Didymin

Didymin
Names
IUPAC name
(2S)-7-{[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-({[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy}methyl)oxan-2-yl]oxy}-5-hydroxy-2-(4-methoxyphenyl)-3,4-dihydro-2H-chromen-4-one
Other names
Isosakuranetin 7-O-rutinoside; Neoponcirin
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.034.656 Edit this at Wikidata
EC Number
  • 238-139-6
UNII
  • InChI=1S/C28H34O14/c1-11-21(31)23(33)25(35)27(39-11)38-10-19-22(32)24(34)26(36)28(42-19)40-14-7-15(29)20-16(30)9-17(41-18(20)8-14)12-3-5-13(37-2)6-4-12/h3-8,11,17,19,21-29,31-36H,9-10H2,1-2H3/t11-,17-,19+,21-,22+,23+,24-,25+,26+,27+,28+/m0/s1
    Key: RMCRQBAILCLJGU-HIBKWJPLSA-N
  • COc1ccc([C@@H]2CC(=O)c3c(O)cc(O[C@@H]4O[C@H](CO[C@@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@@H](O)[C@H](O)[C@H]4O)cc3O2)cc1
Properties
C28H34O14
Molar mass 594.56 g·mol−1
Appearance White crystalline powder
Poorly soluble in water; soluble in methanol, ethanol, DMSO
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Didymin (also known as isosakuranetin 7-O-rutinoside or neoponcirin) is an O-methylated flavanone glycoside occurring naturally in citrus fruits, consisting of the flavanone isosakuranetin linked to the disaccharide rutinose.

Occurrence

History of isolation

Didymin was first described in 1965 by German scientists Carl Heinz Brieskorn and Gerhard Meister, who identified isosakuranetin-7-rhamnosidoglucoside in the leaves of Monarda didyma L. The structure of didymin was subsequently clarified and confirmed by total synthesis in 1968 by Wagner, Hörhammer, Aurnhammer, and Farkas.

Distribution in plants

Didymin is found in a variety of citrus fruits, including mandarin oranges, sweet oranges, grapefruit, and lemons, as well as in Origanum vulgare (oregano). In immature dropped fruits of Citrus sinensis, didymin has been quantified alongside other flavanone glycosides such as hesperidin and narirutin, with its content being better preserved by freeze-drying than by hot-air oven drying. It was first identified in grapefruit as a tasteless rutinoside-type flavanone glycoside, in contrast to the bitter neohesperidoside-type glycosides such as naringin. It is also present in chenpi (dried citrus peel), a traditional ingredient in Chinese medicine.

Biological activities

Antioxidant activity

Didymin exhibits antioxidant properties by scavenging free radicals and reducing reactive oxygen species (ROS). In neuronal cell studies, it was found to protect cells against hydrogen peroxide-induced oxidative damage, increase cell viability, and stimulate antioxidant defence enzymes including superoxide dismutase, catalase, and glutathione peroxidase. Didymin is among the flavonoids present in orange juice that have been associated with a reduction in markers of oxidative stress and DNA damage.

Neuroprotective activity

In vitro studies have demonstrated that didymin can rescue neuronal cells from oxidative damage. In a membrane-based neuronal cell model, it inhibited hydrogen peroxide-induced mitochondrial dysfunction, reduced caspase-3 activation, and suppressed JNK phosphorylation, suggesting potential relevance for neurodegenerative diseases associated with oxidative stress.

Anticancer activity

Didymin has been studied for its effects on various cancer cell lines in vitro. In human hepatocellular carcinoma (HepG2) cells, it inhibited cell viability, migration, and colony formation, induced apoptosis, and caused G2/M cell cycle arrest. These effects were associated with changes in the Bcl-2/Bax ratio and activation of caspase-mediated apoptosis, as well as upregulation of Raf kinase inhibitor protein (RKIP) and suppression of the ERK/MAPK and PI3K/Akt pathways. Didymin has also been investigated for its effects against p53-mutant neuroblastoma.

Cardioprotective activity

Didymin has been shown to protect against doxorubicin-induced cardiotoxicity in mouse models and cardiomyocyte cell cultures, reducing oxidative stress, mitochondrial dysfunction, and apoptosis via activation of the PI3K/Akt/Nrf2 signalling pathway. In endothelial cell studies, didymin prevented hyperglycaemia-induced dysfunction and death in human umbilical vein endothelial cells (HUVECs) by reducing ROS generation, lipid peroxidation, and inflammatory cytokine release, and by inhibiting NF-κB activation.

