Product name: Tomatine
Synonym name:
Catalogue No.: BP1726
Cas No.: 17406-45-0
Formula: C₅₀H₈₃NO₂₁
Mol Weight: 1034.2
Botanical Source: Lycopersicon esculentum
Physical Description:
Type of Compound: Alkaloids

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, upto kilograms..

Inquire for bulk scale.

HPLC  of  Tomatine

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

Introduction/Overview

Tomatine (CAS number: 17406-45-0) is a substance mainly found in tomatoes（Lycopersicon esculentum Mill.， Currently classified as Solanum lycopersicum）Glycoside alkaloids in the green parts of plants, such as stems, leaves, and immature fruits. As a secondary metabolite of plants, tomato alkaloids play a key role in the plant defense system, able to resist the invasion of pathogens, insects, and herbivores. In recent years, with the deepening of pharmacological research on natural products, tomato alkaloids have received widespread attention in the pharmacological community due to their extensive biological activities, especially their potential anti-tumor effects. Research has shown that tomato alkaloids not only induce neurotoxicity through unique RIP1 kinase and caspase independent pathways, upregulate apoptosis inducing factor (AIF), but also inhibit 20S proteasome activity, demonstrating the potential for multi-target action. Especially in solid tumor models such as colorectal cancer, tomato alkaloids have shown regulatory effects on multiple key targets such as AMPK, MCL1, STAT3, ABC transporters, suggesting that they may become a promising anti-tumor lead compound. This article aims to systematically review the chemical structure, plant origin, pharmacological activity, mechanism of action, and medicinal properties of tomato alkaloids, and to provide prospects for their clinical applications.

Chemical structure and physicochemical properties

Lycopene is a steroid glycoside alkaloid, whose molecular structure is composed of hydrophobic steroid aglycones (tomatidine) connected to a hydrophilic oligosaccharide chain through glycosidic bonds. This oligosaccharide chain typically consists of two molecules of glucose, one molecule of galactose, and one molecule of xylose, forming a large polar head. Its molecular formula is C50H83NO21, with a molecular weight of up to 1034.2000 daltons. This unique "amphiphilic" structure (with one end being a hydrophobic steroid nucleus and the other end being a hydrophilic sugar chain) is the structural basis for its interaction with biofilms and the production of various biological activities.

In terms of physicochemical properties, the lipid water partition coefficient (LogP) of tomato alkaloid glycosides is 1.3637, indicating that they have a certain degree of lipophilicity, but their large sugar chain structure gives them a high polar surface area (TPSA: 337.8600 Å ²). Its water solubility value is 0.3237 (usually referring to logS or related measures, indicating limited solubility), belonging to compounds that are slightly soluble in water. These parameters collectively determine its absorption and distribution characteristics within the organism. In addition, preliminary pharmacological predictions indicate that lycopene has a low ability to penetrate the blood-brain barrier and has no significant inhibitory effect on hERG potassium channels (suggesting a low potential risk of cardiac toxicity), and the Ames test result is 0.0 (indicating no mutagenicity), providing some basis for its relative safety.

Plant sources and extraction methods

Lycopene mainly comes from plants of the tomato genus in the Solanaceae family, especially in immature green tomato fruits and in the stems and leaves of tomatoes, where its content is relatively high. As the fruit matures and turns red in color, the content of tomato alkaloids significantly decreases and is converted into other metabolites, which is also one of the reasons why mature tomatoes are safe to consume. Its biosynthetic pathway originates from cholesterol and is formed through a series of hydroxylation, amination, and glycosylation reactions.

Solvent extraction is commonly used in laboratory and industrial extraction of tomato alkaloid glycosides. The common process includes: extracting or refluxing dried and crushed tomato stems, leaves, or immature fruit materials using polar solvents such as methanol, ethanol, or aqueous ethanol. After concentration, the extraction solution is preliminarily purified by utilizing the characteristic of tomato alkaloid glycosides that can form salts with acids and dissolve in water, and then react with bases to form free precipitates. Further refinement can be achieved through column chromatography techniques, such as using silica gel, macroporous adsorption resin, or reverse phase C18 chromatography materials, combined with gradient elution separation. Modern separation techniques such as high-speed countercurrent chromatography (HSCCC) can also be used for efficient preparation of high-purity tomato alkaloid glycosides. The optimization of extraction process mainly focuses on improving yield, maintaining activity, and environmental friendliness.

Pharmacological activity research

The pharmacological activity research of tomato alkaloids has revealed that they have multiple biological effects, among which anti-tumor activity is the most prominent.

