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

30 November 2021, Version 2
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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, the pharmacokinetic properties of neurotrophins present challenges to their administration. Therefore, neurotrophic small molecules such as the cis- and trans-banglenes offer attractive alternatives. We describe the synthesis and testing of banglene derivatives and establish a structure-activity response for the banglene family. We demonstrate that (–) trans-banglene is the primarily active enantiomer, and that select modifications on the cyclohexene ring of trans-banglene do not significantly impair its bioactivity. Finally, we demonstrate that (–) trans-banglene potentiation of NGF induced neuritogenesis is unaffected by the presence of these Erk1/2, Akt and Pkc inhibitors. Our structure-activity results also suggest that (–) trans-banglene neurotrophic activity and its potentiation of NGF activity might be distinct unassociated processes.

Keywords

neurotrophic
structure-activity relationship
NGF signaling
TrkA signaling
natural product

Supplementary materials

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Title
Supplemental Information A
Description
Supporting information document A includes synthetic protocols, characterization data for all compounds (including purity and enan-tio-enrichment data), HPLC traces, PC 12 cell assay protocols and dose response study of (–) t-BG. Supporting information document A also includes all relevant spectra.
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