Prenylated Flavonoids with PTP1B Inhibitory Activity from the Root Bark of Erythrina mildbraedii

Jang, Jun‐Pil; Na, MinKyun; Thương, Phương Thiện; Njamen, Dieudonné; Mbafor, Joseph Tanyi; Fomum, Zacharias Tanee; Woo, Eun‐Rhan; Oh, Won Keun

doi:10.1248/cpb.56.85

Cited by 44 publications

(25 citation statements)

References 23 publications

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“…Our data are also in agreement with other studies in which several natural products were shown to inhibit PTP1B, including phenylated flavonoids from the root bark of Erythrina mildbraedii [29], isoprenylated flavonoids from Ficustikoua [30], and tea catechins [31]. Therefore, significant results of inhibitory capacity in MOE can be attributed to the presence of diverse compounds.…”

Section: Citationsupporting

confidence: 92%

Modes of Inhibition of Human Protein-Tyrosine Phosphatase 1B and Aldose Reductase by Moringa oleifera Lam Leaves Extract

Sierra-Campos¹

2017

MOJBOC

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Insulin resistance is the main feature of Type 2 diabetes, due to attenuated or diminished signaling from insulin receptors, resulting in hyperglicemia. Inhibition of protein tyrosine phosphatase 1B (PTP1B) has been suggested as an attractive target to improve insulin sensitivity in different cell types. In addition, hyperglycemia activates the intracellular polyol pathway causing accumulation of sorbitol. This results in cellular water and electrolyte imbalance and oxidative injury. Aldose reductase inhibitors block the rate-limiting enzyme of the polyol pathway, decreasing the accumulation of sorbitol. Moringa oleifera is a plant widely used in traditional Indian and African medicine, e.g. for its antidiabetic effect. However, studies about the inhibitory effect of M. oleifera on diabetic complications mediated via diverse enzymes as PTP1B and aldose reductase have not been carried out yet. To potentially identify targets responsible for this antidiabetic effect, we conducted kinetic studies to investigate the inhibitory capacity of M. oleifera extract (MOE) over PTP1B. MOE possess the highest inhibitory activity against PTP1B (IC 50 value of 346.8 µg/mL). We also found that the extract inhibited the recombinant human aldose reductase (rhAR) activity with an IC 50 of 3.55 µg/mL. Subsequent kinetic analysis revealed that MOE behaved as an uncompetitive inhibitor (K i of 19.65 µg/mL) against PTP1B, since it markedly modified K m and also modified V max to a lesser extent. As for the rhAR, the extract behaved as mixed inhibitor (Ki = 18.6 µg/mL, alpha = 1.3). Our results help to understand the inhibition mechanism of PTP1B and rhAR by phenolic compounds and flavonoids present in MOE, which is essential for the development of improved natural inhibitors.

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Section: Citationsupporting

confidence: 92%

Modes of Inhibition of Human Protein-Tyrosine Phosphatase 1B and Aldose Reductase by Moringa oleifera Lam Leaves Extract

Sierra-Campos¹

2017

MOJBOC

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“…Triterpene carboxylic acid and prenylated flavonoids are the two main groups of plant-derived PTP1B inhibitors. 25,26) Ursolic acid (2) and oleanolic acid (4), which are classified into pentacyclic triterpene carboxylic acid, have been previously reported to have significant PTP1B inhibitory activity. 27,28) Ursolic acid inhibits PTP1B in a competitive manner.…”

Section: Resultsmentioning

confidence: 99%

Chemical Constituents from Sambucus adnata and Their Protein-Tyrosine Phosphatase 1B Inhibitory Activities

