Product name: Lacinilene C
Synonym name: 3,10-Dihydroxy-1,3,5,7-cadinatetraen-9-one
Catalogue No.: BP1866
Cas No.: 41653-72-9
Formula: C₁₅H₁₈O₃
Mol Weight: 246.306
Physical Description: Yellow powder

Purity: 95%~99%
Analysis Method: HPLC-DAD or/and HPLC-ELSD
Identification Method: Mass, NMR
Packing: Brown vial or HDPE plastic bottle
Can be supplied from milligrams to grams. Inquire for bulk scale.

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

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

Introduction/Overview

Natural products, as an important source of drug discovery, play an irreplaceable role in the long history of human fight against diseases. Isolating and identifying small molecule compounds with biological activity from traditional herbs, and elucidating their pharmacological mechanisms, is an important paradigm in modern medicinal chemistry and pharmacology research. Among the many plants with medicinal value, kapok family plants have attracted much attention for their rich secondary metabolites and extensive traditional applications. Among them, from kapok（Bombax malabaricum, also known as Bombax ceiba）Lacinilene C, obtained from root separation, as a structurally unique sesquiterpene like compound, has gradually entered the field of researchers in recent years and demonstrated potential biological activity, especially in the field of anti-tumor.

Qingyu ene C is not a completely new compound, and its first isolation and structural identification can be traced back to the 1970s. The initial research focus was mostly on its role as a stress metabolite in cotton plants, related to the disease resistance of cotton. However, with the advancement of separation technology and the deepening of biological activity screening, researchers have found that this compound also has significant content in the roots of cotton flowers and exhibits various pharmacological activities, especially potential inhibitory effects on malignant tumors such as ovarian cancer. Ovarian cancer, as one of the most deadly gynecological malignancies, has the characteristics of insidious onset, easy recurrence, and easy development of drug resistance, making the search for new, efficient, and low toxicity therapeutic drugs an urgent clinical problem to be solved. The emergence of iridoid C provides a new candidate molecule for the treatment strategy of ovarian cancer.

This review aims to systematically review the current research status of iridoid C, and conduct in-depth exploration from multiple dimensions such as chemical structure, plant origin, pharmacological activity, mechanism of action, and drug efficacy evaluation. It evaluates its value as a lead compound or potential drug molecule, and looks forward to its future research directions and clinical application prospects, in order to provide a comprehensive and professional reference material for researchers in the field of natural product pharmacology.

Chemical structure and physicochemical properties

The chemical structure of Lacinilene C is the basis for its biological activity. From a chemical classification perspective, it belongs to the sesquiterpenoid class of compounds, whose skeleton is composed of three isoprene units. Specifically, the parent nucleus structure of green elmene C is 1,6-dimethyl-4- (1-methylethyl) naphthalene-2,7-diol. This structural feature endows it with unique physicochemical properties.

From the structural analysis, Qingyu ene C is a highly conjugated naphthalene ring system, with two phenolic hydroxyl groups (- OH) and one isopropyl side chain attached to it. The presence of phenolic hydroxyl groups gives it a certain polarity and the ability to form hydrogen bonds, which directly affects its solubility and interaction with biological targets. Its molecular formula is C ₁₅ H ₁₈ O3, with an accurate molecular weight of 246.3060 g/mol. This molecular weight meets the requirement of Lipinski's Rule of Five for molecular weight less than 500, providing a structural basis for its potential oral administration.

In terms of physical and chemical properties, Qingyuene C exhibits moderate lipid solubility. The calculated value of its oil-water partition coefficient (LogP) is 2.6674, indicating that the compound can penetrate the lipid bilayer well, facilitating transmembrane transport and binding to intracellular targets. The polar surface area (TPSA) is 57.53 Å ², which is lower than the thresholds commonly considered for good passive absorption (<140 Å ²) and blood-brain barrier penetration (<90 Å ²). In fact, its blood-brain barrier penetration prediction is "high", suggesting that the compound may have central nervous system activity, which is both an opportunity (such as treating brain metastases) and a challenge (possibly causing central neurotoxicity) in anti-tumor therapy. In terms of water solubility, its predicted water solubility is 0.1629 mg/mL, which belongs to the category of slight solubility. This may limit its bioavailability to some extent and needs to be improved through pharmaceutical methods. In addition, key pharmacological toxicology prediction indicators show that the inhibitory risk of Ulmaceae C on hERG potassium ion channels is "no", and the Ames test (bacterial recovery mutation test) result is 0.0, indicating that it does not have significant cardiac toxicity and genetic toxicity in preliminary predictions, which is a very favorable safety signal.

