title: Structure-activity relationships of neoechinulin A analogues with cytoprotection against peroxynitrite-induced PC12 cell death.
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.
authors.affiliation: Department of Applied Biological Science, Faculty of Science and Technology, Chiba, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Kimoto
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Aoki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shibata
authors.forename: Shinji
authors.initials: S
authors.lastname: Kamisuki
authors.forename: Fumio
authors.initials: F
authors.lastname: Sugawara
authors.forename: Kouji
authors.initials: K
authors.lastname: Kuramochi
authors.forename: Atsuo
authors.initials: A
authors.lastname: Nakazaki
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Kuroiwa
authors.forename: Nobuo
authors.initials: N
authors.lastname: Watanabe
authors.forename: Takao
authors.initials: T
authors.lastname: Arai
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D007202:Indicators and Reagents; D026121:Indole Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D008165:Luminol / Q000737:chemistry / Q000378:metabolism; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009252:NADPH Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D016716:PC12 Cells; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D007202:Indicators and Reagents; D026121:Indole Alkaloids; D018696:Neuroprotective Agents; D010879:Piperazines; D026361:Reactive Nitrogen Species; C490266:neoechinulin A; D030421:Peroxynitrous Acid; D008165:Luminol; C002385:linsidomine; D008981:Molsidomine; D009252:NADPH Dehydrogenase