivit&agrave; enzimatica tramite amplificazione del segnale catalitico con le nanoparticelle d&#39;oro funzionalizzate.

Detecci&oacute;n de actividad de la enzima a trav&eacute;s de la amplificaci&oacute;n de la se&ntilde;al catal&iacute;tico con nanopart&iacute;culas de oro funcionalizadas.

We report the synthesis and fibrillogenesis inhibiting activity of the new peptide derivatives 1-4, related to the pentapeptide Ac-LPFFD-NH(2) (iAÎ²5p), proposed by Soto and co-workers and widely recognized as one of the most active Î²-sheet breaker agents. The AÎ²(25-35) fragment of the parent full-length AÎ²(1-42) was used as fibrillogenesis model. The activity of peptide derivatives 1-4 was tested in vitro by thioflavin T binding assay, far UV CD spectroscopy, and scanning electron microscopy. Their ability to hinder the toxic effect of AÎ²(25-35) in vivo was studied by monitoring the viability of human SH-SY5Y neuroblastoma cells and the prevention of superoxide anion radical release from BV2 microglial cells. The results point to a favourable role in the fibrillogenesis inhibitory activity of the sulphonamide junction for compounds 1 and 2, containing an N,N-dimethyltaurine and a taurine amino-terminal moiety, respectively. Furthermore, compounds 1 and 2 show a significant protective effect on cell viability, rescuing the cells from the toxicity exerted by AÎ²(25-35) treatment.

Inhibition of amyloid peptide fragment AÎ²25-35 fibrillogenesis and toxicity by N-terminal Î²-amino acid-containing esapeptides: is taurine moiety essential for in vivo effects?

Nous rapportons la synth&egrave;se et FIBRILLOGENESE inhibant l&#39;activit&eacute; du nouveau peptide d&eacute;riv&eacute;s 1-4, concernant le pentapeptide Ac-LPFFD-NH(2) (iA&beta;5p), propos&eacute; par Soto et ses collaborateurs et largement reconnu comme un des agents plus actifs de disjoncteur feuillet &beta;. Le fragment A&beta;(25-35) du parent qu&#39;a&beta;(1-42) pleine longueur a &eacute;t&eacute; utilis&eacute;e comme mod&egrave;le de FIBRILLOGENESE. L&#39;activit&eacute; des d&eacute;riv&eacute;s de peptide 1-4 a &eacute;t&eacute; test&eacute;e in vitro par essai de liaison thioflavine T loin spectroscopie UV CD et microscopie &eacute;lectronique &agrave; balayage. Leur capacit&eacute; &agrave; emp&ecirc;cher l&#39;effet toxique des A&beta;(25-35) in vivo a &eacute;t&eacute; &eacute;tudi&eacute;e en surveillant la viabilit&eacute; des cellules de neuroblastome humains SH-SY5Y et la pr&eacute;vention de superoxyde anion radical acquit BV2 les cellules microgliales. Les r&eacute;sultats indiquent qu&#39;un r&ocirc;le favorable dans l&#39;activit&eacute; inhibitrice de le FIBRILLOGENESE de la jonction de sulfamide pour des compos&eacute;s 1 et 2, contenant une N, N-dimethyltaurine et une portion d&#39;amino-terminale taurine, respectivement. En outre, les compos&eacute;s 1 et 2 montrent un effet protecteur significatif sur la viabilit&eacute; cellulaire, sauvant les cellules de la toxicit&eacute; exerc&eacute;e par un traitement A&beta;(25-35).

L&#39;inhibition de la toxicit&eacute; par esapeptides de contenant de l&#39;acide &beta;-amin&eacute;s N-terminaux et de peptide b&ecirc;ta-amylo&iuml;de fragment AB25-35 FIBRILLOGENESE : portion taurine il est essentiel pour les effets in vivo ?

