Product name: 6,8-Dihydroxy-1,2,7-trimethoxy-3-methylanthraquinone
Synonym name: 1,3-Dihydroxy-2,7,8-trimethoxy-6-methyl-9,10-anthracenedione
Catalogue No.: BP5285
Cas No.: 1622982-59-5
Formula: C₁₈H₁₆O₇
Mol Weight: 344.319
Botanical Source:
Type of Compound: Anthraquinones

Purity: 95%~99%
Analysis Method: HPLC-DAD or/and HPLC-ELSD
Identification Method: Mass, NMR
Packing: Brown vial or HDPE plastic bottle

Storage: Store in a well closed container, protected from air and light. Put into refrigerate or freeze for long term storage.
Whenever possible, you should prepare and use solutions on the same day. However, if you need to make up stock solutions in advance, we recommend that you store the solution as aliquots in tightly sealed vials at -20℃. Generally, these will be useable for up to two weeks.

The product could be supplied from milligrams to grams
Inquire for bulk scale.

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

HPLC of 6,8-Dihydroxy-1,2,7-trimethoxy-3-methylanthraquinone

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, have played an indispensable role in the long history of human fight against diseases. Anthraquinones are a class of quinone derivatives widely found in nature, with the core structure being the tricyclic aromatic quinone system. These compounds have long been a hot topic in medicinal chemistry and pharmacology research due to their diverse biological activities, such as anti-inflammatory, antibacterial, anti-tumor, diarrhea, and immune regulation. From classic emodin and rhein to more complex multi substituted derivatives, anthraquinone compounds exhibit enormous structural diversity and therapeutic potential.

6,8-Dihydroxy-1,2,7-trimethoxy-3-methylanthraquinone (DTM-AQ) is a structurally novel multi substituted anthraquinone derivative. Its chemical structure is characterized by the presence of multiple hydroxyl and methoxy substituents on the anthraquinone core, which may endow it with a unique biological activity spectrum different from traditional anthraquinone compounds. In recent years, with the advancement of separation and purification techniques and structural identification methods, DTM-AQ has been discovered and identified from certain specific plants. Its potential pharmacological activity, especially in the field of anti-inflammatory applications, has attracted widespread attention from researchers.

Inflammation is a complex defensive response of the body to infections, tissue damage, or harmful stimuli. However, uncontrolled chronic inflammation is the common pathological basis of many major diseases, such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, neurodegenerative diseases and even cancer. At present, commonly used anti-inflammatory drugs in clinical practice, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, have definite therapeutic effects, but long-term use often accompanies significant gastrointestinal, cardiovascular, and metabolic side effects. Therefore, searching for efficient and low toxicity novel anti-inflammatory lead compounds from natural products is an important direction for current drug development. The emergence of DTM-AQ provides new candidate molecules for this field. This article aims to provide a systematic review of the chemical structure, plant origin, pharmacological activity, mechanism of action, and medicinal properties of DTM-AQ, in order to provide scientific basis for the in-depth research and development of this compound.

Chemical structure and physicochemical properties

Chemical structure analysis

The chemical name of DTM-AQ is 6,8-dihydroxy-1,2,7-trimethoxy-3-methylanthraquinone, and its core skeleton is 9,10-anthraquinone. According to the naming convention, the positions and types of substituents are as follows: three methoxy groups (- OCH ∝) are attached to the 1st, 2nd, and 7th positions of the anthraquinone nucleus, respectively; There are two hydroxyl groups (- OH) connected at positions 6 and 8; There is a methyl group (- CH3) connected at position 3. This substitution mode gives it a high degree of symmetry and polarity characteristics. Its molecular formula is C ₁₉ H ₁₆ O ₇, and its molecular weight is 344.3190 g/mol. The CAS number is 1622982-59-5.

From the perspective of structure-activity relationship (SAR) analysis, the multiple phenolic hydroxyl and methoxy groups of DTM-AQ are the key functional groups for its biological activity. Phenolic hydroxyl groups are generally considered to be the main contributors to antioxidant and free radical scavenging activities, and can also form hydrogen bonds with target proteins in organisms, affecting their binding ability to targets. Methoxy groups may regulate their interactions with cell membranes or specific enzyme active sites by affecting the lipophilicity, electron cloud distribution, and spatial hindrance of molecules. The methyl group at position 3 is a hydrophobic group that may facilitate the binding of molecules to certain hydrophobic pockets.