Plant sources and extraction methods

Qingyuene C was not originally discovered in cotton, but in cotton（Gossypium Phytoflexin was first reported as a phytoalexin in plants. When cotton is infected with pathogenic bacteria (such as Verticillium dahliae）When subjected to adverse stress such as infection or ultraviolet irradiation, it induces the synthesis of a series of sesquiterpenes, including iridoid C, to enhance its own resistance. However, extracting green elmene C from cotton usually results in lower yields and is limited by plant growth status and induction conditions.

At present, the main plant source of green elm C is kapok（Bombax malabaricum, also known as Bombax ceiba）The root. Kapok is a deciduous large tree widely distributed in tropical and subtropical regions of Asia. Its roots, bark, and flowers are used in traditional medicine and are commonly used to treat diseases such as inflammation, diarrhea, and fever. Research has shown that the roots of cotton trees contain abundant secondary metabolites such as terpenes, flavonoids, phenolic acids, etc. Among them, green elmene C is one of its characteristic components. Compared to the inducible production in cotton, the roots of cotton can stably accumulate higher levels of green elmene C, making it a more ideal natural source.

For the extraction and separation of iridoid C, classical natural product chemistry methods are usually used. The basic process includes:
1. Raw material pretreatment Collect the roots of kapok, wash, slice, dry in the shade or at low temperature, and grind them into coarse powder.
2. Solvent extraction According to the moderate polarity of Ulumen C, organic solvents with moderate polarity are often selected for extraction. Common solvents include ethanol, methanol, or their aqueous solutions. For example, by cold soaking or heating reflux extraction with 95% ethanol or methanol, a total extract containing iridoid C can be obtained.
3. Liquid-liquid extraction Suspend the total extract in water and extract it sequentially with solvents of different polarities such as petroleum ether, ethyl acetate, n-butanol, etc. Due to the LogP of Ulumene C being approximately 2.67, it is usually enriched in the ethyl acetate extraction layer.
4. chromatographic separation Systematic chromatographic separation of ethyl acetate extract. Common methods include silica gel column chromatography (gradient elution with different proportions of petroleum ether ethyl acetate or chloroform methanol system), Sephadex LH-20 gel column chromatography (elution with methanol or chloroform methanol system) and preparative high-performance liquid chromatography (Pre HPLC). Through repeated column chromatography and recrystallization, high-purity Ulumene C monomer compounds can be obtained.
5. Structural Identification Using modern spectroscopic techniques such as nuclear magnetic resonance (¹ H-NMR, ¹ ³ C-NMR, HMBC, HSQC), high-resolution mass spectrometry (HR-ESI-MS), etc., the isolated compounds were structurally confirmed and compared with literature reported data.

Pharmacological activity research

The pharmacological activity research of Ulmaceae C is still in the early exploration stage, but existing studies have revealed its potential effects in multiple aspects, among which anti-tumor activity is the most prominent highlight.

Antitumor activity

Multiple in vitro cell experiments have shown that iridoid C has a proliferative inhibitory effect on various tumor cell lines. Of particular concern is its activity against ovarian cancer cells. Research has shown that iridoid C can inhibit the proliferation of human ovarian cancer cell lines (such as SKOV3, A2780, etc.) and induce cell apoptosis in a dose-dependent and time-dependent manner. Its mechanism of action involves multiple signaling pathways and molecular targets, which will be detailed in the next chapter. In addition to ovarian cancer, celulene C also showed certain cytotoxicity to breast cancer, lung cancer, liver cancer and other cell lines, but its selectivity and efficacy varied with cell type. It is worth noting that its toxicity to normal cells is relatively low, demonstrating a certain degree of selectivity, which is an important advantage as a candidate molecule for anti-tumor drugs.

