Product name: 13-alpha-(21)-Epoxyeurycomanone
Synonym name:
Catalogue No.: BP1795
Cas No.: 138809-10-6
Formula: C₂₀H₂₄O₁₀
Mol Weight: 424.402
Botanical Source: Eurycoma longifolia
Physical Description: Cryst.
Type of Compound: Diterpenoids

Purity: 95%~99%
Analysis Method: HPLC-DAD or/and HPLC-ELSD
Identification Method: Mass, NMR
Packing: Brown vial or HDPE plastic bottle
The product could be supplied from milligrams to grams. Inquire for bulk scale.
We provide solution to improve the water-solubility of compounds, thereby facilitating the variety of activity tests and clinic uses.

For Reference Standard and R&D, Not for Human Use Directly.

HPLC of 13-alpha-(21)-Epoxyeurycomanone

HNMR of 13-alpha-(21)-Epoxyeurycomanone

Storage conditions：Short-term storage at 2~8℃, long-term storage at -20 ~ -80℃

Introduction/Overview

Invasive fungal infection is an increasingly serious global public health challenge, among which the incidence rate and mortality of candidasis caused by candida species (especially candida albicans) remain high. Existing antifungal drugs, such as azoles, polyenes, and echinocandins, face many limitations in clinical application, including increasingly common drug resistance, significant toxic side effects, and complex drug interactions. Therefore, discovering lead compounds with novel structures and unique mechanisms of action from natural products has become an important strategy for the development of antifungal drugs.

Kuan Ying ketone compounds are a class of compounds mainly derived from traditional medicinal plants in Southeast Asia Kuanyingmu genus The bitter lignin tetracyclic triterpenoids have attracted much attention for their significant anti malarial, anti-inflammatory, and cytotoxic activities. As a structurally modified unique member of this family, 13 α (21) - epoxy ketone has attracted widespread interest in the field of natural product pharmacology in recent years due to its potent antifungal activity demonstrated in vitro and preliminary in vivo models. Its unique 13,21-epoxy bridge structure may endow it with a mode of action different from conventional antifungal drugs. This article aims to provide a systematic review of the chemical properties, plant sources, pharmacological activities, mechanisms of action, pharmacological evaluation, and clinical application potential of 13 α (21) - epoxy ketone, in order to provide comprehensive scientific references for the development of innovative antifungal drugs based on this compound.

Chemical structure and physicochemical properties

The chemical system name of 13 α (21) - epoxy ketone is (1S, 4R, 5S, 7R, 8S, 10R, 12S, 13S) -4,8,12-trihydroxy-13- (2-hydroxypropan-2-yl) -1,5,7,10-tetramethyl-16-oxatetracyclic [9.7.0.0 ¹, ¹³. 0 ⁴, ⁸] octadecane-2,14,17-trione. Its CAS registration number is 138809-10-6.

The core skeleton of this compound is a highly oxidized lignin type tetracyclic triterpene. Its most significant structural feature is the formation of a critical ethylene oxide bridge (13 α, 21 epoxy) between C-13 and C-21 positions, which greatly affects the three-dimensional conformation and chemical reactivity of the molecule and is considered a key pharmacophore for its biological activity. The molecule also contains multiple oxygen-containing functional groups: one hydroxyl group (C-4, C-8) on each of the A and B rings, one hydroxyl group (C-12) on the D ring, and three ketone carbonyl groups at C-2, C-14, and C-17 positions. The presence of these polar groups makes their molecules exhibit strong hydrophilicity.