Metabolic activity

Several studies have investigated didymin's potential in metabolic disorders. In high-fat diet mouse models, didymin reduced postprandial blood glucose levels and improved insulin secretion by enhancing mitochondrial biogenesis and function in pancreatic beta cells. In a separate study, didymin alleviated metabolic dysfunction-associated fatty liver disease (MAFLD) in mice by activating Sirt1, thereby stimulating lipophagy and mitochondrial biogenesis. In insulin-resistant HepG2 cells, didymin enhanced glucose uptake and activated insulin receptor substrate-1, PI3K, Akt, and glycogen synthase kinase-3 (GSK-3), while inhibiting key enzymes of gluconeogenesis.

Geroprotective activity

Didymin is the principal flavonoid constituent of Monarda didyma L. (scarlet beebalm) extract, occurring at concentrations approximately 80-fold higher than the only other detectable flavonoid, isosakuranetin. In a randomized clinical trial, supplementation with 100 mg/day of Monarda didyma L. extract over 12 weeks was associated with reduced telomere attrition and improvements in markers of biological aging and quality of life, with the effects attributed primarily to didymin.

References

  1. 1 2 Yao, Qing; Lin, Meng-Ti; Zhu, Yin-Di; Xu, He-Lin; Zhao, Ying-Zheng (2018). "Recent Trends in Potential Therapeutic Applications of the Dietary Flavonoid Didymin". Molecules. 23 (10): 2547. doi:10.3390/molecules23102547. PMC 6222367. PMID 30297645.
  2. ↑ Brieskorn, Carl Heinz; Meister, Gerhard (1965). "Zum Vorkommen von Isosacuranetin-7-rhamnosidoglucosid in den Blättern von Monarda didyma L." [On the occurrence of isosakuranetin-7-rhamnosidoglucoside in the leaves of Monarda didyma L.]. Archiv der Pharmazie (in German). 298 (7): 435–440. doi:10.1002/ardp.19652980706. PMID 5218336.
  3. ↑ Wagner, H.; Hörhammer, L.; Aurnhammer, G.; Farkas, L. (1968). "Strukturaufklärung und Synthese des Didymins, eines Isosakuranetin-7-β-Rutinosids aus Monarda didyma L." [Structure clarification and synthesis of didymin, an isosakuranetin-7-β-rutinoside from Monarda didyma L.]. Chemische Berichte (in German). 101 (2): 445–449. doi:10.1002/cber.19681010208. PMID 5683142.
  4. 1 2 Ali, Md Yousof; Zaib, Sumera; Rahman, M. Mizanur; Jannat, Susoma; Iqbal, Jamshed; Park, Seong Kyu; Chang, Mun Seog (2019). "Didymin, a dietary citrus flavonoid exhibits anti-diabetic complications and promotes glucose uptake through the activation of PI3K/Akt signaling pathway in insulin-resistant HepG2 cells". Chemico-Biological Interactions. 305: 180–194. doi:10.1016/j.cbi.2019.03.018. PMID 30930107.
  5. 1 2 Wei, Jinbin; Huang, Quanfang; Bai, Facheng; Lin, Jun; Nie, Jinlan; Lu, Shengjuan; Lu, Chunyuang; Huang, Renbin; Lu, Zhongpeng; Lin, Xin (2017). "Didymin induces apoptosis through mitochondrial dysfunction and up-regulation of RKIP in human hepatoma cells". Chemico-Biological Interactions. 261: 118–126. doi:10.1016/j.cbi.2016.11.026. PMID 27889589.
  6. ↑ Kumar, Dinesh; Ladaniya, M. S.; Gurjar, Manju; Kumar, Sunil (2022). "Impact of drying methods on natural antioxidants, phenols and flavanones of immature dropped Citrus sinensis L. Osbeck fruits". Scientific Reports. 12: 6684. doi:10.1038/s41598-022-10661-7. PMC 9023483. PMID 35449208.
  7. ↑ Mizelle, J. W.; Dunlap, W. J.; Hagen, R. E.; Wender, S. H.; Lime, B. J.; Albach, R. F.; Griffiths, F. P. (1965). "Isolation and Identification of Some Flavanone Rutinosides of the Grapefruit". Analytical Biochemistry. 12: 316–324. doi:10.1016/0003-2697(65)90009-3. PMID 5837454.
  8. 1 2 Yang, Jing-wen; Zou, Ying; Chen, Jun; Cui, Chen; Song, Jia; Yang, Meng-meng; Gao, Jing; Hu, Hui-qing; Xia, Long-qing; Wang, Li-ming; Lv, Xiao-yu; Chen, Li; Hou, Xin-guo (2023). "Didymin alleviates metabolic dysfunction-associated fatty liver disease (MAFLD) via the stimulation of Sirt1-mediated lipophagy and mitochondrial biogenesis". Journal of Translational Medicine. 21: 921. doi:10.1186/s12967-023-04790-4. PMC 10731718. PMID 38110963.
  9. 1 2 Morelli, Sabrina; Piscioneri, Antonella; Salerno, Simona; Al-Fageeh, Mohamed B.; Drioli, Enrico; De Bartolo, Loredana (2014). "Neuroprotective Effect of Didymin on Hydrogen Peroxide-Induced Injury in the Neuronal Membrane System". Cells Tissues Organs. 199 (2–3): 184–200. doi:10.1159/000365072. PMID 25402337.
  10. ↑ Rangel-Huerta, Oscar D.; Aguilera, Concepcion M.; Martin, Maria V.; Soto, Maria J.; Rico, Maria C.; Vallejo, Fernando; Tomas-Barberan, Francisco; Perez-de-la-Cruz, Antonio J.; Gil, Angel; Mesa, Maria D. (2015). "Normal or High Polyphenol Concentration in Orange Juice Affects Antioxidant Activity, Blood Pressure, and Body Weight in Obese or Overweight Adults". Journal of Nutrition. 145 (8): 1808–1816. doi:10.3945/jn.115.211698. PMID 26109581.
  11. ↑ Singhal, Sharad S.; Singhal, Sulabh; Singhal, Preeti; Singhal, Jyotsana; Horne, David; Awasthi, Sanjay (2017-04-25). "Didymin: an orally active citrus flavonoid for targeting neuroblastoma". Oncotarget. 8 (17): 29428–29441. doi:10.18632/oncotarget.15204. ISSN 1949-2553. PMC 5438742. PMID 28187004.
  12. ↑ Chen, Rongchang; Sun, Guibo; Xu, Lijiao; Zhang, Xu; Zeng, Wenying; Sun, Xiaobo (2022). "Didymin attenuates doxorubicin-induced cardiotoxicity by inhibiting oxidative stress". Chinese Herbal Medicines. 14 (1): 70–78. doi:10.1016/j.chmed.2021.07.002. PMID 36117638.
  13. ↑ Shukla, Kirtikar; Sonowal, Himangshu; Saxena, Ashish; Ramana, Kota V. (2018). "Didymin prevents hyperglycemia-induced human umbilical endothelial cells dysfunction and death". Biochemical Pharmacology. 152: 1–10. doi:10.1016/j.bcp.2018.03.012. PMC 5970995. PMID 29551519.
  14. ↑ Yang, Jingwen; Zou, Ying; Lv, Xiaoyu; Chen, Jun; Cui, Che; Song, Jia; Yang, Mengmeng; Hu, Huiqing; Gao, Jing; Xia, Longqing; Wang, Liming; Chen, Li; Hou, Xinguo (2024). "Didymin protects pancreatic beta cells by enhancing mitochondrial function in high-fat diet-induced impaired glucose tolerance". Diabetology & Metabolic Syndrome. 16: 7. doi:10.1186/s13098-023-01244-1. PMC 10763415. PMID 38178225.
  15. 1 2 Campisi, M.; Cannella, L.; Paccagnella, O.; Brazzale, A. R.; Agnolin, A.; Grothe, T.; Baumann, J.; Pavanello, S. (2025). "Unveiling the geroprotective potential of Monarda didyma L.: insights from in vitro studies and a randomized clinical trial on slowing biological aging and improving quality of life". Ageing Research Reviews. doi:10.1016/j.arr.2025.102694. PMC 12181487. PMID 40023222.