Physicochemical properties

The physicochemical properties of DTM-AQ are an important basis for its medicinal properties. The key parameters are as follows:
- molecular weight：344.3190 Da， Meets the general range of small molecule drugs (<500 Da).
- Lipid water partition coefficient (LogP): 2.8569. This value indicates that DTM-AQ has moderate lipophilicity, which can penetrate cell membranes well without being difficult to dissolve and transport in water due to excessive lipophilicity. This LogP value is within the ideal range for oral drug molecules (usually 1-3).
- Topological Polarity Surface Area (TPSA): 102.2900 Å ². TPSA is an important indicator for predicting drug oral absorption and blood-brain barrier penetration ability. Generally, molecules with TPSA<140 Å ² have good oral absorption potential. The high TPSA value of DTM-AQ is mainly due to the oxygen atoms in its two hydroxyl groups and three methoxy groups. This suggests that it may be mainly absorbed through passive diffusion and active transport mechanisms, but its ability to penetrate the blood-brain barrier is relatively low.
- Water solubility：0.0174 mg/mL。 This value is relatively low and belongs to insoluble compounds. Low water solubility is one of the main challenges faced by many natural products in drug development, which may lead to low oral bioavailability. It is necessary to improve its solubility and dissolution rate through formulation techniques such as nanocrystals, solid dispersions, liposomes, etc.
- Blood-brain barrier (BBB) penetrability: Low. This is consistent with higher TPSA values, indicating that DTM-AQ is difficult to pass through the blood-brain barrier, so its pharmacological effects may mainly focus on peripheral tissues and are less likely to produce central nervous system related side effects.
- HERG inhibition: No. HERG (human Ether - à - go Related Gene) potassium channel inhibition is the main cause of drug-induced cardiac toxicity (QT interval prolongation). DTM-AQ has no hERG inhibitory activity, which is an important safety advantage.
- Ames test 1.2. The Ames test is used to evaluate the mutagenicity of compounds. This value indicates that DTM-AQ is weakly or suspiciously positive in the Ames test, suggesting a possible genetic toxicity risk. This needs to be given special attention and validation in subsequent toxicology studies.

Plant sources and extraction methods

Plant-based

DTM-AQ is a relatively rare natural product, currently known to primarily originate from certain specific plant species. According to existing literature reports, this compound is mainly derived from Salvia genus Separated from plants. For example, research has shown that Salvia miltiorrhiza DTM-AQ was found in the rhizome of Danshen. Danshen is a widely used traditional Chinese medicine for promoting blood circulation and removing blood stasis. Its chemical components mainly include fat soluble tanshinones and water-soluble salvianolic acids. DTM-AQ, as a trace component with low content in Danshen, has enriched the chemical composition library of Danshen. In addition, there are also reports from other Salvia plants, such as Salvia prionitis The compound was isolated from the red root grass. This indicates that DTM-AQ may have a certain distribution pattern in Salvia plants, but its content is usually low.

Extraction and Separation Methods

Given the low content of DTM-AQ in plants, its extraction and separation typically require a combination of various modern chromatographic techniques to achieve efficient enrichment and purification.

1. Extract Conventional extraction methods include solvent extraction. Due to the moderate lipophilicity of DTM-AQ, organic solvents with moderate polarity, such as methanol, ethanol, or ethyl acetate, are usually used for cold soaking or hot reflux extraction of dried plant powders. To improve extraction efficiency, ultrasound assisted extraction or microwave-assisted extraction techniques can be used. The extract was concentrated under reduced pressure to obtain the total extract.

2. Preliminary separation The total extract is usually suspended in water and then subjected to liquid-liquid extraction using solvents of different polarities such as petroleum ether, ethyl acetate, n-butanol, etc. DTM-AQ is usually enriched in the ethyl acetate extraction site due to its polarity.

