ageladine-a and 2-aminoimidazole

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.

Topics: Aniline Compounds; Animals; Biomimetics; Cell Differentiation; Dyrk Kinases; Guanidines; Humans; Imidazoles; Mice; Molecular Structure; Neural Stem Cells; Neurons; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Pyrroles; Small Molecule Libraries; Structure-Activity Relationship

A series of ageladine A analogs that include 2-aminoimidazo[4,5-c]azepines (seven-membered rings) and 2-amino-3H-imidazo[4,5-c]pyridine (six-membered rings) derivatives were synthesized and evaluated for their anticancer effects against several human cancer cell lines and MMP-2 inhibition in vitro. Only compounds possessing the aromatic azepine (seven-membered ring) core showed anticancer activity with IC(50) values in the low micromolar range.

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Imidazoles; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Oxidation-Reduction; Pyrroles; Structure-Activity Relationship