Riportiamo la sintesi e fibrillogenesis d&#39;inibizione attivit&agrave; del peptide nuovo derivati 1-4, imparentato con il pentapeptide Ac-LPFFD-NH(2) (iA&beta;5p), proposto da Soto e collaboratori e ampiamente riconosciuto come uno dei pi&ugrave; attivi agenti &beta;-foglio dell&#39;interruttore. Il frammento A&beta;(25-35) del padre che A&beta;(1-42) Full-length &egrave; stato utilizzato come modello di fibrillogenesis. L&#39;attivit&agrave; dei derivati del peptide 1-4 &egrave; stato testato in vitro da analisi obbligatoria thioflavin T lontano UV CD spettroscopia e microscopia elettronica a scansione. Loro capacit&agrave; di ostacolare l&#39;effetto tossico di A&beta;(25-35) in vivo &egrave; stato studiato monitorando la vitalit&agrave; delle cellule di neuroblastoma umano SH-SY5Y e la prevenzione di superossido anione radicale rilascio dalle cellule microgliali BV2. I risultati indicano un ruolo favorevole nell&#39;attivit&agrave; inibitoria della giunzione sulfonamide per composti fibrillogenesis 1 e 2, contenente una N, N-dimethyltaurine e un gruppo amminico-terminale taurina, rispettivamente. Inoltre, composti 1 e 2 mostrano un significativo effetto protettivo sulla vitalit&agrave; delle cellule, le cellule dalla tossicit&agrave; esercitata da A&beta;(25-35) trattamento di salvataggio.

Inibizione del peptide amiloide frammento 35 A&beta;25 fibrillogenesis e tossicit&agrave; da &beta;-amminici contenenti acido esapeptides di N-terminale: &egrave; essenziale per gli effetti in vivo moiety taurina?

Divulgamos la s&iacute;ntesis y fibrilog&eacute;nesis inhibiendo la actividad del p&eacute;ptido nuevo derivados 1-4, relacionada con el pentap&eacute;ptido Ac-LPFFD-NH(2) (iA&beta;5p), propuesto por Soto y compa&ntilde;eros de trabajo y ampliamente reconocido como uno de los agentes m&aacute;s activos de la &beta;-hoja interruptor. El fragmento A&beta;(25-35) de los padres que A&beta;(1-42) de larga duraci&oacute;n fue utilizado como modelo de fibrilog&eacute;nesis. La actividad de p&eacute;ptidos derivados 1-4 fue probada in vitro mediante ensayo de enlace tioflavina T lejos espectroscopia UV CD y microscop&iacute;a electr&oacute;nica de barrido. Su capacidad para impedir el efecto t&oacute;xico de A&beta;(25-35) in vivo se estudi&oacute; mediante el control de la viabilidad de las c&eacute;lulas de neuroblastoma SH-SY5Y humanas y la prevenci&oacute;n de la liberaci&oacute;n radical de ani&oacute;n de super&oacute;xido de BV2 las c&eacute;lulas microgliales. Los resultados apuntan a un papel favorable en la actividad inhibitoria de la fibrilog&eacute;nesis de la ensambladura de sulfamidas para compuestos 1 y 2, que contiene un N, N-dimethyltaurine y un grupo amino terminal taurino, respectivamente. Por otra parte, compuestos 1 y 2 muestran un efecto protector significativo en la viabilidad celular, rescatar a las c&eacute;lulas de la toxicidad ejercida por el tratamiento de A&beta;(25-35).

&iquest;Inhibici&oacute;n de p&eacute;ptido amiloide fragmento A&beta;25-35 fibrilog&eacute;nesis y toxicidad por esapeptides de que contiene &aacute;cido &beta;-amino N-terminal: es esencial para efectos in vivo la parte taurina?

The biological consequences of free radical production is the central subject of a very lively scientific debate, focusing on the estimation of the type and extent of damage, as well as the efficiency of the protective and repair systems. When studying free radical based chemical mechanisms, it is very important to establish biomimetic models, which allow the experiments to be performed in a simplified environment, but suitably designed to be in strict connection with cellular conditions. The biomimetic modeling approach has been coupled with physical organic chemistry methodologies and knowledge of free radical reactivity. Molecular basis of important processes have been identified, building up molecular libraries of products concerning unsaturated lipids, sulfur-containing proteins and nucleic acids, to be developed as biomarkers. Ongoing projects in our group deal with lipidomics, genomics and proteomics of free radical stress and some examples will be described.

Biomimetic models of radical stress and related biomarkers.