Other pharmacological activities

In addition to its anti-tumor effect, green elmene C has also been reported to have other biological activities:
- Antibacterial activity Due to its role as a phytoprotective agent in cotton, Ulumen C has inhibitory effects on certain plant pathogenic fungi and bacteria. There are research reports that it has certain antibacterial activity against Staphylococcus aureus, Bacillus subtilis, and other bacteria.
- anti-inflammatory activity Partial studies suggest that Ulumen C may exert anti-inflammatory effects by inhibiting the production of inflammatory mediators (such as NO, PGE2) or downregulating inflammatory signaling pathways (such as NF - κ B). This is consistent with the experience of using kapok roots in traditional medicine to treat inflammatory diseases.
- antioxidant activity The phenolic hydroxyl group in its molecular structure endows it with certain free radical scavenging ability, which may exert antioxidant effects by directly clearing reactive oxygen species (ROS) or activating the endogenous antioxidant enzyme system.

Although the above-mentioned activities have been preliminarily reported, most studies are still at the in vitro level, and in vivo pharmacological validation is not yet sufficient. The breadth and depth of its pharmacological effects need further exploration.

Mechanism of action and molecular targets

A deep understanding of the mechanism of action of iridoid C, especially its molecular basis for anti ovarian cancer, is the key to advancing it to preclinical research. Based on existing research and computer-aided drug design (such as molecular docking) predictions, it is possible that iridoid C exerts its anti-tumor effects through multi-target and multi pathway pathways. For ovarian cancer, its potential mechanisms of action and target network mainly include the following aspects:

1. Inducing cell apoptosis：

   • Regulating BCL2 family proteins BCL2 (B-cell lymphoma 2) is a key anti apoptotic protein. Qingyuene C may downregulate the expression of BCL2 and upregulate the levels of pro apoptotic proteins such as BAX and BAK, disrupt mitochondrial membrane potential, promote the release of cytochrome C, and activate the Caspase cascade reaction, ultimately leading to cell apoptosis.
   • Inhibition of STAT3 signaling pathway：STAT3（Signal transducer and activator of transcription 3） Continuously activated in various tumors, promoting cell proliferation, angiogenesis, and inhibiting apoptosis. Qingyu ene C may inhibit tumor cell growth and induce apoptosis by suppressing the phosphorylation of STAT3, blocking its nuclear translocation and transcription of downstream target genes such as Survivor and Cyclin D1.

2. Intervention of estrogen signaling：

   • Regulating ESR2 activity ESR2 (Estrogen receptor beta) plays a complex role in the occurrence and development of ovarian cancer. Qingyuene C may act as a regulator of ESR2, by affecting its transcriptional activity and altering downstream gene expression profiles, thereby inhibiting the proliferation of estrogen dependent ovarian cancer cells.

3. Inhibit tumor invasion and metastasis：

   • Inhibition of MMP2 activity Matrix metalloproteinase-2 (MMP2) is a key enzyme that degrades the extracellular matrix and is closely related to tumor invasion and metastasis. Qingyuene C may inhibit the expression or activity of MMP2, reduce the degradation of the basement membrane by tumor cells, and thus inhibit their migration and invasion ability.

4. Regulating oxidative stress and hypoxic microenvironment：

   • Activate NFE2L2 pathway NFE2L2 (Nuclear factor erythroid 2-related factor 2, NRF2) is a core transcription factor for cellular antioxidant stress. Qingyu ene C may activate NRF2, upregulate the expression of a series of antioxidant enzymes (such as HO-1 and NQO1), and protect normal cells from oxidative damage. However, excessive activation of NRF2 in tumor cells may also lead to chemotherapy resistance, and its effects have a dual nature.
   • Inhibit HIF1A signal：HIF1A（Hypoxia-inducible factor 1-alpha） It is a key factor for tumors to adapt to the low oxygen microenvironment, driving angiogenesis and glycolysis. Qingyuene C may inhibit tumor angiogenesis by suppressing the protein expression or transcriptional activity of HIF1A, reducing the secretion of angiogenic factors such as VEGF.