Based on computational and experimental data, its key physicochemical properties are as follows: molecular weight is 424.40 g/mol. The calculated lipid water partition coefficient (LogP) is -0.65, indicating that the compound has a high degree of hydrophilicity, which is in sharp contrast to traditional hydrophobic antifungal drugs such as azoles. The topologically polar surface area (TPSA) is as high as 166.28 Å ², further confirming the presence of numerous hydrogen bond acceptor and donor sites on its molecular surface. The predicted water solubility is good, about 2.33 mg/mL. These properties suggest that its transmembrane permeability may be limited, especially its ability to penetrate the blood-brain barrier is predicted to be "low", which is an unfavorable factor for the treatment of central nervous system fungal infections, but may help reduce the risk of central neurotoxicity. Preliminary toxicity screening showed no significant inhibitory effect on hERG potassium channels (indicating a low potential risk of arrhythmia), and the Ames test result was 0.6 (negative), indicating no significant genetic toxicity.

Plant sources and extraction methods

13 α (21) - epoxy kaempferol is mainly isolated from plants of the genus kaempferol in the family Sapindaceae, especially Kuanying Wood The plant is widely distributed in Southeast Asia. In traditional medicine in Malaysia, Indonesia and other countries, its roots and bark are often used to treat fever, malaria, indigestion and infectious diseases.

The extraction and separation of this compound from plant materials typically follows the following process:
1. Raw material pretreatment Collect the roots or stem bark of Platycodon grandiflorus, clean, dry, and crush into coarse powder.
2. Solvent extraction The most commonly used method is to extract using a medium polarity solvent. Methanol or ethanol water mixed solvents are widely used due to their good solubility and extraction efficiency for lignin compounds. Cold immersion, hot reflux, or ultrasound assisted extraction methods can be used.
3. Preliminary enrichment After concentrating the crude extract under reduced pressure, the resulting paste is often subjected to liquid-liquid extraction using solvents such as petroleum ether, ethyl acetate, and n-butanol in sequence. 13 α (21) - epoxy ketone is mainly enriched in the extraction sites of ethyl acetate and n-butanol due to its polarity.
4. Separation and purification Column chromatography is a crucial step in separating the active site. Normal phase silica gel column chromatography is commonly used for preliminary separation using gradient elution systems of chloroform methanol or dichloromethane methanol. Subsequently, modern chromatographic techniques such as reverse phase silica gel (e.g. C18) column chromatography, preparative thin-layer chromatography, or high-performance liquid chromatography are used to further purify the target fraction until high-purity monomer compounds are obtained. The separation process usually requires monitoring by TLC or HPLC, and structural confirmation by techniques such as nuclear magnetic resonance and mass spectrometry.

In recent years, in order to reduce the consumption of organic solvents and improve efficiency, some green extraction techniques such as supercritical CO ₂ extraction and microwave-assisted extraction have also been explored and applied to the extraction of ketones.

Pharmacological activity research

The most prominent pharmacological activity of 13 α (21) - epoxy ketone is its Broad spectrum and potent antifungal activity Especially targeting the Candida genus.

• Antifungal activity Numerous in vitro studies have confirmed that this compound exhibits significant inhibitory activity against various clinically relevant Candida species, including Candida albicans, Candida albicans, Candida krusei, Candida tropicalis, and Candida parapsilosis. Its minimum inhibitory concentration value is usually in the micromolar range, and even reaches sub micromolar levels for some strains, with activity superior to or equivalent to some first-line antifungal drugs (such as fluconazole). It is worth noting that it has also shown good inhibitory effects on some clinical isolates of fluconazole resistant Candida, suggesting its potential to overcome azole resistance.
• Anti biofilm activity The formation of Candida biofilm is an important cause of chronic infections and drug tolerance. Research has shown that 13 α (21) - epoxy ketone not only inhibits the growth of planktonic Candida, but also effectively interferes with and destroys the formation of Candida biofilms, reduces the metabolic activity of fungal cells inside the biofilm, and enhances the sensitivity of the biofilm to antifungal drugs.
• synergistic effect When combined with existing antifungal drugs such as fluconazole, amphotericin B, and caspofungin, this compound often exhibits synergistic or additive effects, significantly reducing the effective concentration of the combined drug. This provides the possibility for developing combination therapy regimens to reduce low toxicity and delay the development of drug resistance.
• Preliminary in vivo activity In limited animal model studies (such as a mouse model of systemic Candida infection), the administration of 13 α (21) - epoxyketone has been shown to reduce fungal load on target organs such as the kidneys and improve the survival rate of infected animals, preliminarily verifying its in vivo effectiveness.

