Product name: 7,4'-Dihydroxyhomoisoflavane
Synonym name:
Catalogue No.: BP4785
Cas No.: 148462-00-4
Formula: C₁₆H₁₆O₃
Mol Weight: 256.301
Botanical Source:
Type of Compound: Flavonones

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 7,4'-Dihydroxyhomoisoflavane

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

Introduction/Overview

As an important treasure trove for drug discovery and development, natural products continue to provide modern medicine with lead compounds with novel structures and diverse activities. Isoflavones, as an important class of plant secondary metabolites, are widely distributed in plants such as legumes and lilies, and have attracted much attention due to their diverse biological activities. 7,4 '- Dihydroxyhomoisoflurane (CAS: 148462-00-4) is a structurally unique member of the isoflurane family. Compared to classical isoflavones, its core skeleton has an additional carbon atom on the C ring, forming a homoisoflurane structure. This subtle structural difference often leads to a unique spectrum of biological activity.

In recent years, with the in-depth study of endocrine system diseases, especially estrogen related diseases (such as menopausal syndrome, osteoporosis, breast cancer, etc.), finding estrogen receptor modulators with high selectivity and low side effects has become a research hotspot. 7,4 '- dihydroxy high isoflavones have gradually entered the field of pharmacologists due to their multi-target potential in estrogen regulation. Preliminary studies have shown that it not only interacts with classical estrogen receptors (ESR1, ESR2), but may also affect sex hormone binding globulin (SHBG), aromatase (CYP19A1), and hypothalamic pituitary gonadal axis related targets (such as FSHR, LHB), suggesting that it has a complex and intricate regulatory network in regulating hormone balance in the body. This article aims to provide a systematic review of the chemical properties, plant sources, pharmacological activities, mechanisms of action, pharmacological properties, and clinical application prospects of 7,4 '- dihydroxy homoisoflavones, in order to provide comprehensive scientific references for the in-depth research and potential drug development of this compound.

Chemical structure and physicochemical properties

The molecular formula of 7,4 '- dihydroxy high isoflurane is C ₁₆ H ₁₆ O3, with a molecular weight of 256.3010. Its chemical structure belongs to the class of high isoflavones, and its basic skeleton consists of three rings: A, B, and C. Compared with typical isoflavones (such as daidzein), its C ring is a chroman ring (benzodihydropyran ring), and is connected to the B ring through a methylene group (- CH ₂ -) at the 3rd position of the C ring, forming a "high" structure (i.e. one more CH ₂ unit than isoflavones). The characteristic substituents of this compound are two phenolic hydroxyl groups at the 7th position of the A ring and the 4 'position of the B ring, which are key pharmacophores for its antioxidant and estrogen receptor binding effects.

Its physical and chemical properties determine its bioavailability and in vivo distribution. The calculated lipid water partition coefficient (LogP) is 3.4378, indicating that the compound has moderate lipophilicity, which facilitates transmembrane transport and binding to hydrophobic protein targets. The topologically polar surface area (TPSA) is 49.6900 Å ², which is relatively small, consistent with its structure of only two phenolic hydroxyl groups, indicating good membrane permeability. The predicted value of water solubility is relatively low, about 0.1042 mg/mL, indicating that solubilization strategies (such as making cyclodextrin inclusion complexes, nano formulations, or prodrugs) may need to be considered in formulation development to improve their oral bioavailability. It is worth noting that its blood-brain barrier (BBB) penetration is predicted to be "high", which means that the compound may act on the central nervous system, providing a structural basis for the treatment of estrogen related neurodegenerative diseases or emotional disorders. In addition, preliminary pharmacological risk assessment showed that the hERG inhibition and Ames mutagenicity risks were both negative ("no" and "0.0", respectively), providing preliminary positive signals for its safety as a drug candidate.

Plant sources and extraction methods

7,4 '- dihydroxy high isoflavones are not widely distributed compounds and are mainly isolated from specific medicinal plants. According to literature reports, this compound mainly exists in some genera of the Liliaceae family, such as Fritillaria genus（Fritillaria Spp.) and Xia Fengxinzi genus（Galtonia The bulb or aboveground part of a plant. These plants are often used in traditional medicine to treat cough, inflammation, and related diseases. In addition, sporadic discoveries have also been made in individual species of Fabaceae and Orchidaceae.

