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Please use this identifier to cite or link to this item: http://hdl.handle.net/10451/3847

Title: Naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates: Potent, Non-cytotoxic, Antiapoptotic Agents
Authors: Santos, Daniela M.
Santos, Maria M. M.
Viana, Ricardo J. S.
Castro, Rui E.
Moreira, Rui
Rodrigues, Cecília M. P.
Keywords: Apoptosis
Bcl-XL
Caspases
Hepatocytes
Naphthoquinone derivatives
Issue Date: 2009
Publisher: Elsevier
Citation: Santos, Daniela M.; Santos, Maria M. M.; Viana, Ricardo J. S.; Castro, Rui E.; Moreira, Rui; Rodrigues, Cecília M. P.Naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates: Potent, Non-cytotoxic, Antiapoptotic Agents, Chemico-Biological Interactions, 180, 175-182, 2009.
Abstract: Compounds containing a quinone moiety represent an important class of biologically active molecules that are widespread in nature, displaying anticancer, antibacterial, antimalarial, and fungicidal activities. In the course of designing 2,3-disubstituted-1,4-naphthoquinones derivatives as potential cysteine protease inhibitors, two naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates, 1a and 1b, were obtained. The antiapoptotic potential of 1a and 1b was then evaluated and compared to that of naphthoquinone 4. Primary rat hepatocytes were incubated with synthesized naphthoquinone derivatives and then exposed to the apoptotic stimulus camptothecin. Our results indicate that naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates 1a and 1b exerted a potent protective role in camptothecin-induced apoptosis in primary rat hepatocytes. Both 1a and 1b significantly increased cell viability, while reducing nuclear fragmentation, caspase-3, -8 and -9 activation, and cytochrome c release induced by camptothecin. In addition, 1a and 1b were shown to up-regulate Bcl-XL, a pro-survival member of the Bcl-2 family of proteins, which modulates the mitochondrial pathway of apoptosis. Similar protective effects of quinone derivatives were seen in HuH-7 and PC12 cells incubated with distinct apoptotic stimuli, such as camptothecin, TGF-β1, or rotenone. Our results suggest that naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates 1a and 1b may act as potent, cytoprotective agents, through modulation of apoptotic pathways.
Peer Reviewed: yes
URI: http://dx.doi.org/10.1016/j.cbi.2009.03.007
http://hdl.handle.net/10451/3847
ISSN: 0009-2797
Publisher version: http://www.sciencedirect.com/science/article/pii/S0009279709001264
Appears in Collections:FF-DQFT - Artigos em Revistas Internacionais

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