Truncated militarinone fragments identified by total chemical synthesis induce neurite outgrowth

A group of natural products produced by entomopathogenic fungi has recently been shown to induce neurite outgrowth in the absence of nerve growth factor (NGF) in pheochromocytoma PC-12 cell culture. After completion of a total synthesis program, we continued our efforts in reducing complexity by synthetically preparing truncated analogs. Using this approach we were able to not only significantly simplify the structures but also decrease the minimum concentration needed for neuritogenic activity by a factor of 20. This activity was suppressed in the presence of an ERK1/2 inhibitor suggesting activation of the mitogen activated protein kinase (MAPK) pathway as a potential mode of action of these pyridone alkaloids.