Amentoflavone

Amentoflavone , a bisapigenin , is one of the best inhibitors in the class of flavonoids , since its active dose is about 0.12uM.
Amentoflavone (C30H18O10) is a well-known biflavonoid occurring in many natural plants. This polyphenolic compound has been discovered to have some important bioactivities, including anti-inflammation, anti-oxidation, anti-diabetes, and anti-senescence effects on many important reactions in the cardiovascular and central nervous system, etc. Over 120 plants have been found to contain this bioactive component, such as Selaginellaceae, Cupressaceae, Euphorbiaceae, Podocarpaceae, and Calophyllaceae plant families.
Amentoflavone is a natural product with several associated biological effects.Its ability to block NF-xβ is the key for its anti-inflammatory potential. BETs were identified as NF-xβ promoters, with JQ-1 being highly effective in psoriasis models.

Biflavonoid with anti-inflammatory, anti-viral and cancer chemopreventive activity. It inhibits vascularization of tumors by blocking the activity of angiogenic VEGFs. Blocks the induction of COX-2 and up-regulates PPAR-γ. It is a negative modulator of the GABAA receptor at the benzodiazepine binding site.

Amentoflavone is a biflavonoid originally isolated from Selaginella. It has a wide variety of biological effects including antibacterial, antioxidant, antiviral, antidiabetic, and neuroprotective activities. Amentoflavone has antiviral activity against the influenza A subtypes H1N1 and H3N2, influenza B, and herpes simplex virus 1 (EC50s = 3.1 and 4.3, 0.56, and 17.9 µg/ml, respectively). It has antidiabetic effects such that it dose-dependently increases insulin receptor phosphorylation and activation and inhibits hydrolysis of p-nitrophenyl phosphate (p-NPP) catalyzed by protein tyrosine phosphatase 1B (PTP1B; IC50 = 7.3 µM). Amentoflavone reduces the time mice spend immobile in the forced swim test, a measure of antidepressant efficacy, in a dose-dependent manner.

Amentoflavone, a biflavanoid, is ubiquitously found in plants such as Calophyllum inophyllum, Eucommia ulmoides, Selaginella doederleinii, Paulownia tomentosa var. tomentosa, Ginkgo biloba, Juglans sigillata, Hypericum perforatum. A wide variety of bioactivities such as anti-viral, anti-inflammatory, anti-tumor, antidepressant, anti-oxidant, anti-microbial, analgesic, antiplasmodial, leishmanicidal, lowering blood lipid and hepatoprotective activities have been reported for amentoflavone and its derivatives. Due to the limited natural abundance, the massive production of amentoflavone is not possible from natural resources. Therefore, total synthesis of amentoflavone would be significant as it will be able to solve the availability issue of amentoflavone. Although the synthesis of amentoflavone through Suzuki-reaction was reported two decades ago, which was to link the flavonyl-8-boronic acid with the 3'-iodoflavone to produce amentoflavone, no synthetic effort has been made ever since to explore an alternative scheme such that the flavonyl3'-boronic acid ester can be linked to the 8-iodoflavone through Suzuki coupling. It would be highly beneficial to the scientific community if this alternative scheme is successful, as this will provide a similar but different route for the synthesis of amentoflavone and other similar biflavonoids, because the preparation of flavonylboronic acid, the key intermediate for the synthesis of biflavonoids, from the corresponding halogenated flavone is sometimes problematic due to steric hindrance or unfavorable electronic effects from neighboring substituting groups in the aromatic ring. Therefore, the goal of this work is to provide an alternative synthetic scheme for the production of amentoflavone and other similar biflavonoids utilizing the coupling of flavonyl-3'-boronic acid ester and 8-iodoflavone, instead of the reported method which was based on the coupling of two different intermediates, the flavonyl-8- boronic acid and the 3'-iodoflavone [10]. Here we describe an efficient synthetic pathway to generate amentoflavone.
https://www.hilarispublisher.com/open-access/total-synthesis-of-amentoflavone-2161-0444-1000302.pdf

Amentoflavone (C30H18O10) is a common biflavonoid chemically named as 8-[5-(5,7-dihydroxy-4-oxo-4H-chromen-2-yl)-2-hydroxyphenyl]-5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one, which naturally occurs in many plants. It is also considered as an apigenin dimer linked by a C3′-C8′′ covalent bond. This compound was firstly isolated by Okigawa and his colleagues in 1971 from three plants of the Selaginella species (Selaginella tamariscina (Beauv.) Spring, Selaginella nipponica, and Selaginella pachystachys) .
https://www.mdpi.com/1420-3049/22/2/299/htm

