Agelastatin E, Agelastatin F, and Benzosceptrin C from the Marine Sponge Agelas dendromorpha

Abstract

The study of the n-butanol extract of the New Caledonian sponge Agelas dendromorpha led to the isolation and identification of three new pyrrole-2-aminoimidazole (P-2-AI) alkaloids, named agelastatins E (3) and F (4) and benzosceptrin C (5), together with 10 known metabolites, agelastatin A (1), agelastatin D (2), sceptrin (6), manzacidin A, tauroacidin A, taurodispacamide A, nortopsentin D, thymine, longamide, and 4,5-dibromopyrrole-2-carboxamide. Their structures were assigned by spectroscopic data interpretation. All the compounds were tested for cytotoxic activity.

Total Synthesis of All (–)‐Agelastatin Alkaloids

“…60 The observed lower efficiency of the desired cyclization with 35 compared to 19 echoes the scarcity of natural (-)-Agelastatin D (4) compared to other N-methyl agelastatin alkaloids. 9,10,61 Furthermore, we have accessed the structures of the two newly isolated (-)-Agelastatins E (5) and F (6) by their direct synthesis from (-)-Agelastatin A (1) and D (4), respectively (Scheme 4). Heating a methanolic solution of (-)-Agelastatin A (1) with BrØnsted acid at 65°C for 2 h afforded (-)-Agelastatin E (5) in 96% yield (Scheme 4).…”

“…9 Recently, Al-Mourabit has reported the isolation of (-)-Agelastatins E (5) and F (6) from the New Caledonian sponge Agelas dendromorpha. 10 (-)-Agelastatin A (1) exhibits significant antitumor activity and inhibits osteopontin-mediated neoplastic transformation and metastasis in addition to slowing cancer cell proliferation by causing cells to accumulate in the G 2 phase of the cell cycle.11 ,12 (-)-Agelastatin A (1) also exhibits toxicity towards arthropods, 9 and selectively inhibits the glycogen synthase kinase-3β, which is a potential target for the treatment of Alzheimer's disease and bipolar disorder. 13,14 These properties have prompted considerable efforts toward the total synthesis of agelastatin A (1), resulting in inventive syntheses from 10 different research groups.…”

Recent advances in the total synthesis of agelastatins

“…Agelastatin C contains an extra hydroxyl group at C(4); whereas agelastatin D lacks an N(1) methyl group. Very recently (2010), agelastatins E (5) and F (6) were isolated as minor components from a butan-1-ol extract of the New Caledonian sponge A. dendromorpha, along with agelastatin A [4]. Agelastatin E is formally O-methylagelastatin A; while agelastatin F is 14-bromoagelastatin D. The question whether agelastatin E is a natural product has not yet been addressed [4].…”

“…Very recently (2010), agelastatins E (5) and F (6) were isolated as minor components from a butan-1-ol extract of the New Caledonian sponge A. dendromorpha, along with agelastatin A [4]. Agelastatin E is formally O-methylagelastatin A; while agelastatin F is 14-bromoagelastatin D. The question whether agelastatin E is a natural product has not yet been addressed [4]. As indicated in Pietra's initial semi-synthesis work [6] (later confirmed by Movassaghi's seminal total synthesis [10]), treatment of 1 in the presence of Amberlyst 15 and MeOH results in methanol exchange at C(8), giving O-methylagelastatin A, the 1 H NMR spectrum of which is identical to that of agelastatin E (eq.…”

“…Given their significance, both in terms of biological activity and the challenge posed by their structural complexity, numerous synthetic approaches have been explored during the past decade. Although some of the earlier efforts have been covered in part of a review by Weinreb in 2007 [2], a tremendous amount of more recent synthetic investigation has been disclosed during the past four years, which has been additionally stimulated by more recent oncology studies during 2008 [3] and isolation of new agelastatins during 2010 [4]. For example, in 2009 alone, no less than six publications appeared on the total syntheses of agelastatin A.…”