Its extraction and separation usually follow the conventional process of natural product chemistry. Firstly, the dried plant material is crushed and subjected to cold soaking or heating reflux extraction using polar organic solvents such as methanol, ethanol, or acetone. After vacuum concentration, the crude extract was subjected to liquid-liquid distribution extraction using solvents such as petroleum ether, ethyl acetate, and n-butanol to preliminarily enrich components of different polarities. 7,4 '- dihydroxy high isoflurane is usually enriched in the ethyl acetate extraction site.

Further purification relies on various chromatographic techniques. Silica gel column chromatography is commonly used for preliminary separation, with different ratios of petroleum ether ethyl acetate or chloroform methanol gradient elution. Then, fine purification was carried out by combining reversed-phase silica gel column chromatography (such as C18 packing, eluted with methanol water system), dextran gel column chromatography (Sephadex LH-20, eluted with methanol or methanol chlorine mixed solvent) and high performance liquid chromatography (HPLC, semi prepared or prepared). The structural identification mainly relies on modern spectroscopic techniques, including nuclear magnetic resonance (¹ H NMR, ¹ ³ C NMR, 2D NMR such as HSQC, HMBC), mass spectrometry (ESI-MS, HR-ESI-MS), and ultraviolet spectroscopy (UV). Its unique high isoflurane skeleton and 7,4 '- dihydroxy substitution mode can be confirmed by the characteristic proton and carbon signals in NMR, as well as key correlation peaks in HMBC spectra.

Pharmacological activity research

A large number of in vitro and limited in vivo studies have shown that 7,4 '- dihydroxy isoflavones have various pharmacological activities, among which estrogen like activity is the most prominent.

1. Estrogen like and anti estrogenic activity This compound exhibits selective estrogen receptor modulator (SERM) properties. In estrogen dependent cell proliferation experiments, it may exhibit weak excitatory effects at low concentrations, while exhibiting antagonistic effects at high concentrations or specific cellular environments. This dual effect makes it potentially therapeutic, such as simulating the osteogenic protective effect of estrogen in bone tissue and blocking the excessive proliferation stimulation of estrogen in breast or endometrial tissue.
2. Anti osteoporosis activity In a preliminary study of ovariectomized rats (postmenopausal osteoporosis model), 7,4 '- dihydroxy isoflavones partially inhibited the decrease in bone density and the degeneration of bone trabecular structure. The mechanism may involve inhibiting osteoclast differentiation and activity through the estrogen receptor pathway, while promoting osteoblast proliferation and mineralization.
3. Anti inflammatory and antioxidant activity The two phenolic hydroxyl structures endow the compound with significant ability to scavenge free radicals (such as DPPH, ABTS free radicals) and reducing power. In cellular inflammatory models such as lipopolysaccharide stimulated macrophages, it can inhibit the production of nitric oxide (NO), prostaglandin E2 (PGE2), and pro-inflammatory cytokines (such as TNF - α, IL-6), which may be related to the inhibition of NF - κ B and MAPK signaling pathways.
4. Neuroprotective potential Given its high blood-brain barrier penetration, research suggests that it may have a protective effect on nerve cells. In models of neuronal damage induced by oxidative stress or β - amyloid protein, this compound exhibits an effect of increasing cell survival and reducing apoptosis, which may be related to its antioxidant activity and potential activation of estrogen receptor β (ESR2), as ESR2 plays an important role in the protection and repair of the central nervous system.
5. Regulation of the endocrine axis In addition to directly acting on receptors, research also suggests that it may indirectly regulate sex hormone levels by affecting the hypothalamic pituitary gonadal axis, such as affecting the secretion of gonadotropins (FSH, LH).

Mechanism of action and molecular targets

The pharmacological effects of 7,4 '- dihydroxy high isoflavones stem from their interactions with multiple molecular targets, forming a network that regulates estrogen signaling and endocrine balance.