Amentoflavone is a biflavonoid originally isolated from Selaginella. It has a wide variety of biological effects including antibacterial, antioxidant, antiviral, antidiabetic, and neuroprotective activities. Amentoflavone has antiviral activity against the influenza A subtypes H1N1 and H3N2, influenza B, and herpes simplex virus 1 (EC₅₀s = 3.1 and 4.3, 0.56, and 17.9 μg/ml, respectively). It has antidiabetic effects such that it dose-dependently increases insulin receptor phosphorylation and activation and inhibits hydrolysis of p-nitrophenyl phosphate (p-NPP) catalyzed by protein tyrosine phosphatase 1B (PTP1B; IC₅₀ = 7.3 μM). Amentoflavone reduces the time mice spend immobile in the forced swim test, a measure of antidepressant efficacy, in a dose-dependent manner.

Yellow crystalline powder, easily soluble in methanol, almost insoluble in ether, derived from Selaginella and fir branches and leaves.

Amentoflavone, is isolated from an Et acetate ext. of the whole plant of Selaginella tamariscina. It has been shown to have antitumor activity, such as mitochondria-mediated apoptotic cell death. Amentoflavone can interact with many medications by being a potent inhibitor of CYP3A4 and CYP2C9, which are enzymes responsible for the metabolism of some drugs in the body.

ChEBI: Amentoflavone is a biflavonoid that is obtained by oxidative coupling of two molecules of apigenin resulting in a bond between positions C-3 of the hydroxyphenyl ring and C-8 of the chromene ring. A natural product found particularly in Ginkgo biloba and Hypericum perforatum. It has a role as a cathepsin B inhibitor, an antiviral agent, an angiogenesis inhibitor, a P450 inhibitor and a plant metabolite. It is a biflavonoid, a hydroxyflavone and a ring assembly.

Biflavonoid with anti-inflammatory, anti-viral and cancer chemopreventive activity. It inhibits vascularization of tumors by blocking the activity of angiogenic VEGFs. Blocks the induction of COX-2 and up-regulates PPAR-γ. It is a negative modulator of the GABAA receptor at the benzodiazepine binding site.

[1] JI HONG HWANG. Antibacterial effect of amentoflavone and its synergistic effect with antibiotics.[J]. Journal of microbiology and biotechnology, 2013, 23 7: 953-958. DOI: 10.4014/jmb.1302.02045
[2] SHENG YU. A Review on the Phytochemistry, Pharmacology, and Pharmacokinetics of Amentoflavone, a Naturally-Occurring Biflavonoid.[J]. Molecules, 2017, 22 2. DOI: 10.3390/molecules22020299
[3] SOJUNG LEE. The biflavonoid amentoflavone induces apoptosis via suppressing E7 expression, cell cycle arrest at sub-G phase, and mitochondria-emanated intrinsic pathways in human cervical cancer cells.[J]. Journal of medicinal food, 2011, 14 7-8: 808-816. DOI: 10.1089/jmf.2010.1428
[4] ZHEN ZHANG. Amentoflavone protects hippocampal neurons: anti-inflammatory, antioxidative, and antiapoptotic effects.[J]. Neural Regeneration Research, 2015, 10 7: 1125-1133. DOI: 10.4103/1673-5374.160109
[5] Y M LIN. Antiviral activities of biflavonoids.[J]. Planta medica, 1999, 65 2: 120-125. DOI: 10.1055/s-1999-13971
[6] MINKYUN NA. Protein tyrosine phosphatase 1B inhibitory activity of amentoflavone and its cellular effect on tyrosine phosphorylation of insulin receptors.[J]. Biological & pharmaceutical bulletin, 2007, 30 2: 379-381. DOI: 10.1248/bpb.30.379
[7] ISMAIL O. ISHOLA . Antidepressant and anxiolytic effects of amentoflavone isolated from Cnestis ferruginea in mice[J]. Pharmacology Biochemistry and Behavior, 2012, 103 2: Pages 322-331. DOI: 10.1016/j.pbb.2012.08.017