Avicequinone C Isolated from Avicennia marina Exhibits 5α-Reductase-Type 1 Inhibitory Activity Using an Androgenic Alopecia Relevant Cell-Based Assay System

Abstract

Avicennia marina (AM) exhibits various biological activities and has been traditionally used in Egypt to cure skin diseases. In this study, the methanolic heartwood extract of AM was evaluated for inhibitory activity against 5α-reductase (5α-R) [E.C.1.3.99.5], the enzyme responsible for the over-production of 5α-dihydrotestosterone (5α-DHT) causing androgenic alopecia (AGA). An AGA-relevant cell-based assay was developed using human hair dermal papilla cells (HHDPCs), the main regulator of hair growth and the only cells within the hair follicle that are the direct site of 5α-DHT action, combined with a non-radioactive thin layer chromatography (TLC) detection technique. The results revealed that AM is a potent 5α-R type 1 (5α-R1) inhibitor, reducing the 5α-DHT production by 52% at the final concentration of 10 µg/mL. Activity-guided fractionation has led to the identification of avicequinone C, a furanonaphthaquinone, as a 5α-R1 inhibitor with an IC 50 of 9.94 ± 0.33 µg/mL or 38.8 ± 1.29 µM. This paper is the first to report anti-androgenic activity through 5α-R1 inhibition of AM and avicequinone C.

Synthesis, Biological Evaluation and Molecular Docking of Avicequinone C Analogues as Potential Steroid 5α-Reductase Inhibitors

“…Spectroscopic data of 5a, b, d, and f were matched with the reported natural furanonaphthoquinone structures of avicequinone C, 20) napabucasin, 29) (±)-stenocarpoquinone B, 30) and avicequinone B, 31) respectively. Next, all synthetic avicequinone C analogues 5a-f, quinone 6 and naphthoquinones 7a and b were evaluated for their in vitro cytotoxicity and steroid 5α-reductase inhibitory activities using the HaCaT cell line.…”

“…20) In this work, the HaCaT cells were cultured and treated with all nine test compounds including 5a-f, 6, 7a, and b using the highest concentration, which no cell death more than half population was observed. Aqueous medium of each experiment was collected and partitioned with ethyl acetate for extracting the remaining 1, which was added as an enzyme substrate and the resulting 2, the steroid 5α-reductase product.…”

“…This finding was based on the use of a newly developed nonradioactive human hair dermal papilla cell-based assay, which directly detects dihydrotestosterone (DHT, 2), the enzymatic product, by high performance thin layer chromatography (HPTLC). 20,21) Even though the steroid 5α-reductase inhibitory activity of 5a was not as potent as dutasteride (4), the discovery of a new chemical scaffold has provided a potential for the development of a new group of steroid 5α-reductase inhibitors. Thus, we hypothesized that compounds having a furanonaphthoquinone, similar to 5a and a more simplified structure, naphthoquinone, would be used as the potential steroid 5α-reductase inhibitors.…”

“…The steroid 5α-reductase inhibition was measured based on the amount of dihydrotestosterone (2) produced, determined using HPTLC as previously described. 20,21) Molecular docking using the homologous protein template of steroid 5α-reductase type 1 19) was performed via AutoDock Vina 25) to predict the biomolecular interaction between the 5α-reductase-reduced nicotinamide adenine dinucleotide phosphate (NADPH) binary complex and the respective furanonaphthoquinones. Herein, an essential pharmacophore and inhibitory activity of a potential steroid 5α-reductase inhibitor are discussed.…”

The genusAvicennia, a pioneer group of dominant mangrove plant species with potential medicinal values: a review

“…These naturally occurring compounds are found to be concentrated in the plant's leaf, stem/bark and aerial roots. A number of pharmacologically important phyto-constituents belonging to different classes of phytochemicals which have been isolated include flavonoids (3) (Konig et al 1994;Gonzales et al 2000;Ramirez & Roa 2003;Han et al 2007Han et al , 2008Manilal et al 2009, Sumithra et al 2011bHossain et al 2012;Mahera et al 2013;Jain et al 2014;Ramanjaneyulu et al 2015). A detailed report on their occurrence, chemical structure and bioactivity has been presented in Table 5.…”