Dehydrated Danshenxin Ketone: Exploration of Multi targeted Active Molecules in Danshen and Their Potential for Pharmaceutical Development
1. Overview
1,2-Dihydromiltirone, as a traditional Chinese medicine derived from Danshen（Salvia miltiorrhiza）The natural products of diterpenoid quinones isolated from Chinese medicine are increasingly receiving attention from modern pharmaceutical researchers. Its CAS number is 116064-77-8, molecular formula is C19H20O2, and molecular weight is approximately 280.37 g/mol. Danshen, also known as "Red Root Grass", has a medicinal history of thousands of years in China and is mainly used to treat cardiovascular diseases. Dihydrotanshinone is one of the important members of a series of biologically active tanshinone compounds in Danshen. In recent years, with the deepening of natural product chemistry and molecular pharmacology research, dehydrodanshenxin ketone has been found to have a wide range of pharmacological activities. Its targets involve multiple key physiological and pathological processes such as cell cycle regulation, inflammatory response, neurodegenerative disease, and tumor occurrence and development. The database information shows that it is related to atherosclerosis, Alzheimer's disease, inflammatory bowel disease, atopic eczema, lymphoma and other diseases, suggesting that it has the potential to intervene in complex diseases with multiple targets and pathways. This article will conduct a systematic professional science popularization analysis of this promising natural compound from its chemical structure, plant origin, pharmacological mechanism, medicinal evaluation, and research prospects.
2. Chemical structure and physicochemical properties
The chemical structure of dehydrodanshenxin ketone is the material basis for its biological activity. Its SMILES string is "CC (C) C1=Cc2ccc3c (c2C (=O) C1=O) C=CCC3 (C) C", which clearly depicts its molecular skeleton: a typical phenanthrenequinone (diterpenoid quinone) core structure with specific substituents. The conjugated quinone ring system in the molecule is a key site for its redox activity and interaction with various biomolecules.
Based on the provided pharmacological parameters, we can conduct in-depth analysis of its physicochemical properties:
- Molecular weight (MW)：280.36 g/mol， Far below the upper limit of 500 Da in Lipinski's Rule of Five, it meets the basic requirements for small molecule drugs.
- Lipid water partition coefficient (LogP/LogD)All are 4.50. This value indicates that dehydrotanshinone has high lipophilicity. According to Lipinski's rule, the ideal range of LogP should be less than 5, and its value of 4.50, although at the upper limit edge, is still within an acceptable range. A higher lipophilicity is beneficial for compounds to penetrate cell membranes, but it may also lead to issues such as poor solubility and rapid metabolism.
- Topological Polarity Surface Area (TPSA): 34.14 Å ². This is a very small value, and it is generally believed that compounds with TPSA<60 Å ² have good intestinal absorption and blood-brain barrier penetration abilities. This is highly consistent with the predicted results of "BBB-permeability: High" (high blood-brain barrier permeability) and "HIA: High" (high human intestinal absorption rate) provided by the database.
- Hydrogen bond acceptor (HBA) and donor (HBD)HBA is 2, in compliance with Lipinski rule (≤ 10); Its structure suggests that the number of hydrogen bond donors (HBDs) may be 0, which also conforms to the rule (≤ 5).
Overall, the molecular weight of dehydrodanshenxin ketone is small, the polar surface area is low, and the lipophilicity is moderate. These physicochemical properties indicate that it has good membrane permeability and oral absorption potential, which basically conforms to the characteristics of drug like small molecules, laying a favorable chemical foundation for its further drug development.