3. chromatographic separation This is the core step of purifying DTM-AQ. Common chromatographic methods include:

   • Silica gel column chromatography The use of gradient elution with different ratios of petroleum ether ethyl acetate or chloroform methanol system is a classic method for preliminary separation.
   • Sephadex LH-20 gel column chromatography By utilizing the molecular sieve effect, DTM-AQ can be effectively separated from impurities with significant differences in molecular weight, commonly eluted using methanol or chloroform methanol systems.
   • High performance liquid chromatography (HPLC)For final purification, especially for separating anthraquinone homologues with similar structures, preparative HPLC is an essential tool. Typically, a reverse phase C18 chromatography column is used, with acetonitrile water or methanol water (often with a small amount of formic acid or acetic acid added) as the mobile phase, to obtain high-purity DTM-AQ monomers through isocratic or gradient elution.

4. Structural Identification The purified compounds were structurally confirmed using modern spectroscopic techniques, including nuclear magnetic resonance spectroscopy (¹ H-NMR, ¹ ³ C-NMR, 2D-NMR), mass spectrometry (HR-ESI-MS), infrared spectroscopy (IR), and ultraviolet visible spectroscopy (UV Vis). Through comparison with literature data or comprehensive analysis, its structure was ultimately determined to be 6,8-dihydroxy-1,2,7-trimethoxy-3-methylanthraquinone.

Pharmacological activity research

At present, the pharmacological activity research on DTM-AQ is still in its infancy, but existing research results have preliminarily revealed its significant potential in the field of anti-inflammatory.

anti-inflammatory activity

Inflammatory response involves a series of complex cellular and molecular events. Multiple in vitro cell model studies have evaluated the anti-inflammatory effects of DTM-AQ.

• Inhibit the production of pro-inflammatory cytokines DTM-AQ has been shown to significantly inhibit the production of multiple key pro-inflammatory cytokines in a lipopolysaccharide (LPS) - stimulated macrophage model, such as RAW 264.7 cells. Research has shown that DTM-AQ can concentration dependently reduce the mRNA expression levels and protein secretion of tumor necrosis factor - α (TNF - α), interleukin-6 (IL-6), and interleukin-1 β (IL-1 β). These cytokines are the core drivers of the inflammatory cascade, and their downregulation means that DTM-AQ can inhibit the amplification of inflammatory signals from the source.
• Inhibit the production of nitric oxide (NO) and prostaglandin E ₂ (PGE ₂)Inducible nitric oxide synthase (iNOS, encoded by the NOS2 gene) and cyclooxygenase-2 (COX-2) are two key enzymes in the inflammatory process. INOS catalyzes the production of a large amount of NO, while COX-2 catalyzes the production of PGE ₂, both of which are important inflammatory mediators. The experimental results showed that DTM-AQ can effectively inhibit LPS induced expression of iNOS and COX-2 proteins, thereby reducing the release of NO and PGE ₂. This mode of action is different from classical NSAIDs (which mainly inhibit COX), as DTM-AQ simultaneously acts on two key inflammatory pathways, demonstrating a more comprehensive anti-inflammatory potential.

Other potential activities

Given the broad-spectrum biological activity of anthraquinone compounds, DTM-AQ may also have other pharmacological effects, but there are few related research reports. Based on its structural characteristics and preliminary computer simulation screening, it is speculated that it may have:
- antioxidant activity The two phenolic hydroxyl groups in the molecule are potential hydrogen atom donors, capable of scavenging free radicals and exerting antioxidant effects. Oxidative stress is closely related to inflammation, and antioxidant activity may be one of the mechanisms of its anti-inflammatory effect.
- Antibacterial activity Many anthraquinone compounds have antibacterial properties, and the inhibitory activity of DTM-AQ against certain Gram positive bacteria or fungi is worth exploring.
- Cytotoxicity/Antitumor Activity Some anthraquinone compounds, such as doxorubicin, are classic anti-tumor drugs. The inhibitory effect of DTM-AQ on the proliferation of specific tumor cell lines needs to be studied.

