Synthesis, stereochemical analysis, and derivatization of myricanol provide new probes that promote autophagic tau clearance

  • ACS Chem Biol. 2015 Apr 17;10(4):1099-109. doi: 10.1021/cb501013w.
Mackenzie D Martin  1 ,  Laurent Calcul  2 ,  Courtney Smith  2 ,  Umesh K Jinwal  1 ,  Sarah N Fontaine  1 ,  April Darling  1 ,  Kent Seeley  2 ,  Lukasz Wojtas  2 ,  Malathi Narayan  1 ,  Jason E Gestwicki  3 ,  Garry R Smith  4 ,  Allen B Reitz  4 ,  Bill J Baker  2 ,  Chad A Dickey  1  2  5
Affiliations
  • 1. †Department of Molecular Medicine and Alzheimer's Institute, University of South Florida, Tampa, Florida 33613, United States.
  • 2. ‡Department of Chemistry and Center for Drug Discovery and Innovation, University of South Florida, Tampa, Florida 33620, United States.
  • 3. §Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States.
  • 4. ∥ALS Biopharma, LLC, 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
  • 5. ⊥James A. Haley Veteran's Hospital, 13000 Bruce B. Downs Boulevard, Tampa, Florida 33612, United States.
PMID: 25588114 DOI: 10.1021/cb501013w
Abstract

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.

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