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

The reaction of 1:1 zwitterionic intermediates generated in situ from either tert-butylisocyanide or cyclohexylisocyanide and acetylenedicarboxylates with 3-formylchromones is described, whereupon either chromenylfurandicarboxylates or cyclopenta[b]chromenedicarboxylates are formed, depending on the nature of the chromone 6-position substituent and also on the acetylene ester group. In addition, from the reaction with a 1:2 zwitterionic intermediate, cyclohepta[b]chromenetetracarboxylates are isolated. The regioselectivity of the reaction was also investigated by DFT calculations. The geometries of the reactants, intermediate zwitterions, transition structures, and intermediate products, leading to the final products, were optimized using the B3LYP functional with the 6-31G(d) basis set. The structures of the products were elucidated by 1D and 2D NMR experiments. Full assignment of all (1)H and (13)C NMR chemical shifts has been achieved. Plausible mechanistic schemes are provided.

One-pot synthesis of chromenylfurandicarboxylates and cyclopenta[b]chromenedicarboxylates involving zwitterionic intermediates. A DFT investigation on the regioselectivity of the reaction.

La r&eacute;action de 1:1 interm&eacute;diaires zwitterioniques g&eacute;n&eacute;r&eacute; in situ &agrave; partir soit tert-isocyanures ou cyclohexylisocyanide et acetylenedicarboxylates avec 3-formylchromones est d&eacute;crite, sur quoi chromenylfurandicarboxylates ou cyclopenta [b] chromenedicarboxylates se forment, selon la nature du substituant en position 6 chromone et aussi sur le groupe d&#39;ester de l&#39;ac&eacute;tyl&egrave;ne. En outre, par r&eacute;action avec un 1:2 zwitterionique interm&eacute;diaire, cyclohepta [b] chromenetetracarboxylates sont isol&eacute;es. La r&eacute;gios&eacute;lectivit&eacute; de la r&eacute;action a &eacute;t&eacute; &eacute;galement &eacute;tudi&eacute;e par calculs DFT. Les g&eacute;om&eacute;tries des r&eacute;actifs, zwitterions interm&eacute;diaires, des structures de transition et des produits interm&eacute;diaires, conduisant &agrave; des produits finis, on a optimis&eacute; en utilisant le B3LYP fonctionnel avec l&#39;ensemble de base de 6-31G(d). Les structures des produits ont &eacute;t&eacute; &eacute;lucid&eacute;es par RMN 1D et 2D exp&eacute;riences. Complet de cession de tout (1) H et d&eacute;placements chimiques en RMN du 13C (13) a &eacute;t&eacute; atteint. Sch&eacute;mas m&eacute;canistes plausibles sont fournis.

Synth&egrave;se one-pot de chromenylfurandicarboxylates et chromenedicarboxylates de cyclopenta [b] impliquant des interm&eacute;diaires zwitterioniques. Une enqu&ecirc;te de DFT sur la r&eacute;gios&eacute;lectivit&eacute; de la r&eacute;action.

La reazione di 1:1 zwitterionici intermedi generati in situ da entrambi tert-butylisocyanide o cyclohexylisocyanide e acetylenedicarboxylates con 3 formylchromones &egrave; descritto, dopo di che o chromenylfurandicarboxylates o ciclopenta [b] chromenedicarboxylates sono formati, a seconda della natura del sostituente di 6 posizioni cromone e anche sul gruppo estere dell&#39;acetilene. Inoltre, dalla reazione con un 1:2 zwitterionici intermedio, cyclohepta [b] chromenetetracarboxylates sono isolati. La regioselettivit&agrave; della reazione &egrave; stato studiato anche da calcoli DFT. Le geometrie di reagenti, zwitterions intermedio, strutture di transizione e prodotti intermedi, che porta a prodotti finali, sono state ottimizzate utilizzando la B3LYP funzionale con il set di base 6-31G(d). Le strutture dei prodotti sono state chiarite da NMR 1D e 2D esperimenti. Completa assegnazione di tutti i (1h) e (13) spostamenti chimici C NMR &egrave; stato raggiunto. Vengono forniti schemi meccanicistici plausibile.

One-pot sintesi di chromenylfurandicarboxylates e chromenedicarboxylates ciclopenta [b] che coinvolgono zwitterionici intermedi. Un&#39;indagine di DFT sulla regioselettivit&agrave; della reazione.