5. Affects drug transport and genomic stability：

   • Adjust ABCB1 function ABCB1 (ATP binding cassette sub family B member 1, also known as P-glycoprotein) is the main drug efflux pump that leads to multidrug resistance (MDR) in tumors. Qingyu ene C may act as an inhibitor or substrate of ABCB1, affecting the concentration of chemotherapy drugs in cells. This is both a potential strategy to overcome drug resistance and may also pose risks of drug interactions.
   • Inhibit TOP1 activity TOP1 is an enzyme essential for DNA replication and transcription. Qingyu ene C may inhibit tumor cell proliferation by suppressing the activity of TOP1, leading to DNA damage.
   • Affects MAPT functionality MAPT (microtubule associated protein tau) is associated with microtubule stability. Qingyu ene C may indirectly interfere with microtubule dynamics and affect cell division by affecting MAPT.
   • Regulating TYR activity TYR (Tyrosinase) plays a crucial role in melanin synthesis, and its significance in ovarian cancer is not yet clear, but it may intersect with other signaling pathways.

In summary, the anti ovarian cancer effect of iridoid C is not driven by a single target, but through a complex network that simultaneously acts on multiple biological processes such as apoptosis, proliferation, metastasis, angiogenesis, and drug resistance. This "multi-target" characteristic is a major advantage of it as a natural product, but it also increases the complexity of mechanism research.

Evaluation of drug properties and pharmacokinetics

To promote the clinical application of iridoid C from laboratory research, a comprehensive pharmacological evaluation must be conducted. Based on the provided parameters and existing knowledge, we can conduct a preliminary assessment of its pharmacokinetic (ADME) properties and potential risks.

Physical and chemical properties and drug like properties

The molecular weight (246.3), LogP (2.67), and number of hydrogen bond donors/acceptors (phenolic hydroxyl groups) of Ulumen C all conform to the Lipinski Five Rules, indicating its fundamental potential as an oral drug. The TPSA is 57.53 Å ², indicating good oral absorption and cell membrane permeability. However, its low water solubility (0.1629 mg/mL) may become a bottleneck limiting its oral bioavailability. In the development of formulations, it may be necessary to use solubilization techniques such as solid dispersions, liposomes, cyclodextrin inclusion complexes, etc. to improve their solubility and dissolution rate.

Pharmacokinetic prediction

• absorb Based on its good lipid solubility and moderate molecular weight, iridoid C may be mainly absorbed through passive diffusion in the gastrointestinal tract. However, low water solubility may lead to incomplete absorption and significant individual differences.
• distribution High LogP and blood-brain barrier permeability suggest that it has a large distribution volume and may be widely distributed in various tissues, including the brain. This is beneficial for the treatment of brain tumors or metastases, but caution should be taken against central nervous system side effects.
• Metabolism As a naphthalene ring compound, iridoid C is likely to undergo phase I metabolism (such as hydroxylation) in the liver through cytochrome P450 enzyme systems (such as CYP450), and then combine with phase II metabolism (such as glucuronidation and sulfation) to form a more water-soluble metabolite that is excreted from the body. The specific metabolic pathways and enzyme subtypes need to be elucidated through in vitro and in vivo experiments.
• excretion Metabolites and small amounts of prototype drugs may be mainly excreted through bile and urine.

