Introduce

Osthole (7-methoxy-8-(3-methyl-2-butenyl) coumarin), also known as osthol, is a coumarin derivative first obtained from the Cnidium plant. It can be obtained through extraction and isolation from plants or complete synthesis. It is mainly found in the 14 genera of Umbelliferae (Angelica, Archangelica, Cachrys, Cnidium, Selinum, Ferula, Heracleum, Libanotis, Petroselinum, Pastinaca, Peucedanum, Pimpinella, Prangos, and Seseli) and 17 genera of Rutaceae (Citrus, Clausena, Feronia, Flindersia, Haplophyllum, Limonia, Melicope, Micromelum, Murraya, Myrtopsis, Pentaceras, Phebalium, Pilocarpus, Poncirus, Skimmia, Thamnosma, and Ticorea). Numerous experiments have shown that osthol exhibits various biological activities, including anti-tumor, anti-inflammatory, neuroprotective, osteogenic, cardiovascular protective, antibacterial, and antiparasitic. In addition, some research has been conducted on the optimization and modification of osthol. It can also be found in Compositae and Leguminosae. Osthole is so named due to its highest content found in Fructus Cnidii, which is the dried and mature fruit of Cnidium monnieri (L.) Cusson and commonly applied in the clinical practice of Traditional Chinese Medicine (TCM) to treat male sexual dysfunction and other symptoms[1]. 

Figure 1 Characteristics of Osthole

Sources of posthole

Plant sources

Osthole belongs to simple coumarins, which originate from the phenylpropanoid pathway. The biosynthesis of coumarins starts with the formation of L-phenylalanine, which is transformed into trans-cinnamic acid catalyzed by phenylalanine ammonia-lyase (PLA). Cinnamtae-4-hydroxylase (C4H) catalyzes the conversion of trans-cinnamic acid to 4-coumaric acid, which is further converted into 4-coumaroyl-CoA catalyzed by 4-coumarate-CoA ligase (4CL). The subsequent reaction of 4-coumaroyl-CoA to 2,4-dihydroxy cinnamoyl CoA is performed in the presence of 4-coumaoyl-CoA 2’-hydroxylase. Then the 2,4-dihydroxy cinnamoyl CoA undergoes spontaneous lactonization to form the critical intermediate, umbelliferone. Although the 6-C- and 7-O-prenylation of umbelliferone has been described in vitro, the enzymatic step of umbelliferone prenylation at 8-position still needs further study. Karamat et al. characterized a membrane-bound prenyltransferase (PcPT) in parsley. It was found that PcPT had strict substrate specificity toward umbelliferone and dimethylallyl diphosphate (DMAPP), affording predominant 6-C-prenylated product (demethylsuberosin) and rare 8-C-prenylated derivative (ethanol). O-methylation is one of the most important reactions in coumarin biosynthesis. However, the methylation mechanism has been little known and few enzymes participating in the O-methylation of specific hydroxylated coumarins have been described. The first enzyme specific to bergaptol O-methylation (BMT) was identified in 2004. Another enzyme similar to caffeic acid O-methyltransferase (COMT-S) involved in catalyzing the hydroxylated coumarins in Peucedanum praeruptorum Dunn was identified in 2019. Despite the unclear methylation mechanism, it is to be expected that a similar O-methyltransferase (OMT) catalyzes the methylation of ethanol to produce ostiole.

Proposed pathway of ostiole biosynthesis. PLA phenylalanine ammonia-lyase, C4H cinnamate-4-hydroxylase, 4CL 4-coumarate-CoA ligase, C2’H 4-Coumaroyl CoA 2′-hydroxylase, PT prenyltransferase, DMAPP dimethylallyl diphosphate, OMT O-methyltransferase.

Summary and outlook

Osthole (7-methoxy-8-(3-methyl-2-butenyl) coumarin), also known as osthol, which was first isolated from the Cnidium plant, has demonstrated its antitumor, anti-inflammatory, neuroprotective, osteogenic, cardiovascular protective, antimicrobial, and antiparasitic activities. Although most published studies have focused on the biological activities of ostiole, some derivatives, and analogs of ostiole have also been obtained in recent years through structural modifications. The structural modifications of ostiole typically focus on the lactone ring, 7-methoxyl, 8-isopentenyl, 3,4-double bond of coumarin, or simultaneous modification of multiple sites of ostiole. Most of these compounds exhibit cytotoxicity, HDACs inhibitory activity, AChE inhibitory activity, antibacterial activity, and insecticidal effect. Several compounds show antagonistic effects on smooth muscle contractions of agonists. In the forthcoming years, with the development of the synthesis and extraction of ostiole, as well as investigations of the pharmacological mechanism, the structural modification of ostiole will be easier, more rational, and more valuable. SARs will be supplemented and clear. From the above review, it’s clear to conclude that ostiole and its analogs are promising candidates for the treatment of cancer, neurodegenerative diseases, osteoporosis, and bacterial/fungal/parasitic infections. They are worthy of further research. We hope this review will serve to stimulate research into this fascinating and very useful area, and that it will lead to the design and discovery of ostiole-furnished drugs[2].