1. Antitumor activity Numerous in vitro and in vivo studies have confirmed that lycopene has inhibitory effects on proliferation and induces apoptosis in various cancer cell lines, particularly exhibiting significant activity in colorectal cancer. Its function is not limited to cytotoxicity, but also includes inhibiting cell migration and invasion, indicating its potential for anti metastasis.
2. neurotoxicity Tomato alkaloids can trigger a unique programmed cell death in neuroblastoma and other neurorelated tumor cells. This mode of death does not rely on classical caspase protease and RIP1 kinase signaling, but rather induces mitochondrial dysfunction, leading to the translocation of apoptosis inducing factor (AIF) from mitochondria to the nucleus, causing chromatin agglutination and large-scale DNA fragmentation, known as "caspase independent apoptosis" or "parthanatos".
3. Proteasome inhibitory activity The 20S proteasome is a key machine for protein degradation within cells, and its functional abnormalities are closely related to the occurrence and development of tumors. Lycopene has been identified as a natural proteasome inhibitor that can directly or indirectly interfere with its chymotrypsin like or trypsin like activity, leading to misfolding and accumulation of damaged proteins in cells, thereby triggering endoplasmic reticulum stress and cell apoptosis.
4. Antibacterial and antifungal activity As a defense molecule of plants, lycopene has inhibitory effects on various bacteria and fungi. The main mechanism is that its amphiphilic structure can bind to sterols in microbial cell membranes (such as ergosterol in fungi), disrupting membrane integrity and causing content leakage.
5. Immune regulation and anti-inflammatory activity Research suggests that lycopene may exert anti-inflammatory effects by regulating immune related receptor signaling pathways such as TLR4, affecting the expression of inflammatory factors.

Mechanism of action and molecular targets

The anti-tumor mechanism of tomato alkaloid glycoside is complex, involving network regulation of multiple pathways and targets. In models such as colorectal cancer, its targets mainly include:

1. Energy metabolism and apoptosis regulation targets：

   • AMPK（PRKAA1）Lycopene can activate AMP activated protein kinase (AMPK), which is the energy sensor of cells. The activation of AMPK inhibits synthetic metabolic pathways such as mTOR, induces cell cycle arrest and autophagy, and promotes apoptosis.
   • Bcl-2 family (MCL1, BCL2)Lycopene can downregulate the expression of anti apoptotic proteins MCL1 and BCL2, disrupt mitochondrial outer membrane stability, promote the release of pro apoptotic factors such as cytochrome C, and activate endogenous apoptotic pathways.

2. Signal transduction and transcriptional activation targets：

   • STAT3 Signal transduction and transcription activator 3 (STAT3) is an important oncogenic transcription factor. Lycopene can inhibit the phosphorylation (activation) of STAT3 and suppress the transcription of downstream genes related to proliferation (such as Cyclin D1), survival (such as Survivor), and angiogenesis (such as VEGF).

3. Drug efflux and metabolic targets：

   • ABC transporter protein (ABCB1/P-gp, ABCG2/BCRP)These proteins are the main cause of multidrug resistance (MDR) in tumors. Research has shown that lycopene may act as a substrate or inhibitor to interfere with the function of these efflux pumps, thereby reversing drug resistance and increasing the intracellular concentration of chemotherapy drugs.
   • Carboxyesterase (CES1, CES2)These enzymes are involved in prodrug activation or drug metabolism. The effect of lycopene on its activity may alter the sensitivity of tumor cells to certain chemotherapy drugs, such as irinotecan.

4. Extracellular matrix degradation and immune recognition targets：

   • Matrix metalloproteinase-2 (MMP2)Lycopene can inhibit the expression or activity of MMP2, thereby reducing the ability of cancer cells to degrade the basement membrane and extracellular matrix, and inhibiting invasion and metastasis.
   • Toll like receptor 4 (TLR4)By regulating TLR4 signaling, lycopene may affect the immune response and inflammatory response in the tumor microenvironment.

5. Integration of core mechanisms：

   • Proteasome inhibition Direct inhibition of the 20S proteasome is one of its core mechanisms, leading to the accumulation of ubiquitinated proteins, activation of unfolded protein response (UPR), and apoptosis signals.
   • AIF mediated caspase independent apoptosis In the neurotoxic model, lycopene induces mitochondrial membrane potential loss, promotes AIF release and translocation into the nucleus, and executes a unique death program.

These targets are not isolated, and tomato alkaloids are likely to form a synergistic anti-tumor effect by simultaneously acting on multiple links such as energy metabolism, apoptosis balance, signal transduction, and drug disposal.

