Table 1.
Comparison of biological activity of dihydrochalcones in various experimental models.
| Therapeutics | Compound | Treatment and Methods | Targets and Effects | Experimental Model | Ref. |
|---|---|---|---|---|---|
| Anticancer | evelynin A | SRB assay | antiproliferative activity IC50 = 6.3 ± 0.7µM (HeLa) IC50 = 4.7 ± 0.4 µM (PC-3) |
In vitro, HeLa (cervical carcinoma), A549 (lung cancer), and PC-3 (prostate cancer) | [87] |
| evelynin B | antiproliferative activity IC50 =8.8 ± 0.5 µM (HeLa) IC50 = 8.3 ± 0.6 µM (A549) IC50 = 5.0 ± 0.8 µM (PC-3) inhibits tubulin polymerization |
||||
| aspalathin | 0.2–1.0 µM | Co-treatment with aspalathin attenuates doxorubicin-induced cardiotoxicity by improving endogenous antioxidant levels and mitochondrial membrane potential while inhibiting reactive oxygen species production and cellular apoptosis. | In vitro, H9c2 cardiomyoblasts | [88] | |
| zornioside | 0.39–50 µg/mL MTT assay |
IC50 = 37.26 µM | In vitro, HL60 (leukemia cells) | [89] | |
| sakenins F and H | PC50 values of 8.0 µM and 11.1 µM | In vitro, PANC-1 human pancreatic cancer cells | [90] | ||
| 2′,6′-dihydroxy- -4′4-dimethoxydihydrochalcone, 2′,6′-dihydroxy- -4′-methoxydihydrochalcone, and 2′,4′,6′-trihydroxydihydrochalcone |
MTT assay 50–100 μM |
Augment TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis and cytotoxicity | In vitro, LNCaP (human hormone-sensitive prostate cancer) | [91] | |
| 2′-dihydroxy-4,4′-dimethoxydihydrochalcone | 8–32 µM 12–48 mg/kg |
Antiproliferative activity, suppresses cell proliferation, induces excess of reactive oxygen species (ROS) accumulation, and inhibits the invasion and migration ability of MKN45 cells. Upregulates the autophagy-related proteins Beclin-1, Atg5, and Atg7; induces formation of Autophagosomes and regulatory role of ROS/MEK/ERK signaling pathways. In vivo inhibits the growth of MKN45 xenograft tumors in nude mice and suppresses Ki67 expression. |
In vitro, MKN45 (human gastric cancer) In vivo, BALB/C nude mice |
[92] | |
| conjugates of phloretin (Pht) and phlorizin (Phl) with gold nanoparticles (AuNPs) | Fourty-five-fold increase in the efficacy in the antineoplastic activity of Pht-AuNPs over pure phloretin and 4.49-fold increase in efficacy of Phl-AuNP over pure phlorizin. | In vitro, HeLa (cervical carcinoma) | [93] | ||
| phloretin | 0–60 µM 10–20 mg/kg |
Marked suppression of invasion and migration through downregulation of matrix metalloproteinase (MMP)-2, MMP-3, and cathepsin Sin human SiHa cervical cancer cells. Suppresses lung metastasis and tumor growth. |
In vitro, SiHa (cervical cancer), HeLa, and CaSki (cervical cancer) In vivo, BALB/c AnN.CgFoxnnu/Crl Narl mice |
[94] | |
| 0.1–0.2 mM | Induces apoptosis by the inhibition of glucose transmembrane transport and internucleosomal DNA fragmentation | In vitro, B16 (mouse melanoma 4A5 cells) | [95] | ||
| 20–100 µM | Inhibits cancer cell proliferation and migration by increasing the ROS production in the cells | In vitro, PC-3 and DU-145 (human prostate cancer) | [96] | ||
| 60–100 µg/mL | Induces cancer cellapoptosis via a mitochondrial-dependent pathway. Downregulates the antiapoptosis-associated molecule B-cell lymphoma 2 (bcl-2) and increases the levels of the apoptosis-associated molecules bcl-2-like protein 4 and tumor protein p53. Affects the expression of apoptotic protease activating factor-1. |
In vitro, EC-109 (human esophageal cancer) | [97] | ||
