NPEdia Epolactaene
Producing organism
Penicillium sp.
Biological activity
induction of neurite outgrowth
We have screened microbial products to discover neuritogenic compounds which induced neurite outgrowth in the human neuroblastoma cell line SH-SY5Y that lacks significant TRK family mRNAs. During the screening, we isolated a novel, non-protein neurotrophic compound, epolactaene, produced by Penicillium sp. 1689-P, having an epoxide-containing γ-lactam ring in the molecule. However, only small quantities of epolactaene could be isolated from the fungus; furthermore, the compound was unstable under light because of a labile triene group in the side chain and an epoxide fused to a γ-lactam ring. In the present paper, we prepared a number of epolactaene derivatives, 3-substituted 3-pyrrolin-2-ones possessing a double bond in the γ-lactam ring, to find compounds with more effective neuritogenic activity. In addition, we described the structure-activity relationship of 3-substituted 3-pyrrolin-2-ones on the neuritogenic effect in SH-SY5Y cells. MT-5, 3-acetyl-4,5-dimethyl-5-octadecyloxy-3-pyrrolin-2-one, the most effective derivative for neuritogenic activity in SH-SY5Y cells, also arrested cell cycle progression at G0/G1 like epolactaene.
isolation and structural determination
  • Kakeya H, Takahashi I, Okada G, Isono K, Osada H.: Epolactaene, a novel neuritogenic compound in human neuroblastoma cells, produced by a marine fungus.
    J Antibiot, 48(7): 733-735 (1995) PMID: 7649877
  • biological activity and structure-activity relationship
  • Nagumo Y, Kakeya H, Shoji M, Hayashi Y, Dohmae N, Osada H.: Epolactaene binds human Hsp60 Cys442 resulting in the inhibition of chaperone activity.
    Biochem J, 387(Pt 3): 835-840 (2005) PMID: 15603555 [ doi: 10.1042/BJ20041355 ]
  • Kakeya H, Onozawa C, Sato M, Arai K, Osada H.: Neuritogenic effect of epolactaene derivatives on human neuroblastoma cells which lack high-affinity nerve growth factor receptors.
    J Med Chem, 40(4): 391-394 (1997) PMID: 9046328 [ doi: 10.1021/jm960719a ]
  • Kakeya H, Osada H.
    Induction of neurite outgrowth by epolactaene derivatives, 3-substituted 3-pyrrolin-2-ones.
    RIKEN Review 18, 35-36 (1998) [ RIKEN Review: No_18/18_035 ]
  • synthesis by other group
  • Hayashi Y, Kanayama J, Yamaguchi J, Shoji M.: Diastereoselective total synthesis of both enantiomers of epolactaene.
    J Org Chem, 67(26): 9443-9448 (2002) PubMed
  • Additional information