title: Synthesis, stereochemical analysis, and derivatization of myricanol provide new probes that promote autophagic tau clearance.
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.
authors.affiliation: †Department of Molecular Medicine and Alzheimer's Institute, University of South Florida, Tampa, Florida 33613, United States.
authors.forename: Mackenzie D
authors.initials: MD
authors.lastname: Martin
authors.affiliation: ‡Department of Chemistry and Center for Drug Discovery and Innovation, University of South Florida, Tampa, Florida 33620, United States.
authors.forename: Laurent
authors.initials: L
authors.lastname: Calcul
authors.affiliation: ‡Department of Chemistry and Center for Drug Discovery and Innovation, University of South Florida, Tampa, Florida 33620, United States.
authors.forename: Courtney
authors.initials: C
authors.lastname: Smith
authors.affiliation: †Department of Molecular Medicine and Alzheimer's Institute, University of South Florida, Tampa, Florida 33613, United States.
authors.forename: Umesh K
authors.initials: UK
authors.lastname: Jinwal
authors.affiliation: †Department of Molecular Medicine and Alzheimer's Institute, University of South Florida, Tampa, Florida 33613, United States.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Fontaine
authors.affiliation: †Department of Molecular Medicine and Alzheimer's Institute, University of South Florida, Tampa, Florida 33613, United States.
authors.forename: April
authors.initials: A
authors.lastname: Darling
authors.affiliation: ‡Department of Chemistry and Center for Drug Discovery and Innovation, University of South Florida, Tampa, Florida 33620, United States.
authors.forename: Kent
authors.initials: K
authors.lastname: Seeley
authors.affiliation: ‡Department of Chemistry and Center for Drug Discovery and Innovation, University of South Florida, Tampa, Florida 33620, United States.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Wojtas
authors.affiliation: †Department of Molecular Medicine and Alzheimer's Institute, University of South Florida, Tampa, Florida 33613, United States.
authors.forename: Malathi
authors.initials: M
authors.lastname: Narayan
authors.affiliation: §Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
authors.affiliation: ∥ALS Biopharma, LLC, 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
authors.forename: Garry R
authors.initials: GR
authors.lastname: Smith
authors.affiliation: ∥ALS Biopharma, LLC, 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
authors.forename: Allen B
authors.initials: AB
authors.lastname: Reitz
authors.affiliation: ‡Department of Chemistry and Center for Drug Discovery and Innovation, University of South Florida, Tampa, Florida 33620, United States.
authors.forename: Bill J
authors.initials: BJ
authors.lastname: Baker
authors.affiliation: †Department of Molecular Medicine and Alzheimer's Institute, University of South Florida, Tampa, Florida 33613, United States.|‡Department of Chemistry and Center for Drug Discovery and Innovation, University of South Florida, Tampa, Florida 33620, United States.|⊥James A. Haley Veteran's Hospital, 13000 Bruce B. Downs Boulevard, Tampa, Florida 33612, United States.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
mesh_terms: D000818:Animals; D001343:Autophagy; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D036381:Diarylheptanoids / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D000939:Epitopes / Q000378:metabolism; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D024801:Tauopathies / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D036381:Diarylheptanoids; D000939:Epitopes; D054852:Small Molecule Libraries; D016875:tau Proteins; C041794:myricanol