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Natural products, as important sources of drug discovery, have attracted much attention due to their structural diversity and broad biological activity. As an important class of natural products, coumarins show broad application prospects in anti-inflammation, antioxidant, and antitumor fields due to their diverse pharmacological activities and good biocompatibility. Dihydroselin (CAS No.: 2221-66-1) is a derivative of 7-hydroxycoumarin, HY-N0573. As a structurally unique coumarin-type compound, it has become a hot topic in pharmacological research of natural products in recent years due to its potential anti-inflammatory activity and favorable druggability parameters.
This paper aims to systematically review the chemical structure and physicochemical properties of Dihydroseselin, plant origin and extraction methods, pharmacological activity, mechanism of action and molecular targets, druggability evaluation, and pharmacokinetic characteristics. Combined with its potential applications in inflammation-related diseases, it explores its clinical translation possibilities and future research directions, providing theoretical basis and practical guidance for the development of natural product drugs.
Dihydroseselin is a derivative of 7-hydroxycoumarin, with a molecular formula of C13H14O4 and a molecular weight of 230.2630. Its core structure is based on the coumarin-based framework, featuring a typical benzo-α-pyranone ring system, and the presence of a 7-position hydroxyl group gives it unique chemical activity and biological functions. Dihydroseselin's LogP value was 3.3123, indicating moderate lipid solubility, which facilitates membrane penetration and distribution in vivo. The polar surface area (TPSA) is 39.44 Ų, and the lower TPSA helps it cross biological barriers, especially the blood-brain barrier. Its low water solubility (0.0083 mg/mL) suggests limited solubility in aqueous media, which may affect its bioavailability.
Structurally, Dihydroseselin's coumarin-based core endows it with natural fluorescent properties, which not only facilitates bioimaging and analytical detection but may also be related to its biological activity. It does not show hERG channel inhibitory activity, suggesting a lower risk of cardiotoxicity. The Ames trial scored 0.9, indicating a low genotoxicity risk and meeting the preliminary safety evaluation requirements.
Dihydroseselin is mainly found in Apiaceae plants, with higher levels in certain medicinal plants such as Saposhnikovia divaricata and Asarum spp.. These plants are used in traditional Chinese medicine to treat rheumatic pain, inflammation, and immune-related diseases, suggesting that Dihydroseselin may be one of its active components.
Common methods for extracting Dihydroselin include solvent extraction and chromatographic separation. Generally, ethanol or methanol is used as extraction solvents, and extraction efficiency is improved through reflux extraction or ultrasonic-assisted extraction. After concentration, the extract was purified using silica gel column chromatography and reversed-phase high-performance liquid chromatography (RP-HPLC). In recent years, the application of supercritical CO2 extraction and membrane separation technology has further improved extraction purity and yield, while reducing the use of organic solvents, aligning with the concept of green chemistry.
The optimization of the extraction process mainly focused on extraction temperature, time, solvent polarity, and solid-liquid ratio to maximize the retention of Dihydroselin's active components and their stability. In addition, the geographical environment, harvest time, and processing method of plant sources also significantly affect their content and quality, necessitating the establishment of standardized raw material control systems.
Pharmacological activity studies of Dihydroseselin mainly focus on anti-inflammatory effects. Multiple in vitro cell models and in vivo animal experiments have shown that Dihydroseselin can significantly inhibit the production of inflammatory mediators and the activation of inflammatory signaling pathways.
In macrophage lines (such as RAW264.7 cells), Dihydroseselin treatment reduced the expression of induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), decreased the release of nitric oxide (NO) and prostaglandin E2 (PGE2), demonstrating potent anti-inflammatory activity. Additionally, it can inhibit the secretion of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), thereby reducing inflammatory responses.
In animal inflammation models, such as the mouse plantar edema model and rat arthritis model, Dihydroseselin significantly reduces tissue swelling and infiltration of inflammatory cells, improving inflammation symptoms. Its anti-inflammatory effect is dose-dependent and has demonstrated good safety and tolerability.
In addition to anti-inflammatory effects, preliminary studies have found that Dihydroseselin possesses certain antioxidant activity, can scavenge free radicals, and reduce oxidative stress damage, which is of great significance for cellular protection during inflammatory pathological processes.
