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15-Oxospiramilactone (CAS No.: 1053172-87-4) is a diterpene compound derived from natural plants, which has recently attracted widespread attention for its potential pharmacological activity in tumor suppression and anti-inflammatory fields. As one of the active components in Spiraea species, 15-oxoxySpiraeolide exhibits significant inhibitory effects on the Wnt/β-catenin signaling pathway, thereby suppressing the proliferation and tumorigenization of colon cancer cells. Moreover, its ability to regulate multiple inflammation-related targets also gives it important research value in the field of anti-inflammatory therapy. This paper will systematically review the chemical structure and physicochemical properties of 15-oxoated spiraetinol, plant origin and extraction methods, pharmacological activity and mechanism of action, druggability evaluation and pharmacokinetic characteristics, and explore its clinical application prospects and future research directions.
15-Oxy-Spiraetinolide belongs to the diterpene class of compounds with a molecular formula of C20H26O4 and a molecular weight of 330.4240. Its structural feature is a typical diterpene lactone backbone, containing a key 15-oxogroup group, which is considered an important determinant of its biological activity. Multiple cyclic structures and unsaturated bonds exist within the molecule, giving it certain spatial conformations and chemical reactivity characteristics.
In terms of physicochemical properties, the LogP value of 15-oxoxy-spiraetin lactone is 2.1593, indicating moderate lipid solubility, which is beneficial for cell membrane penetration and bioavailability. Its topological polar surface area (TPSA) is 63.6 Ų, indicating good equilibrium between polar and nonpolar environments. Low water solubility (0.0416 mg/mL), which poses certain challenges for drug formulation design. Notably, this compound has a high ability to penetrate the blood-brain barrier, suggesting its potential for central nervous system diseases. In terms of safety, 15-oxoxyspiraetinolide did not show hERG channel inhibition, and Ames-induced mutagenic assays were negative, indicating a favorable preliminary safety.
15-Oxy-Spiraea lactone mainly comes from plants of the Spiraea spp., especially species with higher Spiraea lactone content, such as Spiraea japonica and Spiraea prunifolia. Plants of this genus are widely distributed in East Asia. In traditional Chinese medicine, their whole herb or root is often used medicinally, with effects such as clearing heat and detoxifying, reducing swelling, and relieving pain.
The extraction method typically uses organic solvent extraction combined with column chromatography separation technology. The specific steps include:
In recent years, supercritical CO2 extraction and microwave-assisted extraction technologies have also been attempted to extract this compound to improve extraction efficiency and purity.
Research on 15-oxo-spiraetinolide in tumor biology has mainly focused on colon cancer. Multiple in vitro cell experiments have shown that this compound can significantly inhibit the proliferation and migration of colon cancer cell lines (such as HCT116 and SW480). Its antitumor mechanism is closely related to the inhibition of the Wnt/β-catenin signaling pathway. The Wnt signaling pathway plays a key role in tumor development and abnormal activation promotes cancer cell proliferation, invasion, and drug resistance. 15-Oxy-Spiraetrinolin blocks tumor cell proliferation signals by reducing the nuclear translocation of β-catenin and suppressing the expression of downstream target genes (such as c-Myc and Cyclin D1).
Additionally, animal model studies have shown that 15-oxoated spiraeolide can significantly slow the growth of colon cancer xenograft tumors, suggesting potential in vivo antitumor activity.
Inflammatory responses play an important role in various chronic diseases and tumor microenvironments. 15-Oxy-spiraetinolide regulates various inflammation-related targets, including IL-6, STAT3, TNF, NFKB1, PTGS1/2, NOS2, and others. In vitro experiments have shown that this compound effectively inhibits the secretion of inflammatory factors IL-6 and TNF-α, blocks activation of the STAT3 and NF-κB signaling pathways, and alleviates inflammatory responses.
In addition, 15-oxyspiraetinolide also exhibits regulatory effects on pain-related ion channels such as TRPV1 and TRPA1, suggesting potential in alleviating inflammatory pain. Its inhibitory effect on CASP1 further suggests that it may regulate inflammasome activity, reducing apoptosis of inflammatory cells and cytokine release.
