Synthesis, Stereochemical Analysis, and Derivatization of Myricanol Provide New Probes That Promote Autophagic Tau Clearance

We
previously discovered that one specific scalemic preparation
of myricanol (1), a constituent of Myrica
cerifera (bayberry/southern wax myrtle) root bark,
could lower the levels of the microtubule-associated protein tau (MAPT).
The significance is that tau accumulates in a number of neurodegenerative
diseases, the most common being Alzheimer’s disease (AD). Herein,
a new synthetic route to prepare myricanol using a suitable boronic
acid pinacol ester intermediate is reported. An X-ray crystal structure
of the isolated myricanol (1) was obtained and showed
a co-crystal consisting of (+)-aR,11S-myricanol (2) and (−)-aS,11R-myricanol (3) coformers. Surprisingly, 3, obtained from chiral separation from 1, reduced
tau levels in both cultured cells and ex vivo brain
slices from a mouse model of tauopathy at reasonable mid-to-low micromolar
potency, whereas 2 did not. SILAC proteomics and cell
assays revealed that 3 promoted tau degradation through
an autophagic mechanism, which was in contrast to that of other tau-lowering
compounds previously identified by our group. During the course of
structure–activity relationship (SAR) development, we prepared
compound 13 by acid-catalyzed dehydration of 1. 13 had undergone an unexpected structural rearrangement
through the isomyricanol substitution pattern (e.g., 16), as verified by X-ray structural analysis. Compound 13 displayed robust tau-lowering activity, and, importantly, its enantiomers
reduced tau levels similarly. Therefore, the semisynthetic analogue 13 provides a foundation for further development as a tau-lowering
agent without its SAR being based on chirality.