La reacci&oacute;n de 1:1 zwitteri&oacute;nico intermedios generados in situ de cualquiera de los dos terc-butylisocyanide o cyclohexylisocyanide y acetylenedicarboxylates con 3 formylchromones se describe, con lo cual se forman ya sea chromenylfurandicarboxylates o ciclopenta [b] chromenedicarboxylates, dependiendo de la naturaleza del sustituto de 6 posiciones cromona y tambi&eacute;n en el grupo de &eacute;ster de acetileno. Adem&aacute;s, de la reacci&oacute;n con un 1:2 zwitteri&oacute;nico intermedio, cyclohepta [b] chromenetetracarboxylates se a&iacute;slan. La regioselectividad de la reacci&oacute;n tambi&eacute;n fue investigado por c&aacute;lculos de DFT. Las geometr&iacute;as de los reactivos, zwitteriones intermedios, estructuras de transici&oacute;n y productos intermedios, llevando a los productos finales, se optimizaron usando el B3LYP funcional con el conjunto de la base de 6-31G(d). Las estructuras de los productos fueron acladas por RMN 1D y 2D experimentos. Completa la tarea de todos (1) H y desplazamientos qu&iacute;micos de C NMR (13) se ha logrado. Se proporcionan esquemas mecanicistas plausibles.

S&iacute;ntesis de un pote de chromenylfurandicarboxylates y chromenedicarboxylates ciclopenta [b] que implica zwitteri&oacute;nico intermedios. Una investigaci&oacute;n de DFT en la regioselectividad de la reacci&oacute;n.

5',8-Cyclo-2'-deoxyadenosine and 5',8-cyclo-2'-deoxyguanosine in their 5'R and 5'S diastereomeric forms are tandem-type lesions observed among the DNA modifications and identified in mammalian cellular DNA in vivo. These lesions result from the chemistry of the C5' radicals generated by the attack of HOË™ radicals to 2-deoxyribose units. Quantitative determination of these lesions in biological samples as biomarkers of free radical damage is a challenge. Results reported for irradiated samples of calf thymus DNA have been critically reviewed, underlining the need of further research for the potential involvement of these lesions in human health (76 references).

Purine 5',8-cyclonucleoside lesions: chemistry and biology.

5&#39;, 8-Cyclo-2&#39;-d&eacute;soxyad&eacute;nosine et 5&#39;, 8-cyclo-2&#39;-deoxyguanosine dans leurs 5&#39;R et de 5 formes diast&eacute;r&eacute;oisom&egrave;res sont des l&eacute;sions de type tandem observ&eacute; parmi les modifications de l&#39;ADN et identifi&eacute;s dans l&#39;ADN des cellules mammif&egrave;res in vivo. Ces l&eacute;sions r&eacute;sultent de la chimie de la C5&#39; radicaux g&eacute;n&eacute;r&eacute;s par l&#39;attaque des radicaux HO&#x2D9; aux unit&eacute;s 2-d&eacute;soxyribose. D&eacute;termination quantitative de ces l&eacute;sions dans des &eacute;chantillons biologiques comme biomarqueurs des dommages des radicaux libres est un d&eacute;fi. R&eacute;sultats rapport&eacute;s pour irradi&eacute; des &eacute;chantillons d&#39;ADN ont &eacute;t&eacute; revues de fa&ccedil;on critique, en soulignant la n&eacute;cessit&eacute; de poursuivre les recherches pour l&#39;implication potentielle de ces l&eacute;sions en sant&eacute; humaine (76 r&eacute;f&eacute;rences) de thymus de veau.

Purine 5&#39;, 8-cyclonucl&eacute;osides l&eacute;sions : chimie et biologie.

5&#39;, 8-Cyclo-2&#39;-deossiadenosina e 5&#39;, 8-cyclo-2&#39;-deoxyguanosine nel loro 5&#39;R e 5 forme stereoisomere sono lesioni tandem-tipo osservata tra le modifiche del DNA e identificata del DNA cellulare dei mammiferi in vivo. Queste lesioni derivano la chimica della C5&#39; radicali generati dall&#39;attacco di radicali HO&#x2D9; a unit&agrave; 2-desossiribosio. Determinazione quantitativa di queste lesioni, in campioni biologici come biomarcatori di danni dei radicali liberi &egrave; una sfida. Risultati riportati per irradiato campioni di DNA sono stati criticamente esaminati, sottolineando la necessit&agrave; di ulteriori ricerche per il potenziale coinvolgimento di queste lesioni nella salute umana (76 riferimenti) di timo di vitello.

Purina 5&#39;, 8-cyclonucleoside lesioni: chimica e biologia.

5&#39;, 8-Cyclo-2&#39;-Desoxiadenosina y 5&#39;8-cyclo-2&#39;-desoxiguanosina en sus 5&#39;R y de 5 diastereomeric formas son lesiones de tipo t&aacute;ndem observada entre las modificaciones del ADN y en mam&iacute;fero ADN celular in vivo. Estas lesiones resultan de la qu&iacute;mica de la C5&#39; radicales generados por el ataque de los radicales HO&#x2D9; 2-desoxirribosa unidades. Determinaci&oacute;n cuantitativa de estas lesiones en muestras biol&oacute;gicas como biomarcadores de da&ntilde;o del radical libre es un desaf&iacute;o. Reportados para irradiaron muestras de timo de becerro ADN han revisado cr&iacute;ticamente, subrayando la necesidad de investigaci&oacute;n adicional de la implicaci&oacute;n potencial de estas lesiones en la salud humana (76 referencias).

