Growth promoting: The first synthesis of the natural product xanthofulvin (SM‐216289) has resolved issues regarding its structural assignment and that described for the natural product 411J. The structurally and biologically related natural product vinaxanthone was similarly prepared through a novel dimerization reaction. Treatment of C. elegans with synthetic xanthofulvin and vinaxanthone enhanced axonal branching.
The oxidation of arenes by the reagent phthaloyl peroxide provides a new method for the synthesis of phenols. A new, more reactive arene oxidizing reagent, 4,5-dichlorophthaloyl peroxide, computationally predicted and experimentally determined to possess enhanced reactivity, has expanded the scope of the reaction while maintaining a high level of tolerance for diverse functional groups. The reaction proceeds through a novel "reverse-rebound" mechanism with diradical intermediates. Mechanistic insight was achieved through the isolation and characterization of minor byproducts, the determination of linear free energy correlations, and computational analysis of substituent effects of arenes, each of which provided additional support for the reaction proceeding through the diradical pathway.
The natural product vinaxanthone has demonstrated a remarkable capability to promote nerve growth following injury or transplantation. In rats following total transection of the spinal cord delivery of vinaxanthone enhanced axonal regeneration, remyelination and angiogenesis at the site of injury all leading to an improved reinstatement of motor function. Through the development of a new ynone coupling reaction, chemically edited derivatives of vinaxanthone have been prepared and studied for improved activity. The coupling reaction allows rapid access to new derivatives, wherein n ynone precursors provide n(2) vinaxanthone analogues. These compounds have been tested for their ability to promote neuronal regrowth using laser axotomy, severing axonal connections in Caenorhabditis elegans. This precise microsurgery using C. elegans allows a new in vivo approach for medicinal chemistry based optimization of neuronal growth promoting compounds.
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