Product Name: Larixyl Acetate
Synonym name: 6-Acetyllarixol
Catalogue No.: BP0844
Cas No.: 4608-49-5
Formula: C₂₂H₃₆O₃
Mol Weight: 348.527
Botanical Source:

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.

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

HPLC of Larixyl Acetate

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

Introduction/Overview

Larixyl Acetate (CAS No.: 4608-49-5) is a naturally occurring compound originally isolated from plants of the genus Larch. As an effective and selective TRPC6 channel inhibitor, larch acetate demonstrates significant bioactivity in regulating cellular calcium homeostasis and signal transduction. In recent years, with in-depth research into the mechanisms of action of the TRPC (Transient Receptor Potential Canonical) channel in various diseases, larchin acetate has gradually become an important candidate molecule for the research and development of novel anti-inflammatory drugs and neuroprotective agents, thanks to its unique selectivity and low toxicity.

This review aims to systematically summarize the chemical structure and physicochemical properties of larch acetate esters, plant origins and extraction methods, pharmacological activity and mechanism of action, druggability evaluation, and pharmacokinetic characteristics. Combined with its application in disease models such as anti-inflammatory, neuroprotection, and endothelial dysfunction, it explores its potential and challenges for future clinical translation, providing a reference for researchers in the field of natural product pharmacology.

Chemical structure and physicochemical properties

The molecular formula of larch acetate is C22H32O3, with a molecular weight of 348.5270. Its chemical structure belongs to the sesquiterpene compounds, with a core sesquiterpene framework unique to larch esters, containing an acetate group. This structure imparts high lipid solubility (LogP about 4.72), making it easy to penetrate cell membranes and the blood-brain barrier (BBB has high permeability), making it suitable for drug development related to central nervous system diseases.

In terms of physicochemical properties, the polar surface area (TPSA) of larch acetate is 46.53 Ų, indicating moderate molecular polarity and conducive to binding to multiple protein targets. Its low water solubility (about 0.0099 mg/mL) suggests that appropriate formulation techniques may be needed in vivo to improve bioavailability. The hERG channel inhibition test was negative, indicating a low risk of cardiotoxicity. Ames mutagenic test results were zero, indicating a low genotoxicity risk.

Plant Origins and Extraction Methods

Larch acetate mainly comes from plants of the larch genus (Larix spp.), and is especially abundant in larch wood, resin, and leaves. Larch species are widely distributed in temperate regions of the Northern Hemisphere and have traditionally been used for wood processing and folk medicinal purposes.

The extraction method typically uses solvent extraction combined with chromatography separation technology. The specific steps include:

1. Raw material pretreatment: collect larch bark, leaves, or resin, dry and crush it.
2. Solvent extraction: Using organic solvents such as ethanol, methanol, or ethyl acetate for extraction to extract the crude extract containing larch acetate.
3. Separation and purification: Target compounds are separated and purified using technologies such as silica gel column chromatography and reversed-phase high-performance liquid chromatography (RP-HPLC).
4. Structural identification: Confirm the structure using nuclear magnetic resonance (NMR), mass spectrometry (MS), and infrared spectroscopy (IR).

In recent years, the application of ultrasound-assisted extraction and supercritical CO2 extraction technologies has improved the extraction efficiency and purity of larch acetate esters, facilitating large-scale production and pharmaceutical development.

Pharmacological activity research

Selective inhibitory effect of TRPC6

Larch acetate, as an effective inhibitor of the TRPC6 channel, has an IC50 of 0.58 μM for human TRPC6-YFP fusion protein, demonstrating high selectivity and potency. In contrast, inhibition of TRPC3-YFP was weaker, with an IC50 of about 6.83 μM, indicating that its targeting of TRPC6 was significantly superior to TRPC3. This selectivity gives it potential therapeutic value in regulating the TRPC6-related calcium signaling pathway.

Anti-inflammatory activity

Multiple in vivo and in vitro experiments have shown that larch acetate has significant anti-inflammatory effects. Its main mechanism involves inhibiting various inflammatory mediators and signaling pathways, including:

• Reduces the expression of pro-inflammatory cytokines IL-6 and TNF-α.
• Inhibits activation of the STAT3 and NF-κB signaling pathways, reducing transcription of inflammatory genes.
• Inhibits the activity of inflammation-related enzymes PTGS1 (COX-1) and PTGS2 (COX-2), reducing inflammatory responses.
• Inhibits CASP1 (caspase 1) activity, blocking the formation of inflammasomes.
• Regulates TRPV1 and TRPA1 channels, relieving inflammation-related pain and neurological responses.
• Inhibits NOS2 (induced nitric oxide synthase) expression to reduce nitric oxide-mediated inflammatory damage.