Evaluation of drug properties and pharmacokinetics

Although tomato alkaloid glycosides have significant in vitro activity, their medicinal properties face challenges mainly due to their high molecular weight and complex sugar based structure.

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

  • absorb High molecular weight and polarity may limit its oral bioavailability. Glycoside bonds are easily hydrolyzed by gut microbiota or glycosidases in the digestive tract, producing glycosylated tomato alkaloids, the latter of which may have different activity from the prototype.
  • distribution Due to its high molecular weight and TPSA, its transmembrane diffusion ability is limited, and tissue permeability may be poor. It is predicted that its blood-brain barrier permeability is low, which limits its effect on central nervous system tumors, but may also reduce the risk of central neurotoxicity.
  • Metabolism As a glycoside, its main metabolic pathway may be hydrolysis and deglycosylation. The phase I and phase II metabolic enzymes in the liver may also be involved in its metabolic transformation.
  • excretion The prototype drug and its metabolites may be mainly excreted through bile and kidneys.

• Preliminary evaluation of safety：

  • The existing data suggests that it has a low risk of inhibiting hERG channels and a negative Ames test, which is its advantage. However, as an alkaloid, its acute toxicity, subchronic toxicity, and potential effects on the digestive and nervous systems still need to be comprehensively evaluated. Its membrane disrupting activity may cause non selective toxicity to normal cells, especially cholesterol rich cell membranes, while killing cancer cells.

• Formulation strategy：
  To enhance its pharmacological properties, advanced drug delivery technologies may be required. For example, preparing it into liposomes, nanoparticles, or polymer micelles can improve its water solubility, enhance tumor targeting (through EPR effect or active target modification), protect it from premature degradation, and potentially reduce systemic toxicity.

Clinical application prospects and prospects

Lycopene, as a multi-target anti-tumor natural product, has broad clinical application prospects but is also full of challenges.

• Potential application directions：

  1. Adjuvant or combination therapy for colorectal cancer Given its inhibitory effect on multiple key targets in colorectal cancer, especially its potential to reverse ABC transporter mediated drug resistance, lycopene may be used as a sensitizer in combination with existing chemotherapy drugs (such as 5-fluorouracil and oxaliplatin) to improve efficacy and overcome drug resistance.
  2. Developing drugs based on their unique mechanism of action The caspase independent apoptosis and proteasome inhibition mechanism induced by it provides a new approach for the treatment of tumors resistant to traditional apoptosis inducers.
  3. As a lead compound for structural optimization Based on its structure, improving its pharmacokinetic properties, enhancing selectivity, and reducing toxicity through chemical modifications (such as simplifying sugar chains and modifying steroid nuclei) is an important direction in medicinal chemistry research.

• challenges faced：

  1. Drug bottleneck The main obstacles to its clinical application are high molecular weight, low bioavailability, potential metabolic instability, and non selective membrane interactions.
  2. Complexity of mechanism of action Multi targeting is both an advantage and a disadvantage, and it is necessary to more accurately clarify the key targets and pathways that are effective in order to avoid off target effects.
  3. Comprehensive preclinical and clinical evaluation Systematic toxicology studies, appropriate animal model validation of diseases, and final human clinical trials are needed to confirm its safety and efficacy.

• Future Prospects：
  Future research should focus on: ① using systems biology and computational chemistry methods to more accurately depict its target network; ② Conduct in-depth pharmacokinetic research to clarify its in vivo fate; ③ Actively exploring new nano drug delivery systems to overcome their physical and chemical defects; ④ Conduct more effective preclinical studies on combination therapy to find the best treatment plan. The research on tomato alkaloids not only has the potential to generate new anti-tumor drugs, but also provides an important paradigm for understanding the pharmacological effects of glycoside alkaloids.

Conclusion

Lycopene is a glycoside alkaloid derived from tomato plants, which has important pharmacological activity. It exhibits unique potential in anti-tumor (especially colorectal cancer) by regulating multiple targets such as AMPK, STAT3, proteasome, and inducing caspase independent apoptosis. Despite the challenges posed by its large molecular structure and complex pharmacokinetic parameters for drug development, these obstacles are expected to be gradually overcome with the in-depth analysis of the mechanism of action and the application of modern drug delivery technologies. The continuous research on tomato alkaloids not only helps to explore the therapeutic value of natural products, but also provides a new perspective and lead structure for the development of multi-target and drug resistant novel anti-tumor strategies.