Synthesis and biological activities of neoechinulin A derivatives: new aspects of structure-activity relationships for neoechinulin A.
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.
Kuramochi
Kouji
K
Department of Applied Biological Science, Tokyo University of Science, Noda, Chiba, Japan.
Ohnishi
Kensuke
K
Fujieda
Satoshi
S
Nakajima
Mitsuhiro
M
Saitoh
Yoshihiko
Y
Watanabe
Nobuo
N
Takeuchi
Toshifumi
T
Nakazaki
Atsuo
A
Sugawara
Fumio
F
Arai
Takao
T
Kobayashi
Susumu
S
D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry*; D001923:Brain Chemistry / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D007202:Indicators and Reagents; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry*; D015227:Lipid Peroxidation / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008981:Molsidomine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000633:toxicity; D009566:Nitrates / Q000737:chemistry; D016716:PC12 Cells; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry*; D020011:Protective Agents / Q000138:chemical synthesis* / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry
D000975:Antioxidants; D007202:Indicators and Reagents; D026121:Indole Alkaloids; D009566:Nitrates; D010879:Piperazines; D020011:Protective Agents; C490266:neoechinulin A; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; C002385:linsidomine; D008981:Molsidomine