Structure-activity relationships of neoechinulin A analogues with cytoprotection against peroxynitrite-induced PC12 cell death

Kuniaki Kimoto, Toshiaki Aoki, Yasushi Shibata, Shinji Kamisuki, Fumio Sugawara, Kouji Kuramochi, Atsuo Nakazaki, Susumu Kobayashi, Kenji Kuroiwa, Nobuo Watanabe, Takao Arai

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

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/antinitration 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.

Original languageEnglish
Pages (from-to)614-621
Number of pages8
JournalJournal of Antibiotics
Volume60
Issue number10
DOIs
Publication statusPublished - 2007 Oct

Keywords

  • Alkaloid
  • Neoechinulin
  • Reactive oxygen/nitrogen species
  • Structure-activity relationship

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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