Synonym name:
Catalogue No.: BP1475
Cas No.: 34080-08-5
Formula: C₃₀H₅₂O₄
Mol Weight: 476.731
Botanical Source: Panax ginseng

Purity:  30%, 90%, 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, up to kgs.

Inquire for bulk scale.

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

Introduction/Overview

In the vast field where traditional medicine and modern pharmacology intersect, ginseng（Panax ginseng C. As the "King of Herbs", the study of pharmacological active ingredients in A. Mey. and its related plants has always been a hot topic in the fields of natural product chemistry and pharmacology. Ginsenosides, as their main active ingredient, are mainly classified into dammarane type triterpenoid saponins based on their glycosidic skeleton, and further divided into protopanaxadiol type (PPD) and protopanaxatriol type (PPT). Protopanaxatriol (PPT), CAS number 34080-08-5, is a key glycoside produced by deglycosylation metabolism of protopanaxatriol type saponins (such as ginsenosides Re, Rg1, Rf, etc.) in vitro and in vivo. Compared to its glycosidic form, aglycones typically have better membrane permeability and bioavailability, thus their direct pharmacological activity is increasingly being valued. In recent years, with the acceleration of global population aging, research on anti-aging and related degenerative diseases has become at the forefront of life sciences. PPT, due to its significant activity in regulating energy metabolism, oxidative stress, cell cycle and apoptosis, telomere maintenance, and other signaling pathways closely related to the core mechanisms of aging, is transforming from a metabolite of a traditional medicinal plant to an anti-aging lead compound with clear molecular targets and broad development prospects. This article aims to systematically review the chemical properties, sources, pharmacological activities of PPT, especially its multi-target mechanism of anti-aging effect, drug evaluation, and prospects for its future translational medicine prospects.

Chemical structure and physicochemical properties

Protonaringenin is a tetracyclic triterpenoid compound belonging to the dammarane type sapogenin. Its systematic chemical name reflects its complex stereostructure: based on the Dammarane skeleton, hydroxyl groups are substituted at positions 3 β, 6 α, 12 β, and 20 (S), and a double bond is introduced between positions C-24 and C-25 on the side chain. This specific hydroxyl substitution pattern (3 β, 6 α, 12 β, 20S) and unsaturated side chain bonds are key features that distinguish it from the protopanaxadiol type (PPD, hydroxyl at position 20, no double bonds) and other triterpenoid compounds.

Its molecular formula is C30H52O4 and its molecular weight is 476.7420. Based on the analysis of drug parameters, the lipid water partition coefficient (LogP) of PPT is 5.3841, indicating its strong lipophilicity; The topological polar surface area (TPSA) is 80.92 Å ², which is relatively small. These two parameters together determine that the water solubility of PPT is extremely low (about 0.0012 mg/mL), which is beneficial for its penetration into the phospholipid bilayer of cells, but also poses challenges for its dissolution and absorption during oral administration. Both computational and experimental data suggest that PPT has a low ability to penetrate the blood-brain barrier (BBB), which may limit its ability to target the central nervous system. However, it does not inhibit hERG potassium channels (hERG inhibition: no) and the Ames test result is negative (0.0), indicating a low risk of cardiac toxicity and genetic toxicity, providing a favorable basis for its subsequent safety development.

Plant sources and extraction methods

The PPT mainly comes from plants of the Panax genus in the Araliaceae family, especially ginseng（Panax ginseng）And Sanqi（Panax notoginseng）. In plants, PPT does not exist in large quantities in the form of free glycosides, but rather serves as the core of saponins' glycosides, which are linked to one or more sugar groups (such as glucose, xylose, arabinose, etc.) through glycosidic bonds to form various protopanaxatriol type saponins, such as ginsenoside Rg1, Re, Rf, etc.

Therefore, there are two main ways to obtain PPT:
1. Direct extraction and separation From the total saponin extract of ginseng or Panax notoginseng, the sugar group of the original ginsenotriol type saponin is cleaved through acid hydrolysis, enzyme hydrolysis, or microbial transformation, releasing free PPT glycosides. Subsequently, high-purity PPT was isolated from the hydrolysis product using separation and purification techniques such as silica gel column chromatography, high performance liquid chromatography (HPLC), and high-speed countercurrent chromatography (HSCCC). The acid hydrolysis conditions are severe, which may produce by-products or damage the structure; Enzymatic hydrolysis and microbial transformation have mild conditions and high selectivity, making them more promising green preparation methods.
2. Chemistry and biosynthesis With the development of synthetic biology, the biosynthesis of PPT or its precursors through metabolic engineering modification of yeast or plant cells has become a research hotspot. In addition, using inexpensive and readily available natural products as starting materials for semi synthesis is also a potential pathway for large-scale production of PPT.

At present, the mainstream approach in laboratory and industry is still to extract, hydrolyze, and purify saponins from plant raw materials.

Pharmacological activity research

The PPT demonstrates a wide range of pharmacological activities, and its research has extended from early enhancement of immunity and anti fatigue to multiple key areas of modern medicine such as anti-tumor, neuroprotection, cardiovascular protection, metabolic regulation, and anti-aging.