Les cons&eacute;quences biologiques de production de radicaux libres est le sujet central d&#39;un tr&egrave;s vif d&eacute;bat scientifique, en se concentrant sur l&#39;estimation du type et l&#39;&eacute;tendue des d&eacute;g&acirc;ts, ainsi que l&#39;efficacit&eacute; des syst&egrave;mes de protection et de r&eacute;paration. Lorsque l&#39;&eacute;tudiant radical libre selon les m&eacute;canismes chimiques, il est tr&egrave;s important d&#39;&eacute;tablir des mod&egrave;les biomim&eacute;tique, qui permettent les exp&eacute;riences &agrave; effectuer dans un environnement simplifi&eacute;, mais convenablement con&ccedil;us pour &ecirc;tre dans le cadre strict des conditions cellulaires. La biomim&eacute;tique, approche de mod&eacute;lisation s&#39;accompagne de m&eacute;thodes de chimie physique organique et connaissance de la r&eacute;activit&eacute; des radicaux libres. Bases mol&eacute;culaires des processus importants, accumulent des biblioth&egrave;ques mol&eacute;culaires de produits concernant les lipides insatur&eacute;s, prot&eacute;ines contenant du soufre et des acides nucl&eacute;iques, &agrave; d&eacute;velopper comme biomarqueurs ont &eacute;t&eacute; identifi&eacute;s. Projets en cours au sein du groupe traitent de la lipidomique, g&eacute;nomique et prot&eacute;omique de stress radicalaire et quelques exemples seront d&eacute;crites.

Mod&egrave;les biomim&eacute;tique du stress radicalaire et de biomarqueurs li&eacute;s.

Le conseguenze biologiche di produzione di radicali liberi &egrave; il soggetto centrale di un vivo dibattito scientifico, concentrandosi sulla stima del tipo e della entit&agrave; del danno, nonch&eacute; l&#39;efficienza dei sistemi di protezione e riparazione. Quando studiare radicale libero, basato su meccanismi chimici, &egrave; molto importante stabilire modelli biomimetici, che permettono gli esperimenti essere eseguito in un ambiente semplificato, ma opportunamente progettati per essere in stretta connessione con condizioni cellulari. Biomimetic approccio di modellazione &egrave; stato accoppiato con metodologie di chimica organica fisica e conoscenza della reattivit&agrave; di radicali liberi. Sono state identificate le basi molecolari di importanti processi, costruzione di librerie molecolari dei prodotti riguardanti i lipidi insaturi, contenenti zolfo proteine e acidi nucleici, per essere sviluppato come biomarcatori. Progetti in corso nel nostro gruppo affrontare lipidomica, genomica e proteomica di stress dei radicali liberi e verranno descritti alcuni esempi.

Article	Year
Beta-peptido sulfonamides: for-Met-Leu-Phe-OMe analogues containing taurine and chiral beta-amino-ethanesulfonic acid residues. Farmaco (SocietÃ chimica italiana : 1989)\| PubMed ID: 15598430	2004
Alpha-peptide/beta-sulfonamidopeptide hybrids: analogs of the chemotactic agent for-Met-Leu-Phe-OMe. Bioorganic & medicinal chemistry\| PubMed ID: 16356729	2006
Effects of intra-articular administration of glucosamine and a peptidyl-glucosamine derivative in a rabbit model of experimental osteoarthritis: a pilot study. Rheumatology international\| PubMed ID: 17924112	2008
Synthesis and activity of fibrillogenesis peptide inhibitors related to the 17-21 beta-amyloid sequence. European journal of medicinal chemistry\| PubMed ID: 18501995	2009
Synthesis and bioactivity of chemotactic tetrapeptides: fMLF-OMe analogues incorporating spacer aminoacids at the lateral positions. Amino acids\| PubMed ID: 18636221	2009
Indolylarylsulfones bearing natural and unnatural amino acids. Discovery of potent inhibitors of HIV-1 non-nucleoside wild type and resistant mutant strains reverse transcriptase and coxsack... Journal of medicinal chemistry\| PubMed ID: 19281225	2009
Synthesis and activity of endomorphin-2 and morphiceptin analogues with proline surrogates in position 2. European journal of medicinal chemistry\| PubMed ID: 20692738	2010
Detection of enzyme activity through catalytic signal amplification with functionalized gold nanoparticles. Angewandte Chemie (International ed. in English)\| PubMed ID: 21351342	2011
Inhibition of amyloid peptide fragment AÎ²25-35 fibrillogenesis and toxicity by N-terminal Î²-amino acid-containing esapeptides: is taurine moiety essential for in vivo effects? Chemical biology & drug design\| PubMed ID: 21995332	2012
Biomimetic models of radical stress and related biomarkers. Chimia\| PubMed ID: 22871276	2012

Anna Sansone

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