Neuroprotection and improved endothelial function

Larchin acetate demonstrated good neuroprotective effects in traumatic brain injury (TBI) models. By regulating the TRPC6 channel, it stabilizes intracellular calcium ion concentrations and prevents apoptosis and inflammatory responses caused by calcium overload. Additionally, larch acetate can effectively prevent high-risk human papillomavirus (HPV) infection, suggesting its potential application in viral infections and related inflammatory diseases.

For systemic endothelial dysfunction, larch acetate improves calcium signaling in endothelial cells, restores vasodilatory function, reduces vascular inflammation, and provides excellent vascular protection.

Mechanism of action and molecular targets

The main molecular target of larch acetate is the TRPC6 channel. TRPC6 belongs to the TRP channel family, a non-selective cation channel widely distributed in the cardiovascular, nervous, and immune systems. Calcium influx mediated by the TRPC6 channel is crucial for cellular function regulation, but its overactivation is closely linked to various diseases such as inflammation, fibrosis, and neurodegenerative diseases.

Larchin acetate specifically binds to the TRPC6 channel, blocking its calcium ion permeability, reducing intracellular calcium concentration, and thereby inhibiting activation of downstream inflammatory signaling pathways. The specific mechanisms include:

• Inhibits the NF-κB signaling pathway, reducing the expression of pro-inflammatory genes.
• It blocks STAT3 phosphorylation, suppresses inflammatory responses, and inhibits cell proliferation.
• Inhibits CASP1 activity and blocks inflammasome-mediated pyroptosis.
• Regulates TRPV1 and TRPA1 channels, alleviating neuroinflammation and pain.
• Inhibits PTGS1 and PTGS2, reduces prostaglandin synthesis, and alleviates inflammatory responses.
• Reduces NOS2 expression and reduces inflammation-related oxidative stress.

Additionally, the weak inhibitory effect of larch acetate on TRPC3 channels may have a synergistic effect on its overall pharmacological effects, but its dominant effect remains concentrated in TRPC6.

Druggability evaluation and pharmacokinetics

Druggability parameters

The molecular weight (348.53) and moderate polarity (TPSA 46.53) of larch acetate comply with the Lipinski rule and have good oral bioavailability potential. Its high lipid solubility (LogP 4.72) facilitates cell membrane penetration and blood-brain barrier permeability, making it suitable for drug development for neurological diseases.

Low water solubility (0.0099 mg/mL) suggests the need for formulation optimization (such as nanocarriers, liposomes, etc.) to improve solubility and bioavailability. hERG channel inhibition was negative, and Ames tests showed no mutagenicity, indicating good safety.

Pharmacokinetic characteristics

Currently, systematic pharmacokinetic research on larch acetate ester is relatively limited. Preliminary in vivo experiments show that it is absorbed orally quickly, has a moderate plasma half-life, and can effectively cross the blood-brain barrier to reach effective concentrations in the central nervous system. Liver metabolism mainly occurs through the CYP450 enzyme system, and the metabolites are safe.

In the future, further detailed pharmacokinetic (PK) and pharmacodynamic (PD) studies are needed to clarify their in vivo distribution, metabolic pathways, and excretion characteristics, laying a foundation for clinical development.

Prospects and outlooks for clinical applications

Larchin Acetate, as a naturally derived TRPC6 selective inhibitor, has broad clinical application prospects, mainly reflected in the following aspects:

1. Anti-inflammatory treatment: By inhibiting inflammatory mediators and signaling pathways through multiple targets, larch acetate can be used to treat chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease.

2. Neuroprotection: Its excellent blood-brain barrier penetration and protective effect against traumatic brain injury make it a potential candidate for neurodegenerative diseases (such as Alzheimer's and Parkinson's) and post-traumatic brain injury rehabilitation.

3. Cardiovascular diseases: By regulating endothelial function and vasodilation, larch acetate is expected to be used to treat hypertension, atherosclerosis, and other cardiovascular conditions.

4. Antiviral applications: The preventive effect against HPV suggests its potential in preventing viral infections and related tumors.

However, the low water solubility and pharmacokinetic properties of larch acetate still require optimization through drug design and formulation technology. In addition, preclinical safety evaluation and clinical trial data are still lacking, and systematic research is needed in the future to verify efficacy and safety.

Conclusion

Larch acetate, a natural sesquiterpene compound derived from Larch species, demonstrates unique pharmacological advantages in anti-inflammation, neuroprotection, and endothelial function improvement due to its selective inhibition of TRPC6 channels. Its excellent druggability parameters and safety provide a solid foundation for new drug development. In the future, through in-depth research into mechanisms of action, optimization of pharmacokinetics, and preclinical evaluations, larch acetate is expected to become a novel drug for treating various inflammatory and neurological diseases.

In summary, larch acetate not only enriches the research field of natural product pharmacology but also provides new ideas and directions for the development of multi-target anti-inflammatory and neuroprotective drugs. We look forward to more basic and clinical research in the future promoting its clinical translation and realizing its value in modern medicine.