1. Anti-aging activity This is the most eye-catching core activity of PPT currently. Research has shown that PPT can delay the aging process of various aging models, such as replicative aging cell models, D-galactose-induced subacute aging mouse models, and natural aging animal models. Specifically, it manifests as prolonging the lifespan of model organisms, improving physiological function decline related to aging (such as exercise endurance and cognitive function), reducing the activity of aging related β - galactosidase (SA - β - gal), and decreasing the expression of aging related secretory phenotype (SASP) factors (such as IL-6, TNF - α).
2. Neuroprotective effect PPT has a protective effect on neurodegenerative disease models such as Alzheimer's disease (AD) and Parkinson's disease (PD). It can improve the learning and memory impairment of AD model animals, reduce the deposition of β - amyloid protein (A β) and excessive phosphorylation of Tau protein; In the PD model, it can protect dopaminergic neurons, alleviate oxidative damage and mitochondrial dysfunction.
3. antitumor activity PPT can inhibit the proliferation, induce apoptosis, autophagy, migration and invasion of many tumor cells (such as lung cancer, liver cancer, breast cancer, colon cancer cells). Its function has the characteristics of multi-target and multi pathway, and its toxicity to certain normal cells is relatively low.
4. Cardiovascular protective effect PPT can improve myocardial ischemia/reperfusion injury, alleviate myocardial cell apoptosis and oxidative stress; At the same time, it has anti atherosclerosis potential and can play a role by regulating lipid metabolism and inhibiting vascular inflammation.
5. Metabolic regulation effect PPT can improve insulin resistance, reduce blood sugar and lipids, and shows therapeutic potential in animal models of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD).

Mechanism of action and molecular targets

The anti-aging and other pharmacological effects of PPT are not achieved through a single target, but like a "multi node regulator" that acts on multiple key hubs in the aging network. The core mechanism and molecular targets can be summarized as follows:

1. Activate energy metabolism and longevity pathway：

   • AMPK（AMP-activated protein kinase）PPT has been confirmed to be an activator of AMPK. AMPK is an energy receptor in cells, and its activation can promote ATP production, inhibit synthetic metabolism, and upregulate downstream longevity related factors such as SIRT1 and FOXO.
   • SIRT1（Sirtuin 1）PPT can upregulate the expression or activity of SIRT1. SIRT1 is an NAD+- dependent deacetylase that plays a central role in regulating metabolism, stress resistance, genomic stability, and cell survival by deacetylating histones and various non histones (such as p53, FOXO, PGC-1 α). The AMPK-SIRT1 positive feedback loop is a key axis for PPT to exert anti-aging effects.

2. Enhance antioxidant defense system：

   • NRF2（Nuclear factor erythroid 2-related factor 2）PPT can activate the NRF2 signaling pathway, promote its translocation from the cytoplasm to the nucleus, and thereby initiate downstream gene transcription driven by a series of antioxidant response elements (ARE), including HMOX1 (heme oxygenase-1)、SOD1 (Superoxide Dismutase 1)、CAT (catalase)Wait. These enzymes together form a powerful endogenous antioxidant defense system, clearing excess reactive oxygen species (ROS), maintaining redox homeostasis, and thus delaying oxidative stress-induced aging.

3. Regulating cell cycle and aging related signals：

   • TP53 (p53) and CDKN1A (p21)P53 is an important tumor suppressor and cellular stress sensor. PPT can regulate the activity of p53 (possibly through SIRT1 deacetylation) and affect the expression of its downstream target p21. P21 is a cyclin dependent kinase inhibitor, and its moderate expression can mediate cell cycle arrest for DNA repair, but sustained high expression can lead to cellular aging. PPT may achieve a balance between DNA damage response and inhibition of excessive aging by finely regulating the p53-p21 axis.
   • FOXO1（Forkhead box O1）PPT can activate FOXO1 transcription factor. The FOXO family is crucial in regulating antioxidant stress, metabolism, cell apoptosis, and autophagy. PPT activates FOXO1 through the AMPK/SIRT1 pathway, thereby upregulating the expression of antioxidant genes and autophagy promoting genes, enhancing cellular stress tolerance.

4. Telomere maintenance：

   • TERT（Telomerase reverse transcriptase）Telomere shortening is a major sign of cellular replicative aging. Telomerase (composed of TERT catalytic subunits, etc.) can maintain telomere length. There are studies suggesting that PPT may indirectly affect the expression or activity of TERT through certain signaling pathways (such as SIRT1), thereby helping to delay telomere depletion, but further evidence of its direct effect is needed.

In summary, PPT synergistically activates AMPK/SIRT1 energy and longevity pathway, NRF2 antioxidant pathway, and cross regulates key factors such as p53/p21 and FOXO through dialogue, forming a multidimensional anti-aging network to combat the driving factors of aging from multiple levels such as energy metabolism, oxidative damage, cell cycle, and genome stability.

Evaluation of drug properties and pharmacokinetics

Despite the significant pharmacological activity of PPT, its pharmacological development still faces some challenges, mainly due to its physicochemical properties.