The anti-inflammatory mechanism of Dihydroselin mainly regulates multiple inflammation-related signaling pathways. Its key molecular targets include TNF, NOS2, PTGS2, NFKB1, IL6, IL1B, and others, involving multiple inflammatory mediators and transcription factors.
NF-κB signaling pathway inhibition
NF-κB is a core transcription factor regulating inflammatory responses, and when activated, it promotes the expression of various inflammatory genes. Dihydroselin can inhibit the nuclear translocation of NF-κB, block its binding to DNA, and reduce the expression of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β, thereby alleviating inflammatory responses.
Inhibition of iNOS and COX-2 expression
iNOS and COX-2 catalyze the production of NO and PGE2, respectively, and are key enzymes in the inflammatory process. Dihydroselin reduces the release of inflammatory mediators by inhibiting the expression of these two enzymes, thereby alleviating inflammatory symptoms.
Regulates cytokine networks
Dihydroseselin can regulate the expression levels of various cytokines, balance pro-inflammatory and anti-inflammatory factors, maintain immune homeostasis, and reduce excessive inflammatory damage.
Antioxidant mechanism
By scavenging reactive oxygen species (ROS) and suppressing oxidative stress-related signals, Dihydroseselin protects cells from oxidative damage, indirectly inhibiting inflammatory cascade reactions.
Molecular docking and computational simulation studies further support Dihydroseselin's binding ability to the above targets, suggesting its multi-target coordinated regulation and providing a molecular basis for its anti-inflammatory pharmacological effects.
The druggability parameters of Dihydroselin indicate that it has promising potential for drug development. A molecular weight of 230.2630 conforms to the Lipinski rule, and a LogP value of 3.3123 indicates moderate lipid solubility, which is beneficial for cell membrane penetration and distribution in vivo. The TPSA is 39.44 Ų, and its low polarity surface area helps it cross the blood-brain barrier, supporting its potential application in central nervous system inflammatory diseases.
Low water solubility (0.0083 mg/mL) may limit oral bioavailability, requiring formulation optimization or structural modification to improve solubility. It does not exhibit hERG channel inhibition, reducing the risk of cardiotoxicity. Ames test results indicate that it carries a low genotoxicity risk and is relatively safe.
Pharmacokinetics, Dihydroseselin has good blood-brain barrier permeability, suggesting its potential in treating inflammatory diseases related to the nervous system. The metabolic pathways in vivo are not yet fully understood. Preliminary studies suggest it may be metabolized via the hepatic cytochrome P450 enzyme system, and the activity and toxicity of these metabolites require further study.
Key pharmacokinetic parameters such as in vivo half-life, oral absorption rate, volume of distribution, and clearance rate still lack systematic data, and future evaluation is needed through animal models and preclinical trials.
Given Dihydroseselin's significant anti-inflammatory activity and favorable druggability parameters in inflammation-related diseases, its clinical application prospects in various inflammatory diseases are broad. As the common pathological basis of various chronic diseases, including rheumatoid arthritis, inflammatory bowel disease, neuroinflammation, and metabolic syndrome, Dihydroseselin is expected to become a candidate molecule for novel anti-inflammatory drugs.
In particular, its excellent blood-brain barrier permeability gives it potential application value in neurological inflammatory diseases such as multiple sclerosis, Alzheimer's-related inflammation, and brain injury repair. Additionally, its low toxicity and genetic safety ensure its clinical translation.
Future research should focus on:
By combining modern drug design technology with advantages in natural product resources, Dihydroseselin is expected to become a key breakthrough in anti-inflammatory drug development.
As a derivative of 7-hydroxycoumarin, Dihydroselin, with its unique chemical structure and excellent pharmacological activity, shows broad research and application prospects in the anti-inflammatory field. It regulates inflammatory responses through multiple targets and pathways, offering good safety and druggability, especially its blood-brain barrier permeability, offering new ideas for neuroinflammation treatment.
Although current research on Dihydroselin is still in the basic stage, with advances in extraction techniques, pharmacological mechanism analysis, and pharmacokinetic studies, its potential for clinical translation is promising. Systematic drug development strategies and multidisciplinary collaboration will help Dihydroseselin move from the laboratory to clinical practice, bringing new treatment options for patients with inflammation-related diseases.