| MTT assay, DAPI, annexin V/PI, Transwell assay, and Western blotting. 0–16 µM |
Inhibits cell proliferation. IC50 = 8.0 µM (AGS) IC50 = 16.0 µM (MGC80-3, BGC-823, SGC-7901, SNU-5) IC50 = 32.0 µM (SNU-1, SNU-5, SNU-16, RF-1) IC50 > 60 µM (SNU-16, GES- 1) |
In vitro, MGC80-3, BGC-823, SGC-7901, AGS, SNU-1, SNU-5, SNU-16, RF-1, and GES-1 (gastric cancers) | [98] | ||
| 3‴-methoxy-6″-O-feruloy-4′-O- -glucopyranosyl-phloretin |
MTT assay | IC50 = 39.79 ± 5.72 µg/mL (A549) IC50 = 59.28 ± 5.06 µg/mL (BEL7402) IC50 = 49.36 ± 3.04 µg/mL (HepG2) IC50 = 65.09 ± 2.77 µg/mL (HT-29) Glycoside moiety bound to the phloretin structure decreases its anticancer activity (e.g., in trilobatin) |
In vitro, A549 (lung cancer), BEL 7402 (liver cancer), HepG2 human ileocecal cancer cell line, and HT-29 (colon cancer) | [99] | |
| 3-hydroxyphloretin | IC50 = 39.83 ± 4.23 µg/mL (A549) IC50 = 45.17 ± 8.02 µg/mL (BEL7402) IC50 = 37.79 ± 4.04 µg/mL (HepG2) IC50 = 35.37 ± 2.53 µg/mL (HT-29) |
||||
| α,β-dihydroxanthohumol | SRB assay 0.1–100 µg/mL |
IC50 = 9.15 ± 0.62 µM (MCF-7)) IC50 = 14.73 ± 3.88 µM (PC-3) IC50 = 74.41 ± 23.44 µM (HT-29) |
In vitro, MCF-7 (breast cancer), PC-3 (prostate cancer), and HT-29 (colon cancer) | [100] | |
| 4,2′,4′-trihydroxy-6′-methoxy-3′(2″-hydroxybenzyl)dihydrochalcone, 2′,4′-dihydroxy-4,6′-dimethoxy-3′(2″-hydroxybenzyl)dihydrochalcone | Antitumor activity IC50 = 2.02–20.03 µg/mL |
In vitro, KB (epimermoid carcinoma), MCF-7 (breast cancer, and NCl-H187 (lung cancer) | [101] | ||
| Antidiabetic | panduratin isopanduratin |
MG–BSA assay | Antiglycation agents, α-glucosidase inhibition | In vitro, bovine serum albumin and α-glucosidase (from rat intestine) | [102] |
| 3′-O-β-d-glucopyranosyl α,4,2′,4′,6′-pentahydroxy-dihydrochalcone | 25, 50, and 100 mg/kg diabetic nephropathy | Antiglycation compound inhibits protein glycation and decreases accumulation of advanced glycation end products (AGEs). | In vivo, STZ (streptozotocin)-induced diabetic mice (C57BL/6) | [103] | |
| phlorizin | Improves the symptoms of diabetes and diabetic complications. | [104] | |||
| dihydrochalcones from the roots of Sophora flavescens | Inhibitors of PTP1B | PTP1B inhibition assay | [105] | ||
| hydroxydihydrochalcones from Artemisia (Astraceae) | spectrophotometric method | Have inhibitory activity against principal enzymes of carbohydrate metabolism, such as α-amylase (IC50 = 150.24–384.14 μg/mL) and α-glucosidase (IC50 = 214.42–754.12 μg/mL). May become a complement to synthetic antidiabetic drugs for controlling blood glucose level. | In vitro, α-glucosidase from Saccharomyces cerevisiae, α-amylase from Aspergillus oryzae | [106] | |
| aspalathin | 130 mg/kg | Protects against diabetes-associated symptoms in mice. | In vivo, type-2 diabetic mouse model | [107] | |
| complications associated with hepatic insulin resistance and metabolic disease-relate | Plays a significant role in the maintenance of hormonal homeostasis. Influences the steroid hormone biosynthesis and the flux through the mineralocorticoid, glucocorticoid, and androgen pathways, thus possibly contributes to the alleviation of negative effects arising from elevated glucocorticoid levels. | In vitro, H295R | [108] | ||
| 10 µM | Reverses the palmitate-induced insulin resistance. Suppresses nuclear factor kappa beta (NF-κB), insulin receptor substrate one (serine 307) (IRS1 (Ser (307) and AMP-activated protein kinase (AKT) phosphorylation and increases serine/threonine kinase AKT activation. Increases the peroxisome proliferator-activated receptor alpha and gamma (PPARα and γ) and carnitine palmitoyltransferase one (CPT1) expression. | In vitro, 3T3-L1 adipocytes exposed to palmitate | [109] | ||
