Structure−Activity Relationship Studies of Nordihydroguaiaretic Acid Inhibitors toward Soybean, 12-Human, and 15-Human Lipoxygenase

Whitman, Stephanie; Gezginci, Mikail H.; Timmermann, Barbara N.; Holman, Theodore R.

doi:10.1021/jm0201262

Cited by 101 publications

(102 citation statements)

References 20 publications

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“…Pseudoperoxidase studies of 15-hLO-1 were performed as previously described to determine if a particular inhibitor could function as a reductant to the active site iron. 47 Baicalein's mode of inhibition against 15-hLO-1 proved to follow a redox mechanism as seen previously with NDGA and other catechol like compounds, 19 while apigenin followed reversible binding inhibition. It should be noted that the pseudoperoxidase activity was reliable and consistent with 15-hLO-1, but for 12-hLO, only the inhibitor BWB70C could support the assay.…”

Section: Expressionsupporting

confidence: 60%

“…Numerous other catechol inhibitors are reductive inhibitors 19 but it had never been directly demonstrated whether baicalein was a reductive inhibitor against human LO or not. Utilizing the established psuedoperoxidase assay 47 , we show that baicalein is a reductive inhibitor against 15-hLO-1.…”

Section: Insert Figure 4 Discussionmentioning

confidence: 99%

“…For this reason and its well documented role in cancer progression, our laboratory has become increasingly interested in discovering selective platelet 12-hLO inhibitors. [14][15][16][17][18][19][20] Plant extracts are a rich source of LO inhibitors 16,[21][22][23] and one particular class, the flavonoids, is relatively nontoxic, phenolic, and potent against LO. 16,[24][25][26][27] In addition, flavonoids have been shown to have antioxidant 24, 28 , anti-inflammatory 26,29 , antitumor 30 , antimicrobial 31 and antiviral properties 32 .…”

Section: Introductionmentioning

confidence: 99%

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Baicalein is a potent in vitro inhibitor against both reticulocyte 15-human and platelet 12-human lipoxygenases

Deschamps

Kenyon

Holman

2006

Bioorganic & Medicinal Chemistry

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Abstract. Lipoxygenases (LO) have been implicated in asthma, immune disorders, and various cancers and as a consequence, there is great interest in isolating selective LO isozyme inhibitors.Currently, there is much use of baicalein as a selective human platelet 12-LO (12-hLO) inhibitor however, our current steady-state inhibition data indicates that baicalein is not selective against 12-hLO versus human reticulocyte 15-LO-1 (15-hLO-1) (15/12 = 1.3), in vitro. However, in the presence of detergents baicalein is slightly more selective (15/12 = 7), which may imply greater selectivity in a cell based assay but has yet to be proven. The mechanism of baicalein inhibition of 15-hLO is reductive, which computer docking suggests is through direct binding of the catecholic moiety of baicalein to the iron. A structurally related flavonoid, apigenin, is not reductive, however, computer docking suggests a hydrogen bond with Thr591, may account for its inhibitor potency.

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Section: Expressionsupporting

confidence: 60%

Section: Insert Figure 4 Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Baicalein is a potent in vitro inhibitor against both reticulocyte 15-human and platelet 12-human lipoxygenases

Deschamps

Kenyon

Holman

2006

Bioorganic & Medicinal Chemistry

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144

125

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“…[6][7][8] The lignane nordihydroguaiaretic acid (NDGA), isolated from L. divatricata in 1945 by Waller and Gisvold,9) is considered to be a powerful inhibitor of lipoxygenase enzymes, which play an important role in cardiac diseases, asthma, arteriosclerosis, viral infections and cancer. [10][11][12][13][14][15][16] Plant cell culture represents a useful production alternative to direct extraction of valuable secondary metabolites from wild plants. The major advantages of tissue culture techniques over traditional cultivation of wild plants are: (a) useful compounds can be produced under controlled conditions, (b) plants are free of microbes and insects, (c) plants can easily be multiplied to yield specific metabolites, (d) a stable and uniform year-round supply of selected medicinal plants is guaranteed, independent of seasonal variations.…”

mentioning

confidence: 99%

In Vitro Propagation of "Jarilla" (Larrea divaricata CAV.) and Secondary Metabolite Production

Palacio

Baeza

Cantero

et al. 2008

Biological & Pharmaceutical Bulletin

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Medicinal value has been attributed to Larrea divaricata CAV. (Zygophylaceae family) by the Indian tribes from South America. 1,2) In Argentina, Hieronymus 3) mentioned the medicinal properties of L. divaricata for a variety of diseases such as venereal disease, tuberculosis, colds, bowel cramps, rheumatism, and also as an antiseptic, expectorant, emetic and diuretic. 2-4) L. divaricata presents abundant flavonoids, 5) mainly quercetine and kaempferol, which are considered to be anticancerigenic agents. [6][7][8] The lignane nordihydroguaiaretic acid (NDGA), isolated from L. divatricata in 1945 by Waller and Gisvold,9) is considered to be a powerful inhibitor of lipoxygenase enzymes, which play an important role in cardiac diseases, asthma, arteriosclerosis, viral infections and cancer. [10][11][12][13][14][15][16] Plant cell culture represents a useful production alternative to direct extraction of valuable secondary metabolites from wild plants. The major advantages of tissue culture techniques over traditional cultivation of wild plants are: (a) useful compounds can be produced under controlled conditions, (b) plants are free of microbes and insects, (c) plants can easily be multiplied to yield specific metabolites, (d) a stable and uniform year-round supply of selected medicinal plants is guaranteed, independent of seasonal variations. [17][18][19][20][21] The aim of this work was to evaluate the conditions for in vitro regeneration of L. divaricata plants as an alternative technique for active compound production. MATERIALS AND METHODSPlant Material L. divaricata seed collection was carried out at Santa María de Punilla, "Sierras de Córdoba," located at 45 km north of Córdoba city, Argentina. This region has a temperate Mediterranean climate, with warm summers and dry winters (not excessively hard). The annual mean temperature is 16°C (the mean maximum and minimum temperatures being 34°C in January and 6°C in July, respectively), with an average annual rainfall of 550 mm. The location's average altitude is 700 m above sea level. 22) A voucher specimen was deposited in the International Herbarium of the National University of Río Cuarto, Argentina (RIOC).Germination Germination rates were assessed in different conditions: 1) control, 2) washing seeds overnight in running tap water, 3) scarification, 4) washing overnight in running tap waterϩscarification, 5) soaking overnight with 0.3 mM gibberellic acid (GA 3 ), 6) soaking overnight with 3 mM GA 3 , 7) soaking overnight with 15 mM GA 3 , 8) soaking overnight with 0.3 mM GA 3 ϩscarification, 9) soaking overnight with 3 mM GA 3 ϩscarification, 10) soaking overnight with 15 mM GA 3 ϩscarification.Seed surfaces were disinfected with ethanol 70% (v/v) for 10 min, followed by sodium hypochlorite 1.5% (v/v) for 15 min, and finally washed three times with sterile distilled water. Sterilized seeds were transferred to culture tubes containing 15 ml of agarized (0.8% w/v) half-strength MS 23) major and minor salt medium with 3% (w/v) sucrose, without plant growth regu...

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“…The third assay screened the analogs for the inhibition of 15-LOX, a non-target enzyme and one for which NDGA is a known inhibitor. 31 The results from the three assays for NDGA and its synthetic analogs are summarized in Table 1.…”

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confidence: 99%

Inhibition of IGF-1R and lipoxygenase by nordihydroguaiaretic acid (NDGA) analogs

Blecha

Anderson

Chow

et al. 2007

Bioorganic & Medicinal Chemistry Letters

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Herein we pursue the hypothesis that the structure of nordihydroguaiaretic acid (NDGA) can be refined for selective potency against the insulin-like growth factor 1 receptor (IGF-1R) as a potential therapeutic target for breast cancer while diminishing its action against other cellular targets. Thus, a set of NDGA analogs (7a-7h) was prepared and examined for inhibitory potency against IGF-1R kinase and an alternative target, 15-lipoxygenase (15 LOX). The anti-cancer effects of these compounds were determined by their ability to inhibit IGF-1 mediated cell growth of MCF-7 breast cancer cells. The design of the analogs was based upon a cursory Topliss approach in which one of NDGA's aromatic rings was modified with various substituents. Structural modification of one of the two catechol rings of NDGA was found to have little effect upon the inhibitory potency against both kinase activity of the IGF-1R and IGF-1 mediated cell growth of MCF-7 cells. 15-LOX was found to be most sensitive to structural modifications of NDGA. From the limited series of NDGA analogs examined, the compound that exhibited the greatest selectivity for IGF-1 mediated