Efficient Synthesis of Marine Alkaloid Ageladine A and its Structural Modification for Exploring New Biological Activity

Abstract

Natural products have been regarded as a pivotal source for biological active compounds. In addition, structural modification of natural products has been simultaneously received much attention because these modified natural products would show not only enhanced activity and selectivity, but possibly also an entirely distinct bioactivity from those of the parent natural products. We describe herein a series of study on structual modification of ageladine A for exploring new biological activity. Ageladine A was isolated from the marine sponge Agelas nakamurai as an antiangiogenic compound. Based on total syntheses of this alkalod, its structual modifications were caried out as a part of SAR study, which revealed that a pyridine derivative shows a more potent activity. More recently, we have developed an efficient bio-inspired cascade reaction for the synthesis of ageladine A. The cascade reaction involves an aza-electrocyclization and a novel 2-aminoimidazole formation that is modeled after a post-translational modification of arginine residue in protein. Employing the cascade reaction, ageladine A and its N1-substituted analogues were efficiently synthesized in one-pot fashion from anilines or guanidines. In addition, it was found that some analogs showed significant activity on modulating neuronal differentiation. Namely, these analogs selectively activate or inhibit the differentiation of neural stem cells to neurons, while negligible in astrocyte differentiation. The series of study represent a successful case in altering native bioactivity of natural products by structural modification.