| 10 µM | Regulates hepatic cellular metabolism, increases energy expenditure, and modulates PI3K/AKT and AMPK signaling pathways. | In vitro, C3A (liver cells exposed to palmitate) | [110] | ||
| phlorizin | 5–40 mg/kg | Competitive inhibitor of sodium/glucose cotransporters in the intestine (SGLT1) and kidney (SGLT2) involved in intestinal glucose absorption and renal glucose reabsorption. | In vivo, Wistar rats | [111] | |
| Kidney diseases | aspalathin and nothofagin | Induce renal damage. Inhibits nuclear factor (NF)-κB activation and reduces the induction of NO synthase and excessive production of nitric acid. Reduce the plasma levels of NO, TNF-α, and IL-6; increases lipid peroxidation; and markedly enhances the antioxidant defence system by restoring the levels of superoxide dismutase, glutathione peroxidase, and catalase. |
In vivo, mice model sepsis | [112] | |
| Antimicrobial activity | balsacones A, B, and C | MIC = 3.1–6.6 μM (S. aureus) resistance (E. coli) | In vitro, Staphylococcus aureus
Escherichia coli |
[113] | |
| Elastichalcone C | In vitro, methicillin-resistant Staphylococcus aureus SK1, Saprolegnia parasitica Saprolegnia diclina |
[114] | |||
| dihydroisorcordoin | In vitro, Saprolegnia parasitica Saprolegnia diclina | [115] | |||
| phloretin, phlorizin,3’,5’-di-C-glucoside | microdilution method | phloretin: MIC = 7.81–125 μM (S. aureus) MIC = 62.5 μM (L. monocytogenes) MIC = 125 μM (S. typhimurium) MIC > 1000 μM (P. aeruginosa, E. coli) |
In vitro, Staphylococcus aureus ATCC 6538 Listeria monocytogenes ATCC 13932 methicyllin-resistant Staphylococcus aureus (MRSA, clinical strains: 526, 588, 550, 541, 531, 530, 543, 581) Salmonella typhimurium ATCC 13311 Pseudomonas aeruginosa ATCC 27853 Pseudomonas aeruginosa ATCC 15442 E. coli ATCC 10536 |
[116] | |
| 2′,4′-dihydroxy-4- methoxy-3′-prenyldihydrochalcone 2′,4′-dihydroxy-3,4-(2”,2”-dimethylchromeno)-3′-prenyldihydrochalcone |
Inhibition zone: 7.25–10.75 mm MIC = 0.9–1.8 mg/mL |
In vitro, Bacillus subtilis (ATCC 6633), Staphylococcus aureus (ATCC 29737), Escherichia coli (ATCC 10536), Pseudomonas putida (ATCC 49128) | [117] | ||
| 2′,4’-dihydroxychalcone | 105 µg/mL | Inhibits spore germination of plant pathogenic fungi | In vitro, Heiminthosporium oryzae, Aspergillus niger, Rhizopus nigricans | [118] | |
| 2′,6′-dihydroxy-3′-methyl-4′-methoxydihydrochalcone | MIC = 1.0–7.8 mg/L | In vitro, B. cereus (IFO3001) Pseudomonas putida (IFO3738) S. aureus (IFO12732) methicillin-resistant S. aureus (MRSA; RIM0310925) Enterococcus faecalis (IFO12970) Alicyclobacillus acidoterrestris (ATCC49025) Propionibacterium acnes (ATCC6919) Trichophyton mentagrophytes (IFO5466) |
[119] | ||
| dihydrochalcones identified in ethanol extracts from Uvaria chamae roots (uvaretin, uvangoletin, diuvaretin) | Inhibition diameter: 9–30.7 mm |
S. aureus ATCC 259223 S. aureus (clinical isolate) E. faecalis (clinical isolate) |
[120] | ||
| aspalathin, nothofagin | Antibacterial effect | In vitro, Escherichia coli (CFT073) Staphylococcus epidermis (Se19) Staphylococcus aureus (ATCC 25923) |
[121] | ||
| Antioxidant activity | neohesperidin dihydrochalcone | Downregulates cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions. Inhibites PQ-induced nuclear factor-kappa B (NF-κB) expression and mitochondrial-driven apoptotic signaling |