Sasaki

Morimura

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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Type-2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by b-cell dysfunction and insulin resistance, and its prevalence has reached epidemic proportions worldwide.1-3) Protein-tyrosine phosphatase 1B (PTP1B) is a major non-transmembrane phosphotyrosine phosphatase expressing ubiquitously in the classical insulin-targeted tissues 4,5) and functions as a negative regulator of the insulinsignaling pathway.6,7) Inhibition of PTP1B has been demonstrated to be an effective therapeutic approach to treatment of T2DM and much attention has been paid to PTP1B inhibitors for antidiabetic drug design. 8,9) Sambucus adnata (Caprifoliaceae) is a perennial herbaceous plant distributed in Southwest of China, and has long been used in Traditional Chinese Medicine (TCM) to treat bastard measles and acute nephritis.10) The chemical constituents of S. adnata and their bioactive activities are still not well understood, but has been reported to contain triterpenes, lignans, flavonols and sterols, and the isolated flavonols shows angiotensin-converting enzyme inhibitory activity. 11,12)During our PTP1B inhibitor screening program from TCM, 13) the MeOH extract of S. adnata showed significant inhibitory activity against PTP1B with an IC 50 value of 0.96Ϯ0.09 mg/ml. Further bioassay-guided fractionation of this extract resulted in the isolation of a novel acylated triterpene (1), together with other twelve known compounds (2-13). Herein, we report the isolation, structural determination, and evaluation of the PTP1B inhibitory activities of these compounds. The MeOH extract from the whole plants of Sambucus adnata has shown significant protein-tyrosine phosphatase 1B (PTP1B) inhibitory activity. Chemical study on the extract resulted in the isolation of thirteen compounds, including a novel triterpene (1). The structure of 1 was determined to be 1a a,3b b-dihydroxy-urs-12-en-11-one-3-yl palmitate on the basis of extensive spectroscopic analyses. Among the isolated compounds, ursolic acid, oleanolic acid and (؎)-boehmenan showed the most potent PTP1B inhibitory activity in vitro with the IC 50 values of 4.1, 14.4 and 43.5 m mm, respectively. The kinetic analysis indicated that (؎)-boehmenan inhibits PTP1B activity in a competitive manner.

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“…The addition of the prenyl or lavandulyl group on flavonoids and isoflavonoids showed inhibitory or enhancing effects on a number of enzymes (Cho et al, 2011;Habtemariam, 2012;Jang et al, 2008;Kenéz et al, 2007;Kim et al, 2003;Oh et al, 2005;Stec & Li, 2012). This may be caused by the prenyl group, which could increase the lipophilic chain length, consequently enhancing the function of the flavonoids skeleton (Shin et al, 2002).…”

Section: Enzyme Inhibitor and Enhancermentioning

confidence: 99%

A systematic review on biological activities of prenylated flavonoids

Chen

Mukwaya

Wong

et al. 2013

Pharmaceutical Biology

185

136

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Context: Prenylated flavonoids are a unique class of naturally occurring flavonoids that exist especially for the plant's self-defensive strategy. This special class of flavonoids increases the bioactivities of their backbone flavonoids with non-prenylation; therefore, prenylated flavonoids have more potential to be developed and utilized. Objective: The number, position and type of the prenyl group on the flavonoids backbone structure may have close relationships with the bioactivities of flavonoids. Methods: PubMed and WEB OF KNOWLEDGEÕ were used to search articles published in English between 1 January 2002 and 31 December 2012, which discuss the structure-activity relationship between prenylated flavonoids and their bioactivities. Results: It is proposed that the prenyl-moiety makes the backbone compound more lipophilic, which leads to its high affinity with cell membranes. The prenylation brings the flavonoids with enhancement of antibacterial, anti-inflammatory, antioxidant, cytotoxicity, larvicidal as well as estrogenic activities. However, it is reported that the prenyl-moiety decreases the bioavailability and plasma absorption of prenylated flavonoids. Conclusion: The prenyl group affects the bioactivities of flavonoids in certain ways, while the action mechanisms and the structure-activity relationship as well as more in vivo studies even clinical validation trials need to be further investigated.

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Prenylated Flavonoids with PTP1B Inhibitory Activity from the Root Bark of Erythrina mildbraedii

Cited by 44 publications

References 23 publications

Modes of Inhibition of Human Protein-Tyrosine Phosphatase 1B and Aldose Reductase by Moringa oleifera Lam Leaves Extract

Modes of Inhibition of Human Protein-Tyrosine Phosphatase 1B and Aldose Reductase by Moringa oleifera Lam Leaves Extract

Chemical Constituents from Sambucus adnata and Their Protein-Tyrosine Phosphatase 1B Inhibitory Activities

A systematic review on biological activities of prenylated flavonoids

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