Purina 5&#39;, 8-cyclonucleoside lesiones: qu&iacute;mica y biolog&iacute;a.

Another aspect concerning chromone chemistry leading to the one-pot synthesis of functionalized novel spirobenzofuranones has been described. The synthesis involves reaction of the zwitterionic intermediates formed by the 1:1 interaction between isocyanides and acetylenecarboxylates with 3-cyanochromones, whereupon through an unexpected and unprecedented reaction of the chromone moiety the isolated benzofuranones are formed. The regioselectivity of the reaction was investigated by DFT calculations. The geometries of the intermediates, transition structures, and intermediate products, leading to the final products, were optimized using the B3LYP functional with the 6-31G(d) basis set. The structures of the products were elucidated by 1D and 2D NMR experiments. Full assignment of all (1)H and (13)C NMR chemical shifts has been achieved. A plausible mechanistic rationale is proposed.

One-pot synthesis of functionalized spirobenzofuranones via MCR involving 3-cyanochromones.

Un autre aspect concernant la chimie chromone conduisant &agrave; la synth&egrave;se monotope de fonctionnalis&eacute;s spirobenzofuranones roman a &eacute;t&eacute; d&eacute;crit. La synth&egrave;se implique la r&eacute;action des interm&eacute;diaires zwitterioniques form&eacute; par l&#39;interaction de 1:1 entre isocyanures et acetylenecarboxylates avec 3-cyanochromones, apr&egrave;s quoi, gr&acirc;ce &agrave; une r&eacute;action inattendue et sans pr&eacute;c&eacute;dent de la portion chromone le benzofuranones isol&eacute;s sont form&eacute;s. La r&eacute;gios&eacute;lectivit&eacute; de la r&eacute;action a &eacute;t&eacute; &eacute;tudi&eacute;e par des calculs DFT. Les g&eacute;om&eacute;tries des interm&eacute;diaires, des structures de transition et des produits interm&eacute;diaires, conduisant &agrave; des produits finis, on a optimis&eacute; en utilisant le B3LYP fonctionnel avec l&#39;ensemble de base de 6-31G(d). Les structures des produits ont &eacute;t&eacute; &eacute;lucid&eacute;es par RMN 1D et 2D exp&eacute;riences. Complet de cession de tout (1) H et d&eacute;placements chimiques en RMN du 13C (13) a &eacute;t&eacute; atteint. Un raisonnement m&eacute;caniste plausible est propos&eacute;.

Synth&egrave;se one-pot de spirobenzofuranones fonctionnalis&eacute;s par MCR impliquant 3-cyanochromones.

Un altro aspetto riguardante cromone chimica che porta alla sintesi di spirobenzofuranones romanzo funzionalizzate one-pot &egrave; stato descritto. La sintesi coinvolge reazione di intermedi zwitterionici formata dall&#39;interazione di 1:1 tra isocyanides e acetylenecarboxylates con 3-cyanochromones, al che attraverso una reazione inattesa e senza precedenti di moiety il cromone sono formate il benzofuranones isolato. La regioselettivit&agrave; della reazione &egrave; stato studiato da calcoli DFT. Le geometrie di intermedi, strutture di transizione i prodotti intermedi, che porta a prodotti finali, sono state ottimizzate utilizzando la B3LYP funzionale con il set di base 6-31G(d). Le strutture dei prodotti sono state chiarite da NMR 1D e 2D esperimenti. Completa assegnazione di tutti i (1h) e (13) spostamenti chimici C NMR &egrave; stato raggiunto. Una plausibile spiegazione logica meccanicistica &egrave; proposto.

One-pot sintesi di spirobenzofuranones funzionalizzate via MCR che coinvolgono 3-cyanochromones.

Se ha descrito otro aspecto relativo a la qu&iacute;mica de cromona conduce a la s&iacute;ntesis de un pote de spirobenzofuranones novela funcionalizados. La s&iacute;ntesis implica la reacci&oacute;n de los intermedios zwitteri&oacute;nico formado por la interacci&oacute;n de 1:1 entre isocyanides y acetylenecarboxylates con 3-cyanochromones, con lo cual a trav&eacute;s de una reacci&oacute;n inesperada y sin precedentes de la mol&eacute;cula de cromona forman las benzofuranones aisladas. La regioselectividad de la reacci&oacute;n fue investigado por c&aacute;lculos de DFT. Las geometr&iacute;as de los productos intermedios, estructuras de transici&oacute;n y productos intermedios, llevando a los productos finales, se optimizaron usando el B3LYP funcional con el conjunto de la base de 6-31G(d). Las estructuras de los productos fueron acladas por RMN 1D y 2D experimentos. Completa la tarea de todos (1) H y desplazamientos qu&iacute;micos de C NMR (13) se ha logrado. Se propone una l&oacute;gica mecanicista plausible.

