Sparassis crispa Fr. in an edible mushroom recently cultivable in Japan. A branched beta-glucan from S. crispa (SCG) is a major 6-branched 1,3-beta-D-glucan showing antitumor activity. In this study, we examined interferon-gamma (IFN-gamma) induction by SCG from splenocytes in DBA/2 mice in vitro. In the splenocytes derived from almost all inbred strains of mice except for DBA/1 and DBA/2 mice, IFN-gamma production was not induced by SCG. The breeder and genders of DBA/2 mice showed no influence on IFN-gamma induction by SCG. On the other hand, the magnitude of IFN-gamma induction was lower in young mice than in their older counterparts. IFN-gamma was induced by SCG in adherent splenocytes, but IFN-gamma production was most significantly increased by SCG in instances involving coexistence of adherent and nonadherent splenocytes. In fact, inhibition of cell-cell contact reduced IFN-gamma induction by SCG. In addition, interleukin-12 p70 (IL-12p70) was induced by SCG in DBA/2 mice. It was suggested that soluble factors and cell-cell contact mediate synergistic effects on SCG-induced IFN-gamma production.
The major side-effect of most anti-cancer chemotherapeutic drugs is neutropenia, and the administration of these drugs impairs blood-forming functions (e.g. the generation of neutrophils, NK cells, etc.) that are important to maintain the defense systems of the patients. As a result, chemotherapy may accelerate the risk of tumor metastases and fungal infection. Metastasis of tumor cells is a serious concern, causing deterioration in the condition of patients receiving cancer therapy.
Peroxynitrite (ONOO), is a potent oxidant that can cause severe cell damage.1) Specifically, peroxynitrite promotes the oxidation of biomolecules such as lipids, proteins and nucleic acids, [2][3][4] as well as the nitration of tyrosine residues in proteins. 5,6) Furthermore, it has been suggested that peroxynitrite formation plays a role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. [7][8][9] Neoechinulin A (1), an isoprenyl indole alkaloid, can protect neuronal PC12 cells from ONOO Ϫ -induced death. [10][11][12] We have previously shown that the biological effects, rather than scavenging activity against ONOO Ϫ , are likely to play a role in the cytoprotective action of neoechinulin A.12) However, the precise molecular mechanism remains elusive. To investigate the potential mechanism of action, we have designed and prepared a series of neoechinulin A analogues (2-6). We then examined the structure-activity relationships of these analogues in terms of their anti-nitration and anti-oxidant activities as well as their cytoprotective activity against ONOO Ϫ derived from SIN-1 (3-(4-morpholinyl)sydnonimine hydrochloride) using PC12 cells (Fig. 1). The results showed that: 1) the presence of the C-8/C-9 double bond is indispensable for anti-nitration and anti-oxidant activities as well as cytoprotective activity of neoechinulin A against ONOO Ϫ toxicity; 2) in conjunction with the C-8/C-9 double bond, the presence of an intact diketopiperazine moiety is essential for the anti-nitration activity but not for antioxidant or cytoprotective activity.
Results and DiscussionCompound 2 was synthesized from 2-tert-butyl-1H-indole (7) 13) (Chart 1). Methoxy methyl (MOM) protection of 7, followed by the Vilsmeier reaction, gave aldehyde 9. A coupling reaction of the aldehyde 9 with diketopiperazine 10 using tBuOK in DMF afforded 11.14) Subsequent deprotection of protective groups provided the desired product 2.
15)Compound 3 was prepared by coupling of aldehyde 12 with N-Boc-Gly-OEt, followed by treatment of the resulting We synthesized a series of neoechinulin A derivatives and examined the structure-activity relationships in terms of their anti-nitration and anti-oxidant activities as well as their cytoprotective activity against peroxynitrite from SIN-1 (3-(4-morpholinyl)sydnonimine hydrochloride) using PC12 cells. Our results showed that the C-8/C-9 double bond, which constitutes a conjugate system with indole and diketopiperazine moieties of neoechinulin A is essential for anti-nitration and anti-oxidant activities as well as protection against SIN-1 cytotoxicity. The presence of an intact diketopiperazine moiety is an additional requirement for anti-nitration activity but not for the cytoprotective action. Our results suggest that the antioxidant activity or electrophilic nature of the C-8 carbon, both of which are afforded by the C-8/C-9 double bond, may play a role in the cytoprotective properties of this alkaloid.
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