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.

Novel mechanism of napabucasin, a naturally derived furanonaphthoquinone: apoptosis and autophagy induction in lung cancer cells through direct targeting on Akt/mTOR proteins

“…NB was obtained as a yellow powder at 420 mg, whereas NB-acid was afforded as an orange solid at 160 mg after a purification by silica gel column chromatography. The spectroscopic data of NB and NB-acid was matched with the previous reports [38,40].…”

“…2-Acetylnaphtho[2,3-b]furan-4,9-dione (Napabucasin, NB) and 4,9-Dihydro-4,9-dioxonaphtho[2,3-b]furan-2-carboxylic acid (NB-acid) were synthesized according to previously described procedures [38][39][40]. NB was obtained as a yellow powder at 420 mg, whereas NB-acid was afforded as an orange solid at 160 mg after a purification by silica gel column chromatography.…”

Marine natural products

“…720,721,725 The ability of avicequinone C (Avicennia marina) and synthetic analogues to exhibit cytotoxicity and to inhibit steroid 5a-reductase has been studied. 732…”

Napabucasin and Related Heterocycle-Fused Naphthoquinones as STAT3 Inhibitors with Antiproliferative Activity against Cancer Cells

“…Naphtho [2,3-b]furan-4,9-dione (avicequinone-B, 4) was isolated 15 from the Indian mangrove species Avicennia alba and has recently been reported as a 5α-reductase inhibitor. 16 Furthermore, the gray mangrove (Avicennia marina), which is distributed in Africa, Asia, and Australia, contains the angular analogue of avicequinone-B, naphtho [1,2-b]furan-4,5-dione (NFD, 5), 17 for which activity against cancer cell lines has been reported. 18 Our group has evaluated previously a comparable set of lapacho-analogous compounds as potential antipsoriatic agents against the hyperproliferation of human keratinocytes (HaCaT).…”

“…Besides these lapacho-derived substances, there are unsubstituted furan-fused naphthoquinones found in Avicennia species. Naphtho­[2,3- b ]­furan-4,9-dione (avicequinone-B, 4 ) was isolated from the Indian mangrove species Avicennia alba and has recently been reported as a 5α-reductase inhibitor . Furthermore, the gray mangrove ( Avicennia marina ), which is distributed in Africa, Asia, and Australia, contains the angular analogue of avicequinone-B, naphtho­[1,2- b ]­furan-4,5-dione (NFD, 5 ), for which activity against cancer cell lines has been reported …”