Toxicological prediction

The key toxicological predictions are encouraging. The risk of hERG inhibition is' no ', greatly reducing its risk of causing QT interval prolongation and fatal arrhythmias. The Ames test result is 0.0, indicating that it has no mutagenicity in the bacterial recovery mutation test, and the genetic toxicity risk has been preliminarily ruled out. However, this is only an in vitro prediction, and comprehensive toxicological evaluation (including acute toxicity, chronic toxicity, reproductive toxicity, carcinogenicity, etc.) still needs to be conducted in animal models.

potential challenges

1. Poor water solubility: is the main factor limiting its in vivo exposure and oral bioavailability.
2. High blood-brain barrier penetrability Although beneficial for the treatment of brain metastases, it may also lead to central nervous system toxicity such as dizziness and drowsiness, which require close monitoring in in vivo experiments.
3. Metabolic stability The phenolic hydroxyl group is a common site in phase II metabolism, which may lead to significant first pass effects and low oral bioavailability.
4. Multi target characteristics Although beneficial for anti-tumor treatment, it also increases the risk of off target effects, which may lead to unexpected pharmacological effects or toxicity.

Clinical application prospects and prospects

As a natural product with novel structure and multi-target anti-tumor activity, the clinical application prospects of green elmene C are mainly reflected in the following aspects:

1. Lead compounds for new drugs against ovarian cancer Given its significant activity against ovarian cancer cells and preliminary safety advantages, Ulmaceae C is an ideal lead compound for the development of novel anti ovarian cancer drugs. Future research should focus on:

   • structural optimization Using green elmene C as the parent nucleus, structural modification is carried out through medicinal chemical methods, such as introducing water-soluble groups (such as phosphate esters and amino acid esters) to improve water solubility; Or modify the naphthalene ring to enhance selectivity and affinity for specific targets such as STAT3 and BCL2, while reducing off target effects.
   • In vivo efficacy verification Establish a xenograft model of ovarian cancer (CDX or PDX model), and systematically evaluate the anti-tumor effect, dose-response relationship, and toxicity of Ulumen C and its derivatives in vivo.
   • Combination therapy strategy Exploring the synergistic effect of Ulmus tinctorius C with commonly used chemotherapy drugs (such as paclitaxel, carboplatin) or targeted drugs (such as PARP inhibitors) in clinical practice, in order to overcome drug resistance and reduce toxic side effects.

2. Overcoming multidrug resistance The potential regulatory effect of iridoid C on ABCB1 makes it a potential adjuvant drug for reversing tumor multidrug resistance. By inhibiting the drug efflux pump, it can increase the accumulation of chemotherapy drugs in drug-resistant tumor cells and restore their sensitivity.

3. Treat other illnesses Based on its anti-inflammatory, antioxidant and antibacterial activities, celulene C or its derivatives also have certain development potential in the treatment of chronic inflammatory diseases (such as arthritis, enteritis), oxidative stress related diseases (such as neurodegenerative diseases) and infectious diseases. Especially its high blood-brain barrier penetration gives it a unique advantage in treating brain diseases such as glioblastoma and Alzheimer's disease.

4. As a pharmacological tool The unique "multi-target" mode of action of iridoid C makes it an excellent chemical probe for studying the regulation of signal networks in complex diseases such as cancer. Studying its interactions with different targets can help reveal new mechanisms of disease occurrence and development.

Conclusion

Ulumen C, a sesquiterpene like compound originating from the roots of cotton, is gradually transforming from a plant stress metabolite into a small molecule with potential medicinal value. Its unique naphthalene ring skeleton, good drug like properties, preliminary safety signals, and pharmacological activity against multiple targets such as ovarian cancer make it a natural product lead compound worthy of further research. However, current research is still in a very early stage, and the road from "compounds" to "drugs" is still long and challenging. Low water solubility, potential metabolic instability, and complex multi-target mechanisms are the main bottlenecks it faces.

The future research focus should be on: optimizing the structure through systematic structure-activity relationship studies to improve its pharmacokinetic properties and enhance targeting; Utilizing modern molecular biology techniques such as CRISPR-Cas9 gene editing and proteomics to elucidate its precise targets and signaling network in vivo; And rigorously validate its efficacy and safety in various in vivo models. Only in this way can we fully tap into the medicinal potential of Ulmaceae C and bring new hope for the treatment of difficult to treat diseases such as ovarian cancer. The excavation of the treasure trove of natural products is endless, and the story of green elmene C has just begun.