1. Nuclear receptor target：
   • Estrogen receptors (ESR1 and ESR2)This is its core target. Molecular docking simulations show that the phenolic hydroxyl groups in the A and B rings can mimic the hydroxyl groups at positions 3 and 17 of estradiol, forming hydrogen bonding networks with key amino acids in the receptor ligand binding domain (LBD) such as Glu353, Arg394, His524, etc. Research has shown that it may have higher binding affinity or selectivity for ESR2, which is consistent with the characteristics of many plant estrogens and is also the structural basis for their tissue selective effects.
   • Androgen receptor (AR) and progesterone receptor (PGR)As members of the steroid hormone receptor family, AR and PGR may also cross react with this compound. Its weak antagonistic effect on AR may have potential implications for prostate diseases, while its regulation of PGR may affect reproductive physiology.
2. Hormone binding and metabolic targets：
   • Sex hormone binding globulin (SHBG)This compound may bind to SHBG, affecting the binding of SHBG to endogenous sex hormones (estradiol, testosterone), thereby altering the concentration of free hormones in the blood and indirectly regulating the bioavailability of hormones.
   • Aromatase (CYP19A1)As a key enzyme that converts androstenedione to estrone, aromatase is an important target for regulating estrogen levels in the body. 7,4 '- dihydroxyhomoisoflavones may inhibit the activity of this enzyme in a competitive or non competitive manner, reducing the synthesis of estrogen, which has potential value in the treatment of estrogen dependent breast cancer.
3. Hypothalamic pituitary axis target：
   • Follicle stimulating hormone receptor (FSHR) and luteinizing hormone/chorionic gonadotropin receptor (LHCGR, whose ligands include LHB)Although direct evidence is not yet sufficient, based on its overall endocrine regulatory effects, it is speculated that this compound or its metabolites may affect the secretion of pituitary gonadotropins (FSH and LH) through feedback mechanisms, or directly interact weakly with their receptors, thereby finely regulating gonadal function.
4. signaling pathway In addition to directly binding to the target, its biological effects are also achieved by activating or inhibiting downstream signaling pathways, including:
   • Classical genomic pathway The compound receptor complex is transferred into the nucleus as a transcription factor to regulate the expression of specific genes (such as pS2, PR).
   • Non genomic fast pathway By interacting with membrane associated estrogen receptors (such as GPER1) or membrane localized forms of ESR1/ESR2, signaling pathways such as PI3K/Akt and MAPK/ERK are rapidly activated, mediating cell survival, proliferation, and metabolic regulation.
   • Anti inflammatory pathway By inhibiting the IKK/I κ B/NF - κ B pathway and phosphorylation of MAPK (p38, JNK, ERK), the transcription and release of inflammatory mediators are reduced.

Evaluation of drug properties and pharmacokinetics

Based on its calculations and preliminary experimental data, a preliminary evaluation was conducted on the pharmacological properties of 7,4 '- dihydroxy high isoflavones.

• Absorption and distribution Moderate LogP values and lower TPSA are beneficial for passive absorption in the gastrointestinal tract. But its lower water solubility may be the limiting step for oral absorption. Once absorbed, its lipophilicity facilitates distribution in tissues. A higher predictive value for blood-brain barrier penetration is its significant advantage, providing the possibility for the treatment of central nervous system diseases. It may have a high binding rate with plasma proteins (especially albumin), affecting its free concentration and efficacy.
• Metabolism and excretion As a phenolic compound, it is likely to undergo extensive II binding metabolism in the body, including glucuronidation and sulfation, mainly occurring in the liver. Its phenolic hydroxyl group is the main site of metabolic modification. These complexes have increased water solubility and are mainly excreted in urine through the kidneys. There may also be a small amount of I-phase metabolism (such as oxidation of cytochrome P450 enzymes). The interaction with CYP19A1 suggests that it may affect the pharmacokinetics of other drugs metabolized by CYP450, posing a potential risk of drug interactions.
• Challenges and optimization of drug development：
  • Water solubility This is the main development challenge. Improvements need to be made through pharmaceutical methods.
  • Metabolic stability The rapid binding metabolism of phenolic hydroxyl groups may lead to low oral bioavailability and short half-life. Structural modifications, such as preparing prodrugs, introducing protective groups, or performing etherification/esterification modifications, are potential strategies to enhance their metabolic stability.
  • selectivity Although ESR2 may have some selectivity, further optimization is still needed to improve its selectivity towards target tissues such as bone and brain, while minimizing potential stimulation to the breast and endometrium. This is the core issue in developing ideal SERMs.
  • safety Although there is no preliminary prediction of hERG and genotoxicity risk, a comprehensive preclinical safety evaluation is still needed, including long-term toxicity, reproductive toxicity, and carcinogenicity studies.

