RESUMO
Isoindolinones comprise an important class of medicinally active compounds. Herein we report a straightforward functionalization of the isoindolinones with aryl bromides (22 examples) using a Pd(OAc)2/NIXANTPHOS-based catalyst system. Additionally 3-aryl 3-hydroxy isoindolinone derivatives, which exhibit anti-tumor activity, can be accessed via a tandem reaction. Thus, when the arylation product is exposed to air under basic conditions, in situ oxidation takes place to install the 3-hydroxyl group. Furthermore, a tandem arylation/allylic substitution reaction is advanced in which both the arylation and allylic substitution are catalyzed by the same palladium catalyst. Finally, a tandem arylation/alkylation procedure is presented. These tandem reactions enable the synthesis of a variety of structurally diverse isoindolinone derivatives from common starting materials.
RESUMO
The arylation of sp3-hybridized C-H's bonds is a powerful strategy to build molecular complexity and diversity. A novel and efficient palladium-catalyzed direct sp3 C-H arylation of aryl and alkyl benzyl thioether derivatives with aryl bromides is reported. The reaction involves reversible deprotonation of the benzylic C-H's of the thioether with either LiN(SiMe3)2 or NaN(SiMe3)2 and subsequent cross-coupling to provide the functionalized products in up to 97% yield. A screen of 24 of the most successful ligands in cross-coupling chemistry led to the identification of NiXantPhos as the only viable ligand for this challenging coupling.
RESUMO
The present study was carried out to examine possible differential silver distribution among several tissues of three marine invertebrate species: the shrimp Penaeus duorarum, the sea hare Aplysia californica, and the sea urchin Diadema antillarum. Animals were exposed to sub-lethal concentrations of silver (1 or 10 microg/L) in seawater for 48 h. In gill-breathing species (shrimp and sea hare), higher silver accumulation in gills were associated with higher hemolymph silver levels. Furthermore, sea urchin showed lower hemolymph silver concentrations than shrimp and sea hare. These findings suggest that gills are an important route for silver uptake in marine invertebrates. In both sea hare and shrimp, hepatopancreas silver accumulation was concentration-dependent and this organ accumulated the most silver after 48 h of exposure, suggesting a possible involvement of the hepatopancreas in both silver accumulation and detoxification in marine invertebrates. In shrimp and sea hare, substantial silver accumulation in nervous tissues was detected, suggesting the need for further studies on possible behavioral effects of silver in these invertebrate species. In sea urchin, egg mass accumulated more silver than other tissues analyzed, indicating the need for future studies on possible reproductive effects of silver in sea urchin. In all three species, the lowest silver concentrations were observed in muscle, suggesting a low potential of this tissue for trophic transfer of silver.
Assuntos
Aplysia/metabolismo , Penaeidae/metabolismo , Ouriços-do-Mar/metabolismo , Prata/farmacocinética , Poluentes Químicos da Água/farmacocinética , Animais , Aplysia/efeitos dos fármacos , Relação Dose-Resposta a Droga , Brânquias/efeitos dos fármacos , Brânquias/metabolismo , Hemolinfa/metabolismo , Hepatopâncreas/metabolismo , Sistema Nervoso/metabolismo , Penaeidae/efeitos dos fármacos , Ouriços-do-Mar/efeitos dos fármacos , Prata/toxicidade , Especificidade da Espécie , Fatores de Tempo , Distribuição Tecidual , Poluentes Químicos da Água/toxicidadeRESUMO
In freshwater crustaceans and in both freshwater and marine fish, the key mechanism of acute silver toxicity involves ionoregulatory impairment. An inhibition of the Na+ ,K+-ATPase located at the basolateral membrane of the gill epithelium seems to be the key site for silver toxicity. However, studies to determine if the same mechanism of toxicity is occurring in marine invertebrates, which also are ionoregulators, had not been done. Thus, the present study was carried out to determine acute silver effects on hemolymph osmo- and ionoregulation in three marine invertebrates: the shrimp Penaeus duorarum, the sea hare Aplysia californica, and the sea urchin Diadema antillarum. Animals were exposed to silver (1 or 10 microg/L), as silver nitrate, in seawater for 48 h. Results show that acute silver exposure did not affect hemolymph osmolality or ion concentration (Na+, Cl-, K+, Ca2+ and Mg2+) in the three species studied. However, silver induced significant changes in the water content in shrimp gill and sea hare gill and hepatopancreas. Silver also caused significant changes in Na+ ,K+-ATPase activity and in both total and intracellular ion (Cl-, Na+, K+, Mg2+, and Ca2+) concentrations in different tissues of the three species studied. Overall, these results show that the key mechanism of acute silver toxicity in marine invertebrates is not associated with an osmotic or ionoregulatory impairment at the hemolymph level, as observed in freshwater fish and crustaceans and in seawater fish. However, they indicate that acute waterborne silver induces significant changes in Na+ ,K(+)-ATPase activity and probably affects other mechanisms involved in water and ion transport at the cell membrane level, inducing impairments in water and ion regulation at the cellular level in different tissues of marine invertebrates. These results indicate the need to consider other "toxic sites" than gills in any future extension of the biotic ligand model (BLM) for seawater.