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Pharmaceuticals 2010, 3(4), 1063-1069; doi:10.3390/ph3041063
Article

Synthesis and Neuroprotective Action of Optically Pure Neoechinulin A and Its Analogs

1,2, 1,2, 3, 3, 2,3, 3, 1, 3, 2,3, 3 and 1,2,*
1 Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan 2 Genome and Drug Discovery Center, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan 3 Department of Applied Biological Science, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan
* Author to whom correspondence should be addressed.
Received: 21 December 2009 / Revised: 5 January 2010 / Accepted: 29 March 2010 / Published: 31 March 2010
(This article belongs to the Special Issue Asymmetric Synthesis and Medicinal Chemistry)
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Abstract

We developed an efficient, stereoselective synthetic method for the diketopiperazine moiety of neoechinulin A and its derivatives. The intramolecular cyclization at 80 ºC proceeded with minimal racemization of the stereogenic center at C-12 on neoechinulin A, even though the cyclization at 110 ºC caused partial racemization. In contrast with these results, the cyclization on diketopiperazine of 8,9-dihydroneoechinulin A derivatives did not cause epimerization of the stereogenic centers, even at 110 °C. We examined the structure-activity relationships for the cytoprotective activity against cytotoxicity induced by 3-morpholinosydnonimine (SIN-1) in nerve growth factor (NGF)-differentiated PC12 cells. The C-8/C-9 double bond, but not the stereogenic center derived from alanine, was found to play a key role in the cytoprotective activity.
Keywords: neoechinulin A; intramolecular cyclization; cytoprotective activity neoechinulin A; intramolecular cyclization; cytoprotective activity
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Aoki, T.; Ohnishi, K.; Kimoto, M.; Fujieda, S.; Kuramochi, K.; Takeuchi, T.; Nakazaki, A.; Watanabe, N.; Sugawara, F.; Arai, T.; Kobayashi, S. Synthesis and Neuroprotective Action of Optically Pure Neoechinulin A and Its Analogs. Pharmaceuticals 2010, 3, 1063-1069.

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