Structure-Activity-Relationship and Bioactivity of Neurotrophic trans-Banglene

Neurotrophic small molecule natural products are functional analogs of signaling proteins called neurotrophins, which cause a pro-growth, pro-survival, or pro-differentiation response in neuronal cells. While these phenotypic responses are desirable to combat neurodegenerative disease progression, neurotrophin proteins possess pharmacokinetic properties that present challenges to their administration in living organisms, whether in biomedical studies or as therapeutics. Small molecules such as the cis- and trans-banglenes offer attractive alternatives to activate neurotrophic responses. We describe the synthesis and testing of banglene derivatives to establish a structure-activity response for the banglene family. Notably, during the course of our studies trans-banglene was shown to cause nerve growth factor (NGF)-potentiated neuritogenesis that was markedly stronger than the neuritogenic effects of trans-banglene alone. We demonstrate that only (–) trans-banglene is active, while its (+) enantiomer is not, and further demonstrate that select modifications on the cyclohexene ring of trans-banglene does not impair its bioactivity. Finally, to probe the relationship between (–) trans-banglene’s mechanism of ac-tion and canonical NGF signal transduction pathways, we employed kinase inhibitors targeting Pkc, Akt1/2/3 and Erk1/2, designed to inhibit NGF-induced neurotrophic signaling. Interestingly, (–) trans-banglene potentiation of NGF-induced neuri-togenesis was unaffected by the presence of these kinase inhibitors. Collectively, these results suggest a dual-mode of action for (–) trans-banglene (both neurotrophic alone and strongly potentiating of NGF activity), and an independence of its po-tentiating action on Pkc and Erk1/2 enzymatic activity.