Product name: Bisdemethoxycurcumin
Synonym name: Curcumin III; Didemethoxycurcumin; Deleted CAS No: 22608-12-4, 85801-92-9, 91884-88-7, 104024-29-5
Catalogue No.: BP0278
Cas No.: 33171-05-0
Formula: C₁₉H₁₆O₄
Mol Weight: 308.333
Botanical Source: Curcuma zedoaria , Curcuma longa and Curcuma aromatica. Absent in some Curcuma spp.
Physical Description: Yellow powder
Type of Compound: Phenols

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, up to kilograms
Inquire for bulk scale.

Descriptions:
Bisdemethoxycurcumin can regulate anti-inflammatory and anti-proliferative responses through a ROS-independent mechanism, also suppresses MCF-7 cells proliferation by inducing ROS accumulation and modulating senescence-related pathways.[1]
Bisdemethoxycurcumin directly accelerates gastric ulcer healing with potency equal to curcumin, its antiulcer effect might be due to its properties of decreasing gastric acid secretion and enhancing the mucosal defensive mechanism through suppression of iNOS-mediated inflammation.[2]
Bisdemethoxycurcumin differentially inhibit cancer cell invasion through the down-regulation of MMPs and uPA.[3]
Bisdemethoxycurcumin induces apoptosis in activated HSCs, but not in hepatocytes, by impairing cellular energetics and causing a downregulation of cytoprotective proteins, likely through a mechanism that involves CBR2.[4]
Bisdemethoxycurcumin has effects on 12-Ο-tetradecanoylphorbol-13-acetate-induced tumor promotion.[5]
Bisdemethoxycurcumin has antioxidant activities, inhibits ovarian cancer via reducing oxidative stress mediated MMPs expressions.[6,7]

References:
[1] Sandur SK, Pandey MK, Sung B,et al. Carcinogenesis, 2007, 28(8):1765-73.
[2] Mahattanadul S, Nakamura T, Panichayupakaranant P, et al. Phytomed Int J Phytother Phytopharmacol, 2009, 16(4):342-51.
[3] Li Y B, Gao J L, Zhong Z F, et al. Pharmacol Rep Pr, 2013, 65(3):700-9.
[4]Yodkeeree S, Chaiwangyen W, Garbisa S, et al. J Nutl Biochem, 2009, 20(20):87-95.
[5] Lee P J, Woo S J, Jee J G, et al. Molecules, 2015, 20(1):1277-92.
Jayaprakasha G K, Rao L J, Sakariah K K. Food Chem 2006, 98(4):720-4.
[6]Huang M T, Ma W, Lu Y P, et al. Carcinogenesis, 1995, 16(10):2493-7.
[7] Pei H, Yang Y, Lin C, et al. Sci Rep, 2016, 6,28773.
[8] Jadhav B K, Mahadik K R, Paradkar A R. Chromatographia, 2007, 65(7):483-8.

HPLC of Bisdemethoxycurcumin

HNMR of Bisdemethoxycurcumin

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

Introduction/Overview

Natural products, as an important treasure trove for drug discovery, play an irreplaceable role in the history of human disease prevention and treatment. Turmeric（Curcuma longa L. As a traditional Chinese medicine and spice, its pharmacological activity has attracted much attention, and its core active ingredient curcumin compounds are a research hotspot. Bisdemethoxycurcumin (BDMC), as one of the main homologs of curcumin, has a simpler chemical structure and lacks two methoxy groups compared to the well-known curcumin and demethoxycurcumin. This structural difference endows it with unique physicochemical properties and biological activity spectrum. In recent years, with the in-depth study of curcumin compounds, BDMC has gradually moved from "supporting role" to the center of the stage, showing significant potential in anti-inflammatory, antioxidant, anti-tumor, neuroprotective and other aspects, especially in inflammatory bowel disease (such as colitis) and other disease models, showing remarkable efficacy. Its CAS number is 33171-05-0. As a natural β - diketone polyphenol, its mechanism of action involves the regulation of multiple key signaling pathways and molecular targets. This article aims to systematically review the chemical properties, plant sources, pharmacological activities, molecular mechanisms of action, pharmacological characteristics, and clinical application prospects of BDMC, in order to provide comprehensive scientific references for the in-depth research and development of this natural product.