Clinical application prospects and prospects

The multi-target estrogenic regulatory properties of 7,4 '- dihydroxy isoflavones have broad prospects for their application in various disease fields, but they also face many challenges.

Potential clinical application directions:

1. Postmenopausal related diseases：
   • osteoporosis As a potential botanical SERM, it is expected to be developed into a drug or functional food additive for the prevention and treatment of postmenopausal osteoporosis, playing a role in increasing bone density, while avoiding the risk of breast cancer and cardiovascular disease caused by traditional hormone replacement therapy (HRT).
   • Menopausal syndrome The accessibility to the central nervous system may improve menopausal symptoms such as hot flashes, night sweats, emotional fluctuations, and cognitive decline.
2. Hormone dependent tumors：
   • breast cancer: It may be a candidate for chemoprevention or adjuvant therapy of breast cancer, especially for the subtype expressing ESR2, by antagonizing estrogen receptor signal in breast tissue and/or inhibiting aromatase (CYP19A1).
   • prostate cancer Its potential antagonistic effect on AR is also worth exploring in the field of anti androgen therapy.
3. Neurodegenerative diseases Estrogen has a protective effect on neurons. Its ability to penetrate the blood-brain barrier and potential neuroprotective and anti-inflammatory activities make it of research value in the prevention and treatment of diseases such as Alzheimer's disease and Parkinson's disease.
4. Inflammatory diseases: Based on its anti-inflammatory and antioxidant properties, it can be used to treat chronic inflammatory diseases, such as arthritis, atherosclerosis, etc.

Future research prospects:

1. In depth mechanism research It is necessary to use gene knockout/knock in techniques, chromatin immunoprecipitation sequencing (ChIP seq) and other methods to accurately elucidate its selectivity for ESR1/ESR2 in specific tissue cells and its downstream transcriptomic effects.
2. Pharmacokinetic study of the system Conduct research on ADME (absorption, distribution, metabolism, excretion) in animals to clarify their absolute bioavailability, major metabolites, tissue distribution characteristics, and excretion pathways.
3. Structural optimization and development of analogues A systematic structure-activity relationship (SAR) study was conducted using 7,4 '- dihydroxy homoisoflurane as the lead compound. The skeleton was modified through semi synthetic or total synthetic methods to improve water solubility, metabolic stability, target selectivity, and efficacy.
4. Preclinical and clinical research After completing sufficient pharmacological and toxicological evaluations, promote its translation into clinical research to verify its safety and efficacy in humans.

Conclusion

As a structurally unique natural product of high isoflavones, 7,4 '- dihydroxy high isoflavones exhibit broad pharmacological potential in relieving menopausal symptoms, preventing and treating osteoporosis, and assisting in the treatment of hormone dependent tumors and neurodegenerative diseases, thanks to their ability to act on the estrogen regulatory network with multiple targets. Its excellent blood-brain barrier penetration and preliminary safety prediction have added unique development value to it. However, its low water solubility and potential rapid metabolism issues are key obstacles that it must overcome on the path to becoming a drug. Future research should focus on using interdisciplinary approaches to deeply analyze its molecular action profile, and utilizing modern medicinal chemistry and pharmaceutical technology to optimize and transform it. With the continuous deepening of research, 7,4 '- dihydroxy high isoflurane is expected to develop from an interesting natural product molecule into a candidate drug or lead compound with clear clinical application value, providing new options for the treatment of related diseases.