Abstract
Neoechinulin A, an alkaloid from Eurotium rubrum Hiji025, protected neuronal PC12 cells against cell death induced by peroxynitrite derived from SIN-1 (3-(4-morpholinyl)sydnonimine hydrochloride). In this study, we investigated the structure-activity relationships of neoechinulin A and a set of its analogues by using assays to measure anti-nitration and antioxidant activities and cytoprotection against SIN-1-induced PC12 cell death. The presence of the diketopiperazine ring was essential for both the antioxidant and anti-nitration activities of neoechinulin A derivatives. Nevertheless, a derivative lacking the diketopiperazine ring could still protect PC12 cells against SIN-1 cytotoxicity. An acyclic analogue completely lost the cytoprotective effect while retaining its antioxidant/anti-nitration activities. Pre-incubation of the cells with neoechinulin A for at least 12 hours was essential for the cells to gain SIN-1 resistance. These results suggest that neoechinulin A endows the cells with cytoprotection through a biological effect different from the apparent antioxidant/anti-nitration activities.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Phytogenic / chemistry
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Antineoplastic Agents, Phytogenic / pharmacology
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Antioxidants / pharmacology
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Cell Death / drug effects
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Cell Survival / drug effects
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Cytoprotection / drug effects*
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Indicators and Reagents
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Indole Alkaloids / chemistry
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Indole Alkaloids / pharmacology*
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Luminol / chemistry
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Luminol / metabolism
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Molsidomine / analogs & derivatives
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Molsidomine / pharmacology
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NADPH Dehydrogenase / metabolism
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Neurons / drug effects
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Neurons / ultrastructure
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology
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Oxidation-Reduction
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PC12 Cells
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Peroxynitrous Acid / antagonists & inhibitors*
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Peroxynitrous Acid / metabolism
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Peroxynitrous Acid / toxicity*
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Piperazines / chemistry
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Piperazines / pharmacology*
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Rats
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Reactive Nitrogen Species / metabolism
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Structure-Activity Relationship
Substances
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Antineoplastic Agents, Phytogenic
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Antioxidants
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Indicators and Reagents
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Indole Alkaloids
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Neuroprotective Agents
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Piperazines
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Reactive Nitrogen Species
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neoechinulin A
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Peroxynitrous Acid
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Luminol
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linsidomine
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Molsidomine
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NADPH Dehydrogenase