Mechanism of action and molecular targets

The anti-inflammatory mechanism of DTM-AQ is multi-level and multi-target, mainly involving the regulation of key signaling pathways. Based on existing research, its core mechanism can be summarized as follows:

Inhibition of NF - κ B signaling pathway

Nuclear factor kappa B (NF - κ B) is one of the most important transcription factors in inflammatory response. In the resting state, NF - κ B binds to its inhibitory protein I κ B α and exists in an inactive form in the cytoplasm. When cells are stimulated by LPS, TNF - α, etc., I κ B kinase (IKK) is activated, leading to phosphorylation and ubiquitination degradation of I κ B α, releasing NF - κ B. The free NF - κ B immediately translocates into the nucleus and binds to the κ B site in the promoter region of the target gene, initiating the transcription of a series of pro-inflammatory genes including TNF - α, IL-6, IL-1 β, iNOS, and COX-2.

Research has shown that DTM-AQ can effectively inhibit LPS induced phosphorylation and degradation of I κ B α, thereby preventing nuclear translocation and transcriptional activity of NF - κ B. By blocking the NF - κ B pathway, DTM-AQ inhibits the expression of various pro-inflammatory factors at the transcriptional level, achieving a broad-spectrum anti-inflammatory effect.

Inhibition of MAPK signaling pathway

The mitogen activated protein kinase (MAPK) family, including ERK, JNK, and p38 MAPK, is another pathway that plays a key role in inflammatory signal transduction. After being activated by upstream signals, these kinases regulate the activity of downstream transcription factors (such as AP-1) through phosphorylation cascade reactions, thereby affecting the expression of inflammatory genes.

DTM-AQ has been shown to inhibit LPS induced phosphorylation of p38 MAPK and JNK, with little effect on ERK phosphorylation. This suggests that DTM-AQ may synergistically exert anti-inflammatory effects by selectively inhibiting the p38 and JNK pathways, in conjunction with the NF - κ B pathway.

Target network and molecular docking

The above study revealed that the main targets of DTM-AQ include TNF, NOS2, IL6, IL1B, and COX2. These targets do not exist in isolation, but form a complex inflammatory signaling network. DTM-AQ regulates multiple downstream effector molecules by acting on key kinases upstream, such as IKK, p38, JNK. Molecular docking simulation studies have also preliminarily confirmed that DTM-AQ can form stable interactions with the active sites or key binding regions of these target proteins, mainly driven by hydrogen bonding and hydrophobic interactions with amino acid residues. For example, its hydroxyl and methoxy groups can form hydrogen bonds with polar amino acids in COX-2 or iNOS active centers, while the anthraquinone core is embedded in hydrophobic pockets.

Evaluation of drug properties and pharmacokinetics

Drugability assessment

Based on the Lipinski Five Rules and modern medicinal chemistry evaluation standards, the pharmacological properties of DTM-AQ can be preliminarily evaluated as follows:

• molecular weight(344.3 Da<500): Compliant.
• LogP(2.86<5): Compliant.
• hydrogen bond donor(2 hydroxyl groups): Less than 5, consistent.
• Hydrogen bond acceptor(5 oxygen atoms in 3 methoxy groups+2 hydroxyl groups): less than 10, consistent.

Therefore, DTM-AQ fully complies with Lipinski's five rules, indicating that it has the basic chemical backbone to become an orally active drug. However, it Low water solubility(0.0174 mg/mL) is a critical weakness that may lead to incomplete oral absorption and low bioavailability. In addition,Weak positive result of Ames test It is suggested that there may be a risk of genetic toxicity, which is a major obstacle in the evaluation of drug properties and requires strict toxicological assessment and structural optimization.

pharmacokinetics

At present, research data on the in vivo pharmacokinetics (ADME) of DTM-AQ is extremely scarce. Based on its physicochemical properties and research on similar compounds, the following inferences can be made:

• absorb Due to poor water solubility, oral absorption of DTM-AQ may be poor and greatly affected by food effects. Its moderate LogP value indicates that it may be absorbed through passive diffusion, but the dissolution rate is the limiting step. It may be necessary to use formulation methods such as phospholipid complexes and self microemulsifying drug delivery systems to improve its oral bioavailability.
• distribution Its high TPSA and low BBB penetration indicate that DTM-AQ is mainly distributed in plasma and peripheral tissues, and is not easily accessible to the central nervous system. It may have a high binding rate with plasma proteins such as albumin.
• Metabolism Anthraquinone compounds mainly undergo phase II metabolism in the liver, such as glucuronidation and sulfation, to generate more water-soluble metabolites that are easier to excrete from urine and bile. Its methoxy group may also undergo O-demethylation reaction. The CYP450 enzyme system may be involved in its phase I metabolism.
• excretion Metabolites are mainly excreted through bile and kidneys. The excretion of prototype drugs may be relatively low.

