title: Synthesis, Biological Evaluation and Molecular Docking of Avicequinone C Analogues as Potential Steroid 5α-Reductase Inhibitors.
abstract: Avicequinone C (5a), a furanonaphthoquinone isolated from the Thai mangrove Avicennia marina has been shown previously to have interesting steroid 5α-reductase type 1 inhibitory activity. In this study, a series of avicequinone C analogues containing furanonaphthoquinone with different degrees of saturation and substituents at the furan ring were synthesized. The resulting synthetic avicequinone C and analogues (5a-f) along with some related compounds including 2,5-dihydroxy-1,4-benzoquinone (6) and natural naphthoquinones such as lawsone (7a) and lapachol (7b) were evaluated for their in vitro cell viability and steroid 5α-reductase type 1 inhibitory activities using the cultured cell line of human keratinocytes (HaCaT). This cell-based bioassay was performed based on a direct detection of the enzymatic product dihydrotestosterone (2) by using a non-radioactive high performance thin layer chromatography (HPTLC) method. Among the furanonaphthoquinones in this series, 5e having a propionic substituent at furan ring possessed approximately 22-fold more potent than the original isolated compound 5a. However, the compounds without furan motif such as 6, 7a and b could not inhibit the activity of steroid 5α-reductase. Molecular docking results of the in silico three-dimensional steroid 5α-reductase type 1-reduced nicotinamide adenine dinucleotide phosphate (NADPH) binary complex was performed via AutoDock Vina and it illustrated that the furanonaphthoquinone moiety and the substituent at furan ring might play a key role as pharmacophores for the steroid 5α-reductase inhibitory activity.
authors.affiliation: Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University.
authors.forename: Wiranpat
authors.initials: W
authors.lastname: Karnsomwan
authors.forename: Ponsawan
authors.initials: P
authors.lastname: Netcharoensirisuk
authors.forename: Thanyada
authors.initials: T
authors.lastname: Rungrotmongkol
authors.forename: Wanchai
authors.initials: W
authors.lastname: De-Eknamkul
authors.forename: Supakarn
authors.initials: S
authors.lastname: Chamni
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D058891:5-alpha Reductase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011809:Quinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D058891:5-alpha Reductase Inhibitors; D011809:Quinones; C000597823:avicequinone C; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase