Phloretin

Crystalline Solid

White to pale yellow solid.

Phloretin has been used:

• to study its effect on the 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose (2-NBDG) and 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-l-glucose (2-NBDLG) uptake
• to incubate microvesicles in order to inhibit GLUT1 (glucose transporter 1)-mediated transport in radioactive ligand up-take assay
• as a component of KRH buffer to stop glucose uptake by trophoblast cells in vitro

As glucose transport inhibitor, Phloretin can inhibits protein kinase C and has been shown to inhibit the entry of five enveloped viruses into human fibroblasts.

ChEBI: Phloretin is a member of the class of dihydrochalcones that is dihydrochalcone substituted by hydroxy groups at positions 4, 2', 4' and 6'. It has a role as a plant metabolite and an antineoplastic agent. It is functionally related to a dihydrochalcone.

Phloretin is a dihydrochalcone flavonoid with antioxidant activity usually found in apples and apple-derived products. It is extensively used for peroxynitrite scavenging and the inhibition of lipid peroxidation. It has been found to inhibit the growth of several cancer cells and induce apoptosis of B16 melanoma and HL60 human leukemia cells.

phloretin is a dihydrochalcone, a type of natural phenols which can be found in apple tree leaves and manchurian apricot. phloretin inhibits the active transport of glucose into cells via sodium-glucose linked transporter (sglt) 1 and 2 with ic50 value of 49±12 μm [2].sglts are a family of glucose transporter which is found in the small intestine mucosa (sglt 1) and nephron proximal tubule (sglt 2). they contribute to the renal glucose reabsorption.after treatment of phloretin, differentiated 3t3-l1 cells exhibited significantly enhanced glycerol and the inhibition of adipogenesis-related transcription factor that were regulated by sglts. additionally, phloretin promoted phosphorylation of amp-activated protein kinase and increased activity of adipose triglyceride lipase and hormone-sensitive lipase [1]. when raw 263.7 cells were cultured from differentiated 3t3-l1 cell media, pt suppressed the sglt-associated nuclear transcription factor kappab and mitogen-activated protein kinase pathways [1].in streptozotocin-induced rat model of diabetes type i, oral administration of phloridzin (5/10/20/40 mg/kg/day) resulted in significant reduction of blood glucose levels and improved dyslipidemia. additionally, administration of phloridzin reduced urine volume and water intake in a dose-dependent manner [3].

Reacts with vic-dicarbonyl compounds such as glyoxal and methylglyoxal, preventing cytotoxic conjugation with biological macromolecules.

Phloretin biosynthesis originates from phenylalanine or tyrosine. In the natural plant pathway, chalcone synthase (CHS) catalyzes the decarboxylative condensation of phloretoyl-CoA with three molecules of malonyl-CoA to form phloretin[4][5][6]. Artificial biosynthetic pathways have been established in yeast and Escherichia coli. These systems produce phloretin by assembling p-coumaroyl-CoA ligase (4CL) and CHS genes, using 3-(4-hydroxyphenyl) propanoic acid as a low-cost raw material. Optimization of these pathways, including stepwise culture and fed-batch fermentation, has achieved production titers up to 619.5 mg/L[5][6].

Crystallise phloretin from aqueous EtOH. [Zemplen & Bognár Chem Ber 75 1040 1942, Zemplén Chem Ber 76 386 1943, Beilstein 8 IV 3518.]

[1] huang w c et al. , phloretin and phlorizin promote lipolysis and inhibit inflammation in mouse 3t3-l1 cells and in macrophage-adipocyte co-cultures. mol nutr food res. 2013, 57: 1807-1817.
[2] kasahara t, kasahara m.  expression of the rat glut1 glucose transporter in the yeast saccharomyces cerevisiae. biochem j. 1996, 315 ( pt 1):177-182.
[3] najafian m, jahromi m z, nowroznejhad m j, phloridzin reduces blood glucose levels and improves lipids metabolism in streptozotocin-induced diabetic rats.  mol biol rep. 2012, 39(5): 5299-306.
[4] Han, Y., Qiu, Z., Ji, S., & Zhao, G.-R. (2024). Construction and Optimization of Engineered Saccharomyces cerevisiae for De Novo Synthesis of Phloretin and Its Derivatives. Journal of Agricultural and Food Chemistry, 73(1), 735–746. https://doi.org/10.1021/acs.jafc.4c09893
[5] Jiang, C., Liu, X., Chen, X., Cai, Y., Zhuang, Y., Liu, T., Zhu, X., Wang, H., Liu, Y., Jiang, H., & Wang, W. (2020). Raising the production of phloretin by alleviation of by-product of chalcone synthase in the engineered yeast. Science China Life Sciences, 63(11), 1734–1743. https://doi.org/10.1007/s11427-019-1634-8
[6] Lee, S.-W., Lee, G., Jo, J.-H., Yang, Y., & Ahn, J.-H. (2024). Biosynthesis of phloretin and its C-glycosides through stepwise culture of Escherichia coli. Applied Biological Chemistry, 67(1). https://doi.org/10.1186/s13765-024-00955-x