Chemical structure and physicochemical properties

The chemical name of bis (methoxycurcumin) is (1E, 6E) -1,7-bis (4-hydroxyphenyl) -1,6-heptadiene-3,5-dione. Its molecular formula is C19H16O4 and its molecular weight is 308.3330. Structurally, BDMC belongs to the typical class of diarylheptane compounds, with its core skeleton consisting of a seven carbon chain (heptane). The C3 and C5 positions are ketone groups, forming a β - diketone structure, while the C1 and C7 positions are respectively connected to a 4-hydroxyphenyl group (i.e. p-hydroxycinnamoyl group) through an alkene bond. Compared with curcumin, BDMC lacks methoxy groups (- OCH3) on both aromatic rings and only retains phenolic hydroxyl groups (- OH). This structural characteristic makes it the member with relatively high polarity and the smallest molecular weight among curcumin compounds.

Its physicochemical properties directly affect its bioavailability and activity. The calculated lipid water partition coefficient (LogP) is 2.7295, indicating that BDMC has moderate lipophilicity, but slightly stronger hydrophilicity compared to curcumin (LogP of about 3.2). The topologically polar surface area (TPSA) is 74.6000 Å ², reflecting the presence of hydrogen bond donors (two phenolic hydroxyl groups) and acceptors (two carbonyl oxygen groups) in its molecule. The water solubility is poor, about 0.0732 mg/mL, which is a common characteristic of most polyphenolic compounds and limits their dispersion and absorption in aqueous media. Its β - diketone structure may lead to keto enol tautomerism at physiological pH, which may affect its chelating ability with metal ions and interaction with biomolecules. Overall, the chemical structure of BDMC determines its fundamental reactivity as a polyphenol and β - diketone compound, such as scavenging free radicals, chelating metal ions, and acting as a Michael reaction receptor for covalent binding with nucleophilic agents (such as thiol groups in proteins).

Plant sources and extraction methods

Double demethoxycurcumin mainly comes from plants of the Curcuma genus in the ginger family, especially turmeric（Curcuma longa L. The roots and stems of. In the crude extract of turmeric, the content of BDMC is usually lower than that of curcumin and demethoxycurcumin, which together form "curcumin compounds". The relative proportion of BDMC varies depending on the variety, origin, harvest season, and storage conditions, usually accounting for about 3-10%.

The extraction of BDMC from plant materials mainly follows the general extraction principles of polyphenolic compounds. Traditional methods include organic solvent extraction, with commonly used solvents including ethanol, acetone, ethyl acetate, etc. For example, using high concentration ethanol (such as 95%) for Soxhlet extraction or hot reflux extraction can effectively extract BDMC together with other curcumin compounds. In order to improve extraction efficiency and selectivity, modern extraction techniques have been widely applied:
1. Ultrasound assisted extraction Utilizing the cavitation effect generated by ultrasound to destroy plant cell walls, accelerate solvent permeation and solute release, has the advantages of short time, high efficiency, and low temperature.
2. Microwave assisted extraction Microwave energy directly acts on polar molecules inside the material, generating instantaneous high temperature and high pressure, and quickly and efficiently extracting target components.
3. Supercritical fluid extraction CO2 is commonly used as an extractant to change its solubility by adjusting temperature and pressure. This method has no solvent residue and good selectivity, but the equipment cost is high, and for BDMC with high polarity, it is often necessary to add entrainers (such as ethanol) to improve the yield.

The extracted compound is usually a mixture of curcumin compounds, which requires further separation and purification to obtain high-purity BDMC. Conventional separation methods include column chromatography (such as silica gel column chromatography, reverse phase C18 column chromatography), preparative thin-layer chromatography, and high-performance liquid chromatography. Among them, reverse phase high performance liquid chromatography (RP-HPLC) is the most commonly used and effective method for separating and quantitatively analyzing BDMC. It usually uses a C18 chromatographic column and gradient elution with methanol water or acetonitrile water (often containing small amounts of acids such as formic acid or acetic acid to improve peak shape) as the mobile phase. In recent years, preparative chromatography techniques such as high-speed countercurrent chromatography have also provided new options for the large-scale separation of BDMC.