3. Plant sources and traditional applications
The plant source of dehydrodanshenxin ketone is single and clear - Salvia miltiorrhiza, a plant in the Lamiaceae family（Salvia miltiorrhiza Bunge）。 The dried roots and rhizomes of Danshen are known as "Danshen" in traditional Chinese medicine, and its application history can be traced back to the "Shennong Bencao Jing", which is listed as a top-grade product. According to traditional Chinese medicine theory, Danshen is slightly cold in nature, bitter in taste, and has the function of promoting blood circulation, removing blood stasis, unblocking meridians, relieving pain, clearing the heart and eliminating annoyance, cooling blood and eliminating carbuncles. Widely used in clinical practice to treat chest and abdominal pain, epigastric pain, accumulation of symptoms, thermal pain, restlessness and insomnia, menstrual disorders, dysmenorrhea and amenorrhea, ulcer swelling and pain, especially in the treatment of cardiovascular and cerebrovascular diseases, it enjoys a high reputation.
The modern chemical composition research of Danshen reveals that its main active ingredients can be divided into two categories: water-soluble salvianolic acids (such as salvianolic acid B) and lipid soluble tanshinones (diterpenoid quinones). Dihydrotanshinone belongs to the family of tanshinone compounds. These compounds are usually present in the cortex of Danshen roots and are one of the important material bases for Danshen to exert its "blood activating and stasis removing" effects. Traditionally, Danshen is often taken by boiling in water, but the lipid soluble tanshinone components have limited dissolution. Modern formulation technology, such as extraction and concentration, preparation of drop pills, injections, etc., greatly improves the bioavailability of tanshinone components, allowing their pharmacological effects to be more fully exerted. As a member of the tanshinone family, the isolation, identification, and activity research of dehydrodanshenxin ketone are based on a modern scientific interpretation of Danshen, a "treasure in medicine", and serve as a model for connecting traditional experience with modern science.
4. Pharmacological activity and mechanism of action
The database information shows that DHT interacts with as many as 40 potential targets and is highly related to atherosclerosis, Alzheimer's disease, inflammatory bowel disease, atopic eczema and lymphoma. This fully demonstrates the complexity advantage of natural products with multi-target and multi pathway effects. Based on its main targets, analyze its core pharmacological activity and mechanism of action:
4.1 Anti inflammatory and immune regulatory effects
- Key targets：TLR4、IL-6、STAT3、PTPRC（CD45）、PTPN1（PTP1B）。
- Mechanism Explanation Toll like receptor 4 (TLR4) is a core receptor that recognizes pathogen related molecular patterns and initiates innate immune responses. Inhibition of the TLR4 signaling pathway can downregulate the activity of nuclear factor kappa B (NF - κ B) and signal transducer and activator of transcription 3 (STAT3), thereby reducing the production of pro-inflammatory cytokines such as interleukin-6 (IL-6). STAT3 itself is also a key signaling node in the chronic inflammation and tumor microenvironment. Meanwhile, the regulation of protein tyrosine phosphatases (PTPRC, PTPN1) by dehydrodanshenxin ketone may affect immune cell functions such as lymphocyte activation. This multi-level anti-inflammatory mechanism provides scientific basis for its treatment of atherosclerosis (chronic vascular inflammation), inflammatory bowel disease (intestinal mucosal immune disorder) and atopic eczema (skin immune inflammation).
4.2 Neuroprotection and Anti Alzheimer's Disease Potential
- Key targets：APP、BACE1、NOS3、IDO1、HIF-1α。
- Mechanism Explanation The pathological features of Alzheimer's disease include β - amyloid (A β) deposition and neuroinflammation. Dihydrotanshinone may affect the generation of A β by acting on amyloid precursor protein (APP) and β - site APP lyase 1 (BACE1). Meanwhile, its anti-inflammatory properties (inhibition of IL-6/STAT3) help alleviate neuroinflammation. The regulation of endothelial nitric oxide synthase (NOS3) may improve cerebral blood flow. Inhibition of indoleamine 2,3-dioxygenase 1 (IDO1) can regulate tryptophan metabolism and affect neuroimmunity. The regulation of hypoxia inducible factor-1 alpha (HIF-1 alpha) may be related to the survival of nerve cells under stress. In addition, its high blood-brain barrier penetration ability makes it a potential neuroprotective agent.