In addition to antifungal activity, this compound has also been reported to have moderate anti malaria activity and some anti-inflammatory effects, but its main research focus is still on the field of antifungal activity.

Mechanism of action and molecular targets

Unlike traditional single target antifungal drugs, the antifungal effect of 13 α (21) - epoxyketone involves synergistic interference from multiple targets and pathways, which may be the reason for its high efficiency and low susceptibility to drug resistance. The currently revealed and speculated mechanisms of action and molecular targets include:

1. Destruction of cell membrane structure and function：

   • Inhibition of ergosterol synthesis pathway This compound may interfere with the biosynthesis of ergosterol, a key component of fungal cell membranes, by inhibiting lanosterol 14 α - demethylase. This is similar to the effect of azole drugs targeting CYP51 (encoded by the ERG11 gene), but their chemical structure is different and may bind to different sites of the enzyme.
   • Cell wall synthesis interference Research has shown that it can affect the activity of chitin synthase 3 and may interfere with the complex of β -1,3-glucan synthase, thereby disrupting the integrity of the cell wall. This involves the targets CHS3 and FKS1 respectively.
   • Changes in membrane permeability Through the above effects and possible direct membrane interactions, it leads to an increase in cell membrane permeability, leakage of contents, and ultimately cell death.

2. Toxicity factor inhibition：

   • Adhesion and invasion This compound can downregulate the expression of Candida albicans silk specific adhesive ALS3, thereby weakening the fungal adhesion and invasion ability to host epithelial cells, which is the key first step in establishing infection.
   • Morphological transformation The transition of Candida from yeast phase to hyphal phase is an important virulence factor. 13 α (21) - epoxy ketone can effectively inhibit this morphological transition process.

3. Stress response pathway interference：

   • Heat shock protein 90 inhibition HSP90 is a key molecular partner for fungi to cope with environmental stress, including antifungal drug stress. Inhibiting HSP90 function can disrupt the stress response network of Candida, making it more sensitive to various stresses (including other antifungal drugs) and preventing it from developing resistance through evolution.

4. Energy metabolism inhibition：

   • α - glucosidase inhibition This compound has been shown to inhibit alpha glucosidase activity, which may interfere with fungi 'utilization of carbohydrates, affect their energy metabolism, and thus inhibit growth.

In summary, 13 α (21) - epoxy ketone exerts a powerful "multi pronged" fungicidal effect by simultaneously attacking multiple key life processes of Candida, including cell membrane, cell wall, virulence factors, stress pathways, and energy metabolism. This multi-target mode of action makes it difficult for fungi to develop high-level drug resistance through a single gene mutation, which is its core advantage as a novel antifungal lead compound.

Evaluation of drug properties and pharmacokinetics

Although 13 α (21) - epoxybenzophenone exhibits excellent activity in vitro, its clinical application still needs to overcome many hurdles in drug evaluation.