Pharmacological activity research

Numerous in vitro and in vivo studies have confirmed that BDMC has a wide range of pharmacological activities, some of which are even superior to curcumin.

1. Anti inflammatory and immune regulatory activity This is one of the most prominent activities of BDMC. BDMC exhibits strong anti-inflammatory effects in various acute and chronic inflammation models. It can significantly inhibit the production of nitric oxide (NO), prostaglandin E2 (PGE2), and key pro-inflammatory cytokines such as tumor necrosis factor - α (TNF - α), interleukin-6 (IL-6), and IL-1 β in macrophages induced by stimuli such as lipopolysaccharides. In animal models, BDMC has inhibitory effects on acute inflammation such as xylene induced ear swelling in mice and carrageenan induced paw swelling in rats.
2. antioxidant activity The phenolic hydroxyl and β - diketone structures of BDMC are the chemical basis for its antioxidant capacity. It can directly scavenge DPPH radicals, ABTS radicals, superoxide anions, and hydroxyl radicals, demonstrating significant in vitro antioxidant capacity. In addition, it can upregulate the intracellular antioxidant defense system, such as activating the nuclear factor E2 related factor 2 (Nrf2) pathway, promoting the expression of phase II detoxifying enzymes and antioxidant proteins such as heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO1), thereby enhancing the cell's resistance to oxidative stress.
3. Antitumor activity Research shows that BDMC can inhibit the growth and induce apoptosis of many cancer cell lines, including colon cancer, breast cancer, lung cancer, liver cancer, prostate cancer, etc. Its mechanism involves cell cycle arrest (often blocking cells in the G2/M phase), induction of mitochondrial pathway apoptosis (regulating the Bcl-2/Bax ratio and activating the Caspase cascade), inhibition of nuclear factor kappa B (NF - κ B) and its regulated survival genes, as well as inhibition of the expression of tumor invasion and metastasis related proteins (such as matrix metalloproteinases MMPs).
4. Protective effect on colitis Of particular note is the outstanding performance of BDMC in inflammatory bowel disease models. In experimental colitis mouse or rat models induced by dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS), administration of BDMC can significantly improve disease activity index, alleviate colon shortening, and repair pathological damage to colon tissue (such as crypt destruction and inflammatory cell infiltration). Its effect is closely related to inhibiting pro-inflammatory cytokine storms and regulating intestinal immune balance.
5. Neuroprotective activity BDMC shows potential benefits for neurodegenerative diseases. In Alzheimer's disease cell models, it can reduce the neurotoxicity induced by β - amyloid protein; In Parkinson's disease models, dopaminergic neurons may be protected through antioxidant and anti-inflammatory pathways. Its moderate LogP value suggests that it may have some potential to cross the blood-brain barrier, but its specific permeability needs further verification.
6. Metabolic regulatory activity BDMC has been reported to have α - amylase inhibitory activity, suggesting that it may help to delay the digestion and absorption of carbohydrates, and has potential significance for the management of diabetes. In addition, it can regulate lipid metabolism and improve metabolic abnormalities induced by high-fat diet.

Mechanism of action and molecular targets

The multiple pharmacological activities of BDMC stem from its diverse regulation of cellular signaling networks. Its mechanism of action is not to act on a single target, but to intervene in the disease process in a "multi-target" mode. Regarding its outstanding anti colitis activity, research has revealed that it involves multiple key molecular targets and pathways:

