title: The structure-activity relationships of mono-THF ACGs on mitochondrial complex I with a molecular modelling study.
abstract: Annonaceous acetogenins (ACGs) are one of the most powerful groups of mitochondrial complex I inhibitors. In this study, 24 ACGs with different chemical structures have been tested against mitochondrial complex I isolated in our laboratory. Molecular modelling study of the six mono-tetrahydrofuran (THF) ACGs in these 24 compounds has been performed to investigate the relationship between their inhibitory activity and chemical structures. IC50 of every ACGs against mitochondrial complex I was determined with a micro plate reader. The results show that every ACG can inhibit mitochondrial complex I and the six mono-THF ACGs' activities are in agreement with their molecular modelling results. It is suggested that proper length and flexibility of the alkyl spacer moiety, which links the THF and the α,β-unsaturated Q-lactone ring moieties, are essential for the potent activity. Both the number of hydroxyl groups and stereochemical structures of mono-THF ACGs impact the activity.
authors.affiliation: a Nanjing University of Chinese Medicine, Pharmaceutical Institute , Nanjing 210046 , P.R. China.
authors.forename: Yun-Jie
authors.initials: YJ
authors.lastname: Miao
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Xu
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Chen
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
mesh_terms: D054378:Acetogenins / Q000737:chemistry*; D000818:Animals; D005663:Furans / Q000737:chemistry*; D007783:Lactones / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D054378:Acetogenins; D005663:Furans; D007783:Lactones; C018674:tetrahydrofuran
keywords: mitochondrial complex I; molecular modelling; mono-THF annonaceous acetogenins; structure–activity relationship