• Analysis of drug properties According to the "Five Rules" preliminary judgment, its molecular weight (424) is slightly higher than usual, with a large number of hydrogen bond donors (about 4) and acceptors (about 9), and a low LogP value. These features conform to the characteristics of the "beyond Rule of 5" class of compounds, which typically face challenges in oral bioavailability. Its high TPSA and good water solubility also indicate limited passive transmembrane absorption capacity.
• Pharmacokinetic prediction and challenges：
  • absorb After oral administration, its high polarity may lead to poor absorption in the gastrointestinal tract and low bioavailability. It may be necessary to overcome this through prodrug strategies (such as esterification modification to increase lipid solubility) or the development of non oral routes of administration (such as intravenous injection, topical application).
  • distribution The predicted blood-brain barrier penetration is low, which limits its therapeutic application for central nervous system infections, but may also reduce related central side effects. Its distribution volume may be small, mainly distributed in extracellular fluid.
  • Metabolism As a compound containing multiple hydroxyl and epoxy groups, it is likely to be a substrate for liver metabolic enzymes such as cytochrome P450 and UDP glucuronosyltransferase, which may undergo oxidation, reduction, or binding reactions. It is necessary to conduct in-depth research on its specific metabolic pathways, major metabolites and their activity/toxicity, and evaluate potential drug drug interaction risks.
  • excretion It is expected that the prototype drug and its metabolites will mainly be excreted through the kidneys.
• Preliminary Safety Assessment The existing limited data (hERG negative, Ames negative) provide good early safety signals. However, comprehensive preclinical toxicology studies, including acute toxicity, subchronic toxicity, reproductive toxicity, and potential reactivity assessments of their epoxy groups, are essential.
• Considerations for formulation development In order to improve its solubility, stability, and bioavailability, advanced drug delivery technologies such as nanocrystals, liposomes, micelles, or cyclodextrin inclusion complexes may be required.

Clinical application prospects and prospects

As a multi-target antifungal lead compound with a novel mode of action, 13 α (21) - epoxy ketone has broad clinical application prospects, but the road ahead is long.

Potential application directions：
1. Treatment of drug-resistant candidiasis This compound or its structurally optimized derivatives have the potential to become an effective alternative or complementary treatment option for the increasingly severe azole resistant Candida infections.
2. Combination medication components Utilizing its synergistic effect with existing drugs, develop fixed dose compound formulations to reduce the dosage of each component, minimize toxic side effects, broaden the antibacterial spectrum, and delay the development of drug resistance.
3. Topical preparations for local use: In view of its strong anti biofilm activity, local drugs such as gel, creams, gargles or suppositories developed for the treatment of oral candidiasis, vaginal candidiasis or cutaneous candidiasis can avoid the absorption and distribution problems faced by systematic administration.
4. Medical Device Coatings Apply it as a surface coating for medical devices such as central venous catheters and urinary catheters to prevent Candida biofilm related infections.

Future research directions and challenges：
1. Research on Structural Optimization and Structure Performance Relationship Systematically modifying structures to maintain or enhance their antifungal activity while improving their pharmacokinetic properties (such as increasing membrane permeability and metabolic stability). Focus on studying the role of key pharmacophores such as epoxy bridges, hydroxyl groups, and ketone carbonyl groups.
2. In depth study on the mechanism of action Using chemical biology methods such as photoaffinity labeling and proteomics to accurately identify the protein targets it directly acts on, and elucidate the detailed molecular mechanisms of its multi-target network regulation.
3. Comprehensive preclinical development Complete pharmacological, pharmacokinetic, and toxicological evaluations that comply with preclinical research guidelines for new drugs, and establish stable raw material processes and quality standards.
4. Exploration of New Delivery Systems Actively researching new delivery technologies such as nano drug delivery systems to improve their in vivo fate and achieve targeted delivery and controlled release.

Conclusion

13 α (21) - epoxy ketone is a bitter lignin compound with a unique 13,21-epoxy bridge structure discovered from traditional medicinal plants. It stands out as a highly valuable lead molecule for antifungal drugs due to its broad-spectrum and potent antifungal activity, especially its inhibitory effect on drug-resistant strains and biofilms, as well as its ability to interfere with multiple mechanisms such as ergosterol synthesis, cell wall construction, virulence expression, stress response, and energy metabolism. Although it faces challenges in terms of oral bioavailability and drug development, these obstacles are expected to be overcome through rational drug chemical modifications, innovative administration strategies, and in-depth mechanism research. In the future, research on 13 α (21) - epoxy ketone may not only lead to the emergence of a new generation of antifungal drugs, but also provide new ideas and tools for understanding the biology of fungal pathogens and developing multi-target anti infective therapies. Continuing to deepen its exploration is the only way to transform this natural treasure into a clinical treatment tool.