• Inhibition of TLR4/NF - κ B inflammatory axis Toll like receptor 4 (TLR4) is a key receptor that recognizes bacterial lipopolysaccharides and initiates innate immunity. BDMC can inhibit the activation of TLR4 and its downstream myeloid differentiation factor 88 (MyD88) - dependent signaling, thereby blocking the nuclear translocation of nuclear transcription factor NF - κ B (whose key subunit is RELA/p65). The inhibition of NF - κ B leads to significant downregulation of pro-inflammatory mediator genes such as TNF - α, IL-6, IL-1 β, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) downstream, which is its anti-inflammatory core mechanism.
• Regulating the MAPK signaling pathway The mitogen activated protein kinase (MAPK) family (such as p38 MAPK, JNK, ERK/MAPK1) is an important signaling pathway for inflammation and stress response. BDMC can inhibit the excessive phosphorylation activation of MAPK pathways induced by LPS and other factors, thereby synergistically suppressing inflammatory responses at the transcriptional and translational levels.
• Intervention in cell apoptosis and pyroptosis In colitis, abnormal apoptosis and pyroptosis of intestinal epithelial cells exacerbate barrier disruption. BDMC can downregulate the activity of the pro apoptotic protein CASP1 (Caspase-1, also a key executor of apoptosis), and may maintain the survival and integrity of intestinal epithelial cells by affecting signaling molecules such as PRKCA (protein kinase C alpha).
• Affects lipid mediator metabolism BDMC is associated with lipid signaling metabolism. It has been reported as an inhibitor of fatty acid amide hydrolase (FAAH), which is responsible for degrading endogenous cannabinoids (such as arachidonic acid ethanolamine). Inhibiting FAAH can increase endogenous cannabinoid levels and exert anti-inflammatory and protective effects. Meanwhile, it can also affect the activity of sphingosine kinase 1 (SPHK1) and regulate the metabolism of sphingosine-1-phosphate (S1P), which is an important immune cell chemotactic regulator. The regulation of lysophosphatidic acid receptor 2 (LPAR2) may also be involved in maintaining intestinal barrier function.
• Regulating drug metabolizing enzymes Carboxyesterase 1 (CES1) is an important hydrolytic enzyme in the body. The interaction between BDMC and CES1 may affect its own or other drug metabolism, and may also indirectly exert anti-inflammatory effects by regulating the levels of endogenous lipid mediators.
• Direct interaction and epigenetic regulation As a polyphenol and Michael reaction receptor, BDMC can directly covalently bind to the thiol groups of certain signaling proteins, altering their function. In addition, increasing evidence suggests that BDMC may exert long-term stable gene regulatory effects by influencing epigenetic mechanisms such as histone modification or non coding RNA expression.

Evaluation of drug properties and pharmacokinetics

Despite the significant pharmacological activity of BDMC, its potential to become an ideal drug faces challenges similar to those of curcumin compounds in terms of drug development.

• Absorption, distribution, metabolism, excretion The low oral bioavailability of BDMC is mainly due to: 1)Poor solubility Limited dissolution in acidic and neutral environments of the gastrointestinal tract; 2）Significant first pass metabolism It is easily reduced, glucuronidated, and sulfated in the intestine and liver, producing metabolites; 3）Low intestinal absorption rate Research has shown that BDMC mainly exists in the form of bound metabolites in plasma, with low concentrations of the prototype drug. Its LogP is 2.73, which theoretically has a certain membrane permeability, but actual absorption is limited by multiple factors. Regarding its blood-brain barrier permeability, existing data suggests it is "low", but the specific degree needs further experimental confirmation. Its molecular weight (308.33) conforms to the five rules of class drugs, but the relatively large TPSA (74.6) may affect passive diffusion.
• Preliminary evaluation of safety According to the provided pharmacokinetic parameters, BDMC showed a result of 0.0 in the Ames test (a preliminary screening test for mutagenicity), indicating no risk of mutagenicity under the experimental conditions. This is an important safety positive signal. Meanwhile, its' hERG inhibition 'is' no', indicating that at the current research level, it may not inhibit hERG potassium channels, reducing the potential risk of inducing QT interval prolongation and apical torsion type ventricular tachycardia. However, comprehensive safety evaluation still requires systematic preclinical studies on acute toxicity, chronic toxicity, reproductive toxicity, and other factors.
• Formulation strategy and structural modification In order to improve the bioavailability and efficacy of BDMC, researchers are exploring various strategies: 1)New drug delivery system Such as nanoparticles (liposomes, polymer nanoparticles), micelles, microemulsions, self microemulsifying drug delivery systems, phospholipid complexes, cyclodextrin inclusion complexes, etc., improve their pharmacokinetic behavior through solubilization, protection, promotion of lymphatic absorption, or targeted delivery; 2）Prodrug strategy Chemical modification of phenolic hydroxyl or ketone groups to prepare prodrugs that can hydrolyze and restore activity in vivo, in order to improve their stability and absorption; 3）combination therapy Combination therapy with bioavailability enhancers such as piperine (P-gp inhibitor and metabolic enzyme inhibitor), or synergistic therapy with other anti-inflammatory drugs.