4.3 Antitumor activity
- Key targets：CDC25A/B、MCL1、RARA/RARG、RXRB、RECQ1。
- Mechanism Explanation Cyclin 25 (CDC25A/B) is a key phosphatase that regulates the cell cycle process, and its overexpression is associated with various tumors, making it a potential anti-cancer target. Myeloid leukemia factor 1 (MCL1) is an important anti apoptotic protein that is highly expressed in many cancers. Dihydrotanshinone may induce tumor cell cycle arrest and apoptosis by inhibiting these targets. The regulation of retinoic acid receptors (RARA/RARG) and retinoid X receptor beta (RXRB) may affect cell differentiation and proliferation. RecQ helicase 1 (RECQ1) is associated with DNA repair and genome stability. These effects collectively point to its anti-tumor potential, especially in its association with diseases such as lymphoma, which deserves further exploration.
4.4 Cardiovascular protective effects
- Key targets：NOS3、IL-6、STAT3、HIF-1α。
- Mechanism Explanation In atherosclerosis, its anti-inflammatory effect (inhibiting IL-6/STAT3) can directly reduce the inflammatory reaction of vascular wall, which is the core link of the occurrence and development of atherosclerotic plaque. Regulating NOS3 helps maintain endothelial function and produces vasodilatory effects. The regulation of HIF-1 α may play a protective role under conditions such as myocardial ischemia. This is highly consistent with the traditional efficacy of its source plant, Danshen.
In summary, dehydrodanshenxin ketone has formed a complex pharmacological network by acting on multiple levels of targets such as cell cycle, inflammatory signaling, apoptosis pathway, and receptor transcription, thus demonstrating broad application prospects in the prevention and treatment of various major chronic diseases.
5. Evaluation of drug properties
Based on the provided detailed pharmacological parameters, we can systematically evaluate the potential of dehydrodanshenxin ketone as a drug:
5.1 Drug like evaluation
As mentioned earlier, the molecular weight (280), number of hydrogen bond acceptors (2), and calculated LogP value (4.5) of dehydrodanshenxin ketone all follow or approach the Lipinski Five Rules (MW ≤ 500, HBD ≤ 5, HBA ≤ 10, LogP ≤ 5, and the number of rotatable bonds data is not provided but usually there are not many rigid structures of this type). Its TPSA value is extremely low (34.14 Å ²), indicating excellent membrane permeability. Therefore, from the perspective of drug like properties, it is a very attractive small molecule lead compound.
5.2 Prediction of pharmacokinetic (ADME) properties
- Absorption The high HIA (human intestinal absorption) prediction results, combined with its moderate LogP and low TPSA, indicate good oral bioavailability potential.
- Distribution High tissue distribution, high blood-brain barrier permeability (BBB permeable), and placental barrier permeability are significant advantages, especially crucial for the treatment of central nervous system diseases such as Alzheimer's disease. A plasma protein binding rate (PPB) of up to 90% may affect its free drug concentration, and it is necessary to balance the relationship between drug efficacy and pharmacokinetics in subsequent studies.
- Metabolism The data shows that it is not a substrate or inhibitor for a range of major cytochrome P450 enzymes (CYP1A2, 2C9, 2C19, 2D6, 3A4), which reduces the risk of drug drug interactions and is a positive signal. It is also not a substrate for various UDP glucuronosyltransferases (UGTs).
- Excretion The relevant parameters are not provided and need to be determined through subsequent experiments.
5.3 Preliminary prediction of toxicity
The security prediction data provided by the database is very optimistic:
- Genotoxicity The results of Ames test, micronucleus test, chromosome aberration test, and DNA damage test were all negative, indicating no risk of mutagenicity.
- Organ toxicity Hepatotoxicity, cardiotoxicity (including hERG inhibition and QT interval prolongation), nephrotoxicity, and neurotoxicity prediction were all negative.
- Other toxicities No skin sensitization, respiratory sensitization, phototoxicity, etc.
- carcinogenicity Predicted as negative.