Although current research is limited, the high blood-brain barrier permeability of 15-oxoxyspiraetin suggests its potential role in neuroprotection and central nervous system diseases. Future related research is expected to reveal its potential application value in neuroinflammation and neurodegenerative diseases.
The main mechanism of action of 15-oxoated spireolactone focuses on regulation of signaling pathways, especially Wnt/β-catenin and inflammation-related pathways.
Abnormal activation of the Wnt signaling pathway is a key driver of the development of various tumors. 15-Oxy-spiraetrinide inhibits the expression of Wnt target genes by promoting the degradation of β-catenin and blocking its nuclear translocation, thereby suppressing tumor cell proliferation and migration. This process may involve regulation of GSK-3β kinase activity and its phosphorylation modification of β-catenin.
15-Ohydrokinolin significantly inhibits the expression of IL-6 and TNF-α, blocks activation of the STAT3 and NF-κB signaling pathways, and reduces inflammatory responses. Its inhibitory effect on PTGS1 (COX-1) and PTGS2 (COX-2) reduces prostaglandin synthesis and alleviates inflammatory symptoms. Inhibition of NOS2 (induced nitric oxide synthase) reduces the formation of NO as an inflammatory mediator, further alleviating tissue damage.
Additionally, 15-oxyspiraetinide regulates TRPV1 and TRPA1 ion channels, possibly modulating neuroinflammation and pain transmission by affecting calcium influx.
CASP1 (caspase 1) is a key enzyme for inflammasome activation and is involved in the maturation and release of pro-inflammatory cytokines. The inhibitory effect of 15-oxo-Spiraetinolide on CASP1 suggests it may protect tissue function by regulating inflammasomes, reducing cell apoptosis and inflammatory responses, and protecting tissue function.
15-Odo-Spiraetin shows good potential in terms of druggability. Its molecular weight of 330.4240 complies with the Lipinski rule, and a LogP value of 2.1593 indicates moderate lipid solubility, which benefits membrane permeability and bioavailability. TPSA is 63.6 Ų, indicating good balance between polar and non-polar environments, facilitating oral absorption.
Low water solubility (0.0416 mg/mL) may limit the dissolution and absorption of oral formulations, so bioavailability needs to be improved through formulation modifications (such as nanoparticles and solid dispersions). Its high blood-brain barrier permeability offers potential for treating central nervous system diseases, but potential CNS toxicity is also important.
In terms of safety, 15-oxyspiraetinolide did not show hERG channel inhibition, reducing the risk of cardiotoxicity. Ames-induced mutagenic tests are negative, indicating a low genotoxicity risk. In the future, more comprehensive toxicological evaluations are needed, including studies on long-term toxicity, teratogenicity, and reproductive toxicity.
Pharmacokinetics, current literature reports are limited, but preliminary in vivo studies show this compound has a moderate half-life and good tissue distribution, especially enriched in tumor tissues. Metabolic pathways may involve the hepatic cytochrome P450 enzyme system, and the metabolites and their activity require further study.
15-Ohydrosteneolactone, due to its inhibitory effect on the Wnt/β-catenin signaling pathway, shows promising application prospects in the treatment of solid tumors such as colon cancer. Its anti-inflammatory activity offers a new treatment approach for chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. High blood-brain barrier permeability suggests its potential value in the fields of neuroinflammation and neurodegenerative diseases.
Future research should focus on the following aspects:
As a naturally occurring diterpene compound with significant biological activity, 15-oxoated spireotilone shows broad application prospects in anti-tumor and anti-inflammatory fields. By regulating the Wnt/β-catenin signaling pathway and various inflammation-related targets, it exerts multi-target and multi-pathway pharmacological effects, providing valuable lead molecules for the development of natural product drugs. In the future, by integrating modern medicinal chemistry, molecular biology, and pharmaceutical technologies, in-depth exploration of the pharmacological mechanisms of 15-oxoated spiraetinoid and optimizing its pharmacokinetic properties will help promote its clinical translation and benefit more patients.
Shenshuai
Wenjing
Hedandan
