One‐Pot Evolution of Ageladine A through a Bio‐Inspired Cascade towards Selective Modulators of Neuronal Differentiation

Abstract

A bio-inspired cascade reaction has been developed for the construction of the marine natural product ageladine A and a de novo array of its N1-substituted derivatives. This cascade features a 2-aminoimidazole formation that is modeled after an arginine post-translational modification and an aza-electrocyclization. It can be effectively carried out in a one-pot procedure from simple anilines or guanidines, leading to structural analogues of ageladine A that had been otherwise synthetically inaccessible. We found that some compounds out of this structurally novel library show a significant activity in modulating the neural differentiation. Namely, these compounds selectively activate or inhibit the differentiation of neural stem cells to neurons, while being negligible in the differentiation to astrocytes. This study represents a successful case in which the native biofunction of a natural product could be altered by structural modifications.

Total Synthesis and Biological Evaluation of Kakeromamide A and Its Analogues

“…In order to evaluate neural differentiation-modulating activities of kakeromamide a Data obtained from the isolation paper (Nakamura et al, 2018 A and its analogs, we elected to perform the biological tests using the same procedure that we reported in the isolation paper (Nakamura et al, 2018). Neural stem cells were obtained following the procedure (Nakayama and Inoue, 2006;Iwata et al, 2016) with modification. 2.5, 5, and 10 µM of kakeromamide A or its respective derivative was added to astrocytes or neurons.…”

Coronarin D, a Metabolite from the Wild Turmeric, Curcuma aromatica, Promotes the Differentiation of Neural Stem Cells into Astrocytes

“…NSCs were induced from mouse ESCs using a previously reported method, with some modifications. , Briefly, embryoid bodies (EBs) were formed with the hanging drop method using 7500 ESCs in 20 μL of medium in the absence of LIF for 3 days. The obtained EBs were transferred to a low-adhesion plate (Corning Inc., Corning, NY) and cultured in Neuron Culture Medium (Fujifilm Wako Pure Chemical Corporation) supplemented with 20 ng/mL rhEGF (R&D Systems, Minneapolis, MN) and 20 ng/mL rhFGF-2 (R&D Systems) for 96 h. Thereafter, the EBs were transferred to matrigel (BD Biosciences, Franklin Lakes, NJ)-coated dishes and incubated in NSC maintenance medium, MACS NeuroMedium (Miltenyi Biotec, Bergisch Gladbach, Germany) containing 2% MACS NeuroBrew-21 (Miltenyi Biotec), 1% P/S, 20 ng/mL rhEGF, and 20 ng/mL rhFGF-2, for 20 days.…”

Pull‐Pull Alkenes in the Aza‐Michael Reaction

“…(see, for example: [27] ). Another scenario involves the primary amine reacting with formyl group to form azomethine followed by intramolecular aza‐Michael addition to enoate moiety [28] …”

“…Another scenario involves the primary amine reacting with formyl group to form azomethine followed by intramolecular aza-Michael addition to enoate moiety. [28] However, in 2006, the regio-and enantioselective organocatalytic conjugate addition of nitrogen nucleophiles to enals was reported. [29] It was found that due to α-effect of triorganylsilyloxy group, N-siloxycarbamate 25 had a sufficient nucleophilicity to undergo the aza-Michael reaction.…”