Clinical application prospects and prospects

Double demethoxycurcumin, as a natural active molecule with multi-target effects, has broad clinical application prospects but is also full of challenges.

• Potential application directions：

  1. Inflammatory bowel disease Based on its significant therapeutic effect in animal models of colitis, BDMC is expected to be developed as an adjuvant or therapeutic drug for the treatment of ulcerative colitis and Crohn's disease, especially for patients in mild to moderate active phases.
  2. Cancer chemoprevention and adjuvant therapy Its anti-inflammatory, antioxidant, and apoptosis inducing properties make it possible to use it for chemoprevention of certain cancers (such as colorectal cancer) or in combination with conventional chemotherapy/radiotherapy to enhance sensitivity and reduce toxicity.
  3. Metabolic diseases Its α - amylase inhibition and lipid metabolism regulation activities provide ideas for the development of health products or drugs for metabolic diseases such as type 2 diabetes and nonalcoholic fatty liver disease.
  4. Neurodegenerative diseases As a neuroprotective agent, its application in fields such as Alzheimer's disease and Parkinson's disease is worthy of further exploration, but the efficiency of central delivery needs to be addressed first.
  5. Functional foods and dietary supplements As one of the effective ingredients of turmeric, BDMC can be used together with other curcumin compounds to develop products with anti-inflammatory and antioxidant health functions.

• Challenges and Future Prospects：

  1. Bioavailability bottleneck This is the biggest obstacle to its clinical application. Future research needs to focus on developing efficient, stable, and controllable new delivery systems, and optimizing dosing regimens through pharmacokinetic studies.
  2. Deep analysis of the mechanism of action Although multiple targets are known, the direct binding sites, affinity, and dominant pathways of BDMC to these targets still need to be further elucidated at the molecular and systemic levels. It is crucial to use methods such as chemical biology, proteomics, and computational simulation for target fishing and validation.
  3. Lack of clinical evidence Currently, the vast majority of research is still in the preclinical stage. It is urgent to design rigorous clinical trials (phases I-IV) to evaluate the safety, tolerability, pharmacokinetic characteristics, and efficacy of BDMC in humans for specific diseases.
  4. Structural optimization and development of analogues On the basis of clarifying the pharmacophore, the rational structural modification of BDMC and the synthesis of a series of analogues aim to improve its activity, selectivity, metabolic stability, and oral bioavailability, which is an important direction in the field of medicinal chemistry.
  5. Multi component collaborative research BDCM often coexists with curcumin and demethoxycurcumin. Studying the synergistic effects between the three and other plant components has practical significance for the development of turmeric based full component drugs or compound formulations.

Conclusion

As an important natural diarylheptane compound in turmeric, bisdemethoxycurcumin exhibits extensive and significant pharmacological activities, especially in anti-inflammatory, antioxidant, anti-tumor, and colon mucosal protection, due to its relatively simple chemical structure and unique polyphenol and β - diketone properties. Its multi-target mechanism involves the regulation of key inflammatory pathways such as TLR4/NF - κ B and MAPK, as well as multiple molecular targets such as CES1, FAAH, and SPHK1, providing a scientific basis for its treatment of complex diseases such as colitis. Although its poor water solubility and low oral bioavailability limit its current applications due to drug defects, it is expected to overcome these bottlenecks through new drug delivery technologies, structural modifications, and combination therapy strategies. In the future, with a deeper understanding of its mechanism of action, continuous innovation in delivery systems, and the advancement of rigorous clinical research, bisdemethoxycurcumin is expected to gradually develop from a potential natural product into an innovative drug or functional ingredient for the prevention and treatment of inflammatory bowel disease and other related diseases, contributing its unique value to human health.