Isofraxidin: Synthesis, Biosynthesis, Isolation, Pharmacokinetic and Pharmacological Properties

Abstract

Isofraxidin (7-hydroxy-6, 8-dimethoxy coumarin) (IF) is a hydroxy coumarin with several biological and pharmacological activities. The plant kingdom is of the most prominent sources of IF, which, among them, Eleutherococcus and Fraxinus are the well-known genera in which IF could be isolated/extracted from their species. Considering the complex pathophysiological mechanisms behind some diseases (e.g., cancer, neurodegenerative diseases, and heart diseases), introducing IF as a potent multi-target agent, which possesses several herbal sources and the multiple methods for isolation/purification/synthesis, along with the unique pharmacokinetic profile and low levels of side effects, could be of great importance. Accordingly, a comprehensive review was done without time limitations until February 2020. IF extraction methods include microwave, mechanochemical, and ultrasound, along with other conventional methods in the presence of semi-polar solvents such as ethyl acetate (EtOAc). In addition to the isolation methods, related synthesis protocols of IF is also of great importance. From the synthesis point of view, benzaldehyde derivatives are widely used as precursors for IF synthesis. Along with the methods of isolation and biosynthesis, IF pharmacokinetic studies showed hopeful in vivo results of its rapid absorption after oral uses, leading to different pharmacological effects. In this regard, IF targets varieties of inflammatory mediators including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-α (TNF-α), and matrix metalloproteinases (MMPs). thereby indicating anticancer, cardioprotective, and neuroprotective effects. This is the first review on the synthesis, biosynthesis, isolation, and pharmacokinetic and pharmacological properties of IF in combating different diseases.

Fungal Endophytes as Efficient Sources of Plant-Derived Bioactive Compounds and Their Prospective Applications in Natural Product Drug Discovery: Insights, Avenues, and Challenges

“…Isofraxidin has also shown anti-hypertension effects via inhibiting the activity of angiotensin I converting enzyme (ACE). Isofraxidin protects axons and dendrites against amyloid β (Aβ 25–35) and inhibits neuron-degenerating enzyme monoamine oxidase B [ 124 ].…”

Coumarins and Coumarin-Related Compounds in Pharmacotherapy of Cancer

“…In addition to the anticancer activity, coumarins have various pharmacological properties, including anti-HIV, antihypertensive, analgesic, antihyperlipidemic, anti-inflammatory and anticoagulant effects [ 46 , 182 ]. Conversion of prothrombin to thrombin is a crucial step in the coagulation cascade.…”

“…Additionally, hydroxy coumarin derivatives are multi-target agents that exhibit anticancer, antioxidant, hepatoprotective, antidiabetic, neuroprotective, anxiolytic, antidepressant, antibacterial and cardioprotective effects. One of these hydroxy coumarins, isofraxidin, has been revealed to attenuate several signaling pathways, such as NO, PGE2, TNF-α, IL-6, COX-2, iNOS, TLR4 leading to play an important role in the curation of several diseases [ 46 ].…”

“…Several strategies such as maceration, reflux, ultrasonic-assisted and microwave extraction methods are used for the isolation and purification of coumarin compounds. Perkin, Von Pechmann, Knoevenagel and Wittig organic reactions are some of reactions that coumarins can be synthesized [ 46 ]. In the biosynthetic origin of coumarins, the shikimic acid pathway plays an important role.…”

“…In this pathway, there are several enzymatic steps leading to occur chorismic acid, cinnamic acid, p-coumaric acid and umbelliferone. Moreover, the cytochrome P450 enzymes have a crucial role in the ortho-hydroxylation of cinnamic acid leading to occur umbelliferone, scopoletin and isofraxidin [ 46 , 48 ].…”