• Absorption, distribution, metabolism, excretion (ADME)：

  • absorb PPT has strong lipid solubility and poor water solubility, resulting in its low oral bioavailability (F). This is mainly limited by its slow dissolution rate in the gastrointestinal tract and possible first pass effects (metabolized in the intestinal wall and liver). The use of nano formulations (such as liposomes, nanoemulsions, solid dispersions), phospholipid complexes, or prodrug strategies is an effective means of improving their solubility and oral absorption.
  • distribution The high LogP value of PPT is beneficial for its distribution to adipose tissue and certain organs, but its large molecular weight and polarity result in low blood-brain barrier permeability, limiting its direct therapeutic effect on central nervous system diseases. A targeted delivery system needs to be developed to improve its distribution within the brain.
  • Metabolism and excretion PPT is mainly metabolized by the liver cytochrome P450 (CYP) enzyme system in the body, undergoing reactions such as hydroxylation and dehydrogenation, and may also bind with glucuronic acid or sulfuric acid. Its metabolites may still be active. The prototype drug and metabolites are mainly excreted through bile and feces, with less excretion by the kidneys.

• Formulation strategy The research on new drug delivery systems is crucial in order to overcome the bottleneck of PPT's drug efficacy. For example, preparing it into self microemulsions, cyclodextrin inclusion complexes, polymer nanoparticles, etc. can significantly improve its solubility, stability, and biofilm permeability, thereby enhancing oral bioavailability. For local anti-aging applications (such as skin), consideration may be given to developing transdermal drug delivery formulations.

• safety The existing preliminary toxicological data (such as no hERG inhibition and Ames negative) suggest a good safety threshold. However, comprehensive preclinical safety evaluation, including long-term toxicity, reproductive toxicity, carcinogenicity testing, etc., is an indispensable step in its clinical translation.

Clinical application prospects and prospects

As a multi-target anti-aging natural lead compound, PPT has broad clinical application prospects, but solid research is still needed to promote its transformation.

1. Potential application directions：

   • Anti aging health products and drugs Develop functional foods or prescription drugs for delaying overall aging of the body and improving age-related syndromes such as muscle atrophy and weakness. Its multi-target characteristics are in line with the complex nature of aging.
   • Adjuvant therapy for neurodegenerative diseases As an adjuvant therapy for diseases such as AD and PD, it delays disease progression through neuroprotective, anti-inflammatory, and antioxidant mechanisms.
   • Management of metabolic diseases AMPK activation is crucial for improving metabolic disorders such as insulin resistance and fatty liver.
   • Tumor adjuvant therapy and chemoprevention By utilizing its anti-tumor activity and relative protective effect on normal cells, the combination with chemotherapy drugs may have a sensitizing and detoxifying effect; Or for chemical prophylaxis in specific high-risk populations.
   • Skin anti-aging cosmetics Topical application: By activating pathways such as SIRT1 and NRF2 in skin cells, it can combat photoaging and natural aging, reduce wrinkles, and improve skin elasticity.

2. Future research prospects：

   • Deepening of target mechanism Chemical biological methods such as photoaffinity labeled probes and proteomics need to be used to more accurately identify the direct target proteins of PPT and elucidate their initial molecular events.
   • Structural optimization and derivative development Based on the mother core structure of PPT, reasonable chemical modifications are carried out to improve water solubility, targeting, metabolic stability, optimize its activity spectrum, and obtain derivatives with better drug properties.
   • Research on Advanced Drug Delivery System Continue to develop intelligent and targeted nano delivery systems, especially for overcoming the blood-brain barrier and achieving tumor targeted delivery.
   • High quality clinical research After completing the preclinical pharmacology and safety evaluation of the system, we will advance the design of rigorous clinical trials to verify its effectiveness, safety, and optimal application plan in humans.
   • Integration of multi omics and systems pharmacology Using transcriptomics, metabolomics and other techniques, comprehensively characterize the biological effect network of PPT at the system level, providing a basis for its precise application.

Conclusion

As an important active glycoside of ginsenosides in Panax plants, protopanaxatriol (PPT) plays a multiple regulatory role in the core biological process of anti-aging due to its unique tetracyclic triterpenoid chemical structure. It precisely intervenes in key nodes in the aging signaling network such as AMPK/SIRT1, NRF2, p53/p21, FOXO, and exerts the potential to delay aging and prevent aging related diseases from multiple dimensions such as energy metabolism, oxidative stress, and cellular homeostasis. Although its inherent low water solubility and limited bioavailability pose challenges to drug development, modern pharmaceutical and medicinal chemistry strategies provide feasible solutions for this. Digging from the wisdom of traditional Chinese medicine, with the support of modern science and technology, the in-depth study of PPT not only helps to reveal the deep mechanism of natural products' multi target anti-aging, but also lays a solid scientific foundation for its transformation into a new drug or health product to combat the health challenges of aging society. In the future, interdisciplinary collaboration will drive PPT from the laboratory to clinical practice, ultimately benefiting human health.