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

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.

Marine endophytic fungi associated with Halopteris scoparia (Linnaeus) Sauvageau as producers of bioactive secondary metabolites with potential dermocosmetic application

“…Li et al [ 109 ] also isolated this metabolite from the culture broth of a marine Aspergillus sp., and reported its antioxidant and UV-A protective abilities. Moreover, Maruyama et al [ 110 ], Kimoto et al [ 111 ], Kajimura et al [ 112 ], Aoki et al [ 113 ] and Kamisuki et al [ 114 ] revealed the antiapoptotic and cytoprotective activities of neoechinulin A in neuron-like PC12 cells, against peroxynitrite generated from 3-(4-morpholinyl) sydnonimine hydrochloride (SIN-1) and 1-methyl-4-phenylpyridinium (MPP+). The study carried out by Kimoto et al [ 111 ] also suggested that the antioxidant and anti-nitration activities exhibited by neoechinulin A occurred through an independent mechanism of action.…”

Biologically Active Echinulin-Related Indolediketopiperazines from the Marine Sediment-Derived Fungus Aspergillus niveoglaucus

“…Neoechinulin A is well known for its antioxidant properties [35]. Its neuroprotective and anti-inflammatory effects, as well as structure-activity relationships, have been investigated in detail [10,20,36,37]. In this study, we isolated seven previously known echinulin-related compounds from the Vietnamese sediment-derived fungus Aspergillus niveoglaucus and investigated their neuroprotective properties.…”

Synthetic and Structure-Activity Relationship Studies on Bioactive Natural Products

“…Structure-activity relationships of neoechinulin A Our synthetic neoechinulin A and its derivatives were evaluated for antinitration activity against peroxynitritemediated tyrosine nitration, antioxidant activity as to lipid peroxidation, and cytoprotective activity against peroxynitrite from SIN-1 in PC12 cells. [64][65][66] The C-8/ C-9 double bond, which constitutes a conjugate system with the indole and diketopiperazine moieties of neoechinulin A, is essential for antinitration and antioxidant activities as well as protection against SIN-1 cytotoxicity (Fig. 4).…”