title: Structure-activity relationships for withanolides as inducers of the cellular heat-shock response.
abstract: To understand the relationship between the structure and the remarkably diverse bioactivities reported for withanolides, we obtained withaferin A (WA; 1) and 36 analogues (2-37) and compared their cytotoxicity to cytoprotective heat-shock-inducing activity (HSA). By analyzing structure-activity relationships for the series, we found that the ring A enone is essential for both bioactivities. Acetylation of 27-OH of 4-epi-WA (28) to 33 enhanced both activities, whereas introduction of β-OH to WA at C-12 (29) and C-15 (30) decreased both activities. Introduction of β-OAc to 4,27-diacetyl-WA (16) at C-15 (37) decreased HSA without affecting cytotoxicity, but at C-12 (36), it had minimal effect. Importantly, acetylation of 27-OH, yielding 15 from 1, 16 from 14, and 35 from 34, enhanced HSA without increasing cytotoxicity. Our findings demonstrate that the withanolide scaffold can be modified to enhance HSA selectively, thereby assisting development of natural product-inspired drugs to combat protein aggregation-associated diseases by stimulating cellular defense mechanisms.
authors.affiliation: SW Center for Natural Products Research and Commercialization, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona , 250 East Valencia Road, Tucson, Arizona 85706, United States.
authors.forename: E M Kithsiri
authors.initials: EM
authors.lastname: Wijeratne
authors.forename: Ya-Ming
authors.initials: YM
authors.lastname: Xu
authors.forename: Ruth
authors.initials: R
authors.lastname: Scherz-Shouval
authors.forename: Marilyn T
authors.initials: MT
authors.lastname: Marron
authors.forename: Danilo D
authors.initials: DD
authors.lastname: Rocha
authors.forename: Manping X
authors.initials: MX
authors.lastname: Liu
authors.forename: Leticia V
authors.initials: LV
authors.lastname: Costa-Lotufo
authors.forename: Sandro
authors.initials: S
authors.lastname: Santagata
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
authors.forename: Luke
authors.initials: L
authors.lastname: Whitesell
authors.forename: A A Leslie
authors.initials: AA
authors.lastname: Gunatilaka
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D018869:Heat-Shock Response / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry; D014407:Tumor Cells, Cultured; D032341:Withania / Q000737:chemistry; D054358:Withanolides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D013438:Sulfhydryl Compounds; D054358:Withanolides; C009684:withaferin A