5.4 Comprehensive evaluation and potential challenges
Overall, dehydrodanshenxin ketone has shown excellent performance in terms of drug properties, ADME properties (especially absorption and distribution), and preliminary safety prediction, and has a good foundation for becoming an orally active drug. Its multi target mechanism of action is in line with the trend of modern drug development for complex diseases (such as AD, atherosclerosis).
However, potential challenges also need to be addressed:
1. High lipophilicity and high protein binding rate LogP 4.5 and PPB 90% may lead to poor water solubility, large in vivo distribution volume, and low free drug concentration, thereby affecting the actual efficacy. In subsequent chemical optimization, it may be necessary to introduce polar groups appropriately while maintaining activity to improve solubility and pharmacokinetic properties.
2. Specific issues caused by multi-target targeting Although multi-target targeting is an advantage, we also need to be wary of the unpredictable side effects caused by off target effects. More precise cell and animal experiments are needed to clarify the core target pathways that exert therapeutic effects.
3. The necessity of experimental verification All computer predictions must be rigorously validated through in vitro and in vivo experiments. Especially its excellent BBB penetration prediction needs to be confirmed through methods such as parallel artificial membrane permeability assay (PAMPA-BBB) or in vivo distribution experiments.
6. Research Status and Application Prospects
At present, the public research literature on dehydrotanshinone is relatively limited compared to its homologues (such as tanshinone IIA), but the existing target prediction and physicochemical property analysis have painted a hopeful blueprint for it.
Research status Current research mainly focuses on the overall activity of tanshinone compounds, which clearly confirms their extensive effects in cardiovascular protection, anti-tumor, neuroprotection, anti-inflammatory and other aspects. The unique activity spectrum of dehydrodanshenxin ketone, as a member with a specific structure (1,2-dehydrogenation), is gradually being revealed through computational biology and preliminary pharmacological screening. The vast target information provided by the database mostly comes from computer simulations (such as molecular docking, network pharmacology) and activity derivations of similar compounds, which provides clear directions and hypotheses for subsequent empirical research.
Application Prospects：
1. As a lead compound for treating central nervous system diseases Its excellent prediction of BBB penetration, combined with its effects on APP, BACE1, and inflammatory targets, makes it highly distinctive in drug development for neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Priority can be given to conducting in vivo and in vitro neuroprotective pharmacological evaluations in this direction.
2. Developing new drugs to combat chronic inflammatory diseases The multi-target anti-inflammatory mechanism may provide a new treatment strategy for chronic inflammatory diseases such as inflammatory bowel disease and atopic dermatitis that lack curative measures. Further research can be conducted on its specific effects on signaling pathways such as TLR4/NF - κ B/STAT3.
3. Research and development of anti-tumor drugs Based on their effects on tumor related targets such as CDC25 and MCL1, their therapeutic efficacy in specific types of lymphoma or other solid tumors can be explored, and their synergistic effects with existing chemotherapy drugs can be studied.
4. Structural optimization and derivatization Using it as the parent nucleus for structural modification, aimed at improving solubility, reducing protein binding rate, enhancing target selectivity, or enhancing specific drug efficacy, is an important task for medicinal chemists. For example, while maintaining the core activity of phenanthrenequinone, the side chains can be modified to obtain better drug properties.
5. Modernization of Traditional Chinese Medicine and Research on Quality Markers As one of the active ingredients of Danshen, in-depth research on the content, efficacy, and interrelationships of dehydrotanshinone can help establish more scientific quality control standards for Danshen medicinal materials and preparations, and promote the internationalization process of traditional Chinese medicine.
In short, dehydrodanshenxin ketone is a natural small molecule with excellent potential for medicinal properties and multi-target activity discovered from the treasure trove of traditional Chinese medicine. Although extensive experimental research is still needed to validate predictions, elucidate mechanisms, and optimize structures, it undoubtedly provides a valuable candidate molecule and starting point for the treatment of major human health challenges such as cardiovascular and cerebrovascular diseases, neurodegenerative diseases, chronic inflammation, and tumors. With the deepening of interdisciplinary research, this "chemical star" derived from Danshen is expected to shine even brighter in the future drug development sky.