In vivo, mice with paraquat (PQ)-induced acute liver injury | [122] | |
| phlorizin, trilobatin, 3-hydroxyphlorizin, sieboldin, phloretin 2′-xyloglucosid | 3-Hydroxyphloretin was the best antioxidant among the seven compounds. Both glycosylation of the A ring and the ortho phenolic hydroxyl groups of the B ring were important for the cytotoxicity of dihydrochalcone molecules. | DPPH and ABTS assays | [123] | ||
| phloretin, phlorizin, trilobatin, sieboldin, 3-hydroxyphloretin 3-hydroxyphlorizin |
Presence of an o-dihydroxyl group in the B-ring increased activity, whereas glycosylation in the A-ring decreased antioxidant potential of dihydrochalcones. Glycosylation at the 2′-position enhanced the dissociation ability of the 4′-hydroxyl group and increased the antioxidant activity of dihydrochalcones containing o-dihydroxyl. |
DPPH and ABTS assays | [124] | ||
| phloretin, phloridzin, trilobatin, naringin dihydrochalcone, neohesperidin dihydrochalcone | 1 mg/mL (2–10 µL) FRAP, DPPH 0.25 mg/mL (2–10 µL) ABTS 5 mg/mL (2–10 µL) superoxide radical scavenging |
Antioxidant structure-activity relationship. In FRAP assay, antioxidant activity of pairs of dihydrochalcones had the following relationship: phloretin > phloridzin, phloretin > trilobatin, trilobatin > phloridzin, trilobatin > naringin dihydrochalcone, neohesperidin dihydrochalcone > naringin dihydrochalcone. | FRAP, DPPH, ABTS, and superoxide radical scavenging assays |
[125] | |
| aspalathin, nothofagin | Inhibitor of Fe(II)-induced lipid peroxidation: IC50 = 50.2 µM (aspalathin) IC50 = 1388 µM (aspalathin) ABTS assay: IC50 = 3.33 µM (aspalathin) IC50 = 4.04 µM (nothofagin) |
ABTS, metal chelating, and Fe(II)-induced microsomal lipid peroxidation assays | [126] | ||
| trilobatin, hesperetin dihydrochalcone-7-O-glucoside, prunin and hesperetin-7-O-glucoside (obtained in the selective enzymatic hydrolysis of parental flavonoid glycosides using an immobilised α-L-rhamnosidase) | 0.4–1.0 mM (DPPH) 0.025–0.200 mM (FRAP) 20–80 µM (ORAC) |
Some of the flavonoid monoglucosides showed significant improvement in the antioxidant activity. | DPPH, FRAP, and ORAC assays | [127] | |
| flavanones and dihydrochalcones | Dihydrochalcones exhibited higher antioxidant activities than the corresponding flavanones. The hydroxyl group at the 2‘-position in dihydrochalcone A ring is an essential pharmacophore for its radical scavenging potential. |
DPPH assay and lipid peroxidation in the erythrocyte membrane assays | [128] | ||
| phloretin | 1–5 mM | Supresses lipid oxidation in PUFA % of inhibition of the peroxyl radical-induced oxidation in oil-in-water emulsion containing methyl linolenate = 72.5 ± 5.5 |
In vitro, oil–in–water emulsion system, TBARS and fish oil system | [129] | |
| Antiinflammatory activity | phloretin | 125 µM | IC50 = 20 µM (MMP-2) does not inhibit LE and MMP-9 |
In vitro, matrix-proteases, leukocyte elastase (LE), and gelatinase A (MMP-2; human neuroblastoma cells) gelatinase B (MMP-9; HT-1080 human fibrosarcoma cells) |
[130] |
| aspalathin nothofagin |
Inhibits HG-mediated vascular hyperpermeability, adhesion of monocytes toward HUVECs, and expression of CAMs. Suppresses the formation of ROS and the activation of NFκB. |
In vivo, male C57BL/6 mice In vitro, primary human umbilical vein endothelial cells (HUVECs) |
[131] | ||
| α,β-dihydroxantohumol | 1–15 µM | IC50 (COX-1) = 124.50 ± 7.61 IC50 (COX-2) = 103.8 ± 6.11 |
In vitro, binding to human serum albumin (HSA), COX-1, and COX-2 activity | [132] | |
| phloretin | Osteoarthritis (OA) | Inhibits the IL-1β-induced production of NO, PGE2, TNF-α, and IL-6; the expression of COX-2, iNOS, MMP-3, MMP-13, and ADAMTS-5; and the degradation of aggrecan and collagen-II in human chondrocytes. Suppresses the IL-1β-stimulated phosphorylation of PI3K/Akt and activation of NF-κB. Decreass the expression of MMP-13 and increases the expression of collagen-II in mice. |
In vivo, mice In vitro, human OA chondrocytes |
[133] | |
| aspalathin nothofagin |
MTT assay 9.1–27.1 µg/mouse (aspalathin) 8.7–26.2 µg/mouse (nothofagin) | Inhibit LPS-induced barrier disruption, expression of cell adhesion molecules (CAMs), and adhesion/transendothelial migration of neutrophils to human endothelial cells. Suppress LPS-induced hyperpermeability and leukocyte migration. Suppress the production of tumor necrosis factor-α (TNF-α) or interleukin (IL)-6 and the activation of nuclear factor-κB (NF-κB) or extracellular regulated kinases (ERK) 1/2 by LPS |
In vitro, HUVECs (primary human umbilical vein endothelial cells) In vivo, male C57BL/c mice |
[134] | |
| apple polyphenol | Significantly inhibits proinflammatory gene expression and represses NF-jB-, IP-10-, IL-8-promoter-, and STAT1-dependent signal transduction in a dose-dependent manner. | In vitro, T84 cells (colon epithelial cells), the human colon adenocarcinoma 1264 cell line DLD-1 (DSMZ ACC278), the human leukemia T-cell line Jurkat (DSMZ ACC282), and the human monocyticleukemia cell lineMonoMac6 (DSMZ ACC124) |
[135] | ||
| Hepatoprotective | phloretin | 50 mg/kg | Reduces mortality rate in mice, resulting in protection against lethal effect of acetaminophen. Downregulates SGOT serum transaminases. | In vivo, mice with hepatotoxicity induced by acetaminophen | [136] |
| 2′,4′-dihydroxydihydrochalcone-4-O-β-D-glucopyranoside | MTT assay 10 µM |
Cell survival rate (% of normal) 74.63 ± 11.11 |
In vitro, D-galactosamine-induced toxicity inhuman hepatoma HepG2 cells | [137] | |
| Antileishmanial activity | IC50 = 2.98 µg/mL IC50 = 3.65 µg/mL |
In vitro, promastigotes of Leishmania braziliensis | [138] | ||
| Anti-HIV, anti-herpes simplex virus type 2 | trilobatin | Exhibits broad anti-HIV activity and displays synergistic anti-HIV activities combined with antiretroviral agents (e.g., maraviroc, zidovudine, and raltegravir). Effective in inhibiting HSV-2 (at the concetration of 458 µM) |
In vitro, MT-2 and Vero cells | [139] | |
| Cardioprotective | aspalathin | 1 µM 13 and 130 mg/kg |
Protects cardiomyocytes against hyperglycemia-induced shifts in substrate preference and subsequent apoptosis; prevents myocardium apoptosis; modulates key regulators associated with lipid metabolism (Adipoq, Apob, CD36, Cpt1, Pparγ, Srebf1/2, Scd1, and Vldlr), insulin resistance (Igf1, Akt1, Pde3, and Map2k1), inflammation (Il3, Il6, Jak2, Lepr, Socs3, and Tnf13), and apoptosis (Bcl2 and Chuk) | In vitro, H9c2 cardiomiocytes In vivo, C57BLKS/J homozygous Leprdb/db mice |
[140] |
| Anticholinesterase and antibutyrylcholinesterases activity | phloretin phlorizin |
0.2 mM | Exhibit anti-AChE and anti-BChEs activity. Aglycons were more effective than corresponding glucosides. |
In vitro, acetylcholinesterase (AChE, C3389), butyrylcholinesterase (BChE, C7512) | [141] |