S&iacute;ntesis de One-pot de funcionalizados spirobenzofuranones trav&eacute;s de MCR que implica 3-cyanochromones.

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.

Modelli biomimetici di stress radicalico e biomarcatori correlati.

The reaction of the zwitterionic intermediate, generated in situ from either tert-butylisocyanide or cyclohexylisocyanide and acetylenedicarboxylates, with 3-cyanochromones is described, whereupon spirochromenofuran derivatives 5 or 6 were obtained in good yields. The subsequent acid-catalyzed rearrangement of the isolated 2-imino-spirochromenofurans 5 to 2-amino-spirochromenofurans 7 has also been studied. Rational mechanistic schemes for the formation of compounds 5, 6, and 7 are proposed. The structure elucidation of the products was accomplished by 1D and 2D NMR experiments and confirmed by X-ray crystallographic analysis. Full assignment of all (1)H and (13)C NMR chemical shifts has been unambiguously achieved with the aid of DFT/GIAO calculations.

One-pot five-component synthesis of spirocyclopenta[b]chromene derivatives and their acid-catalyzed rearrangement.

La r&eacute;action de la zwitterionique INTERMEDIAIRE, g&eacute;n&eacute;r&eacute; in situe &agrave; partir de tert-isocyanures ou de cyclohexylisocyanide et d&#39;acetylenedicarboxylates, avec 3-cyanochromones est d&eacute;crit, apr&egrave;s quoi les d&eacute;riv&eacute;s spirochromenofuran 5 ou 6 ont &eacute;t&eacute; obtenus avec de bons rendements. Le r&eacute;arrangement acido-catalys&eacute;e subs&eacute;quent de l&#39;isol&eacute; 5 2-imino-spirochromenofurans 2-amino-spirochromenofurans 7 a &eacute;galement &eacute;t&eacute; &eacute;tudi&eacute;. Les sch&eacute;mas m&eacute;canistes rationnelles pour la formation de compos&eacute;s 5, 6 et 7 sont propos&eacute;s. L&#39;&eacute;lucidation de la structure des produits a &eacute;t&eacute; accomplie par des exp&eacute;riences RMN 1D et 2D et confirm&eacute;e par diffraction des rayons x. Complet de cession de tout (1) H et d&eacute;placements chimiques en RMN du 13C (13) a &eacute;t&eacute; atteint sans ambigu&iuml;t&eacute; &agrave; l&#39;aide de calculs DFT/GIAO.

Synth&egrave;se one-pot cinq composants de spirocyclopenta [b] CHROM&Egrave;NE d&eacute;riv&eacute;s et leur transposition acido-catalys&eacute;e.

La reazione della zwitterionici intermedio, generato in situ o tert-butylisocyanide o cyclohexylisocyanide e acetylenedicarboxylates, con 3-cyanochromones &egrave; descritto, dopodich&eacute; derivati spirochromenofuran 5 o 6 sono stati ottenuti buoni rendimenti. Inoltre &egrave; stato studiato il riarrangiamento successivo acido-catalizzata dell&#39;isolato 2-immino-spirochromenofurans 5 a 2-ammino-spirochromenofurans 7. Vengono proposti schemi meccanicistici razionale per la formazione di composti, 5, 6 e 7. La delucidazione della struttura dei prodotti &egrave; stata compiuta dagli esperimenti NMR 1D e 2D e confermata dall&#39;analisi cristallografica dei raggi x. Completa assegnazione di tutti i (1h) e (13) spostamenti chimici C NMR &egrave; stato raggiunto senza ambiguit&agrave; con l&#39;aiuto di calcoli DFT/GIAO.

Article	Year
One-pot synthesis of chromenylfurandicarboxylates and cyclopenta[b]chromenedicarboxylates involving zwitterionic intermediates. A DFT investigation on the regioselectivity of the reaction. The Journal of organic chemistry\| PubMed ID: 20151714	2010
Purine 5',8-cyclonucleoside lesions: chemistry and biology. Chemical Society reviews\| PubMed ID: 21221459	2011
One-pot synthesis of functionalized spirobenzofuranones via MCR involving 3-cyanochromones. The Journal of organic chemistry\| PubMed ID: 21992417	2011
Biomimetic models of radical stress and related biomarkers. Chimia\| PubMed ID: 22871276	2012
One-pot five-component synthesis of spirocyclopenta[b]chromene derivatives and their acid-catalyzed rearrangement. The Journal of organic chemistry\| PubMed ID: 22978377	2012

Michael A. Terzidis

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