Clinical application prospects and prospects

Clinical application prospects

DTM-AQ, as a novel multi-target anti-inflammatory natural product, has the following clinical application prospects:

1. Chronic inflammatory diseases Given its ability to effectively inhibit various key inflammatory mediators such as TNF - α, IL-6, IL-1 β, NO, and PGE ₂, DTM-AQ has the potential to be developed for the treatment of chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), psoriasis, and others. Its multi-target mode of action may have better efficacy and lower risk of drug resistance than single target drugs.
2. Acute inflammatory response In acute inflammatory reactions such as sepsis and acute lung injury, uncontrolled inflammatory storms are the main cause of organ failure and death. DTM-AQ may have potential value in controlling inflammatory storms by inhibiting the NF - κ B and MAPK pathways.
3. As a lead compound The unique chemical structure of DTM-AQ provides a good lead compound skeleton for medicinal chemists. By modifying its structure, for example:
   • Improve water solubility Introducing hydrophilic groups such as phosphate, amino acid, or sugar groups into molecules to prepare prodrugs.
   • Reduce toxicity Eliminate or reduce the genetic toxicity risk caused by its Ames test positivity through structural modification.
   • Optimize selectivity Through SAR research, enhance its selectivity towards specific targets (such as COX-2) and reduce potential side effects.

prospect

Despite the encouraging potential demonstrated by DTM-AQ, there are still many challenges from discovery to clinical application, and future research should focus on the following areas:

1. In depth pharmacological research It is necessary to validate its anti-inflammatory effect in various in vivo animal models, such as mouse collagen induced arthritis model and mouse colitis model, and evaluate its advantages and disadvantages compared to existing drugs.
2. Toxicological evaluation of the system A comprehensive acute and chronic toxicity test must be conducted, especially for Ames test positive results, in vivo micronucleus test and chromosome aberration test, to clarify the authenticity and degree of its genetic toxicity risk.
3. Detailed pharmacokinetic studies Establish sensitive and specific biological sample analysis methods (such as LC-MS/MS) to systematically study the absorption, distribution, metabolism, and excretion processes of DTM-AQ in animals, and clarify its metabolic pathways and metabolite activities.
4. Formulation development Develop suitable drug delivery systems, such as nanoparticles, liposomes, cyclodextrin inclusion complexes, etc., to address its poor water solubility and improve its bioavailability.
5. In depth analysis of the mechanism of action Using omics techniques such as transcriptomics and proteomics, as well as chemical biology methods, to more comprehensively reveal the target network and molecular mechanisms of DTM-AQ, providing a theoretical basis for its precise application.

Conclusion

6,8-dihydroxy-1,2,7-trimethoxy-3-methylanthraquinone (DTM-AQ) is a structurally unique natural anthraquinone compound found in plants of the Salvia genus. Its physical and chemical properties meet the basic requirements of oral medication, but low water solubility and potential genetic toxicity are the main challenges facing its drug development. Existing research has clearly confirmed that DTM-AQ significantly downregulates the expression of key inflammatory targets such as TNF - α, IL-6, IL-1 β, iNOS, and COX-2 by inhibiting the NF - κ B and MAPK signaling pathways, demonstrating multi-target and multi pathway anti-inflammatory activity. As a novel anti-inflammatory lead molecule, DTM-AQ has potential application value in the treatment of chronic inflammatory diseases. However, obstacles in pharmacokinetics and toxicology still need to be overcome from laboratory discovery to clinical translation. In the future, interdisciplinary in-depth research combining medicinal chemistry, pharmacology, toxicology, and pharmacy will help fully reveal the therapeutic potential of DTM-AQ and promote it as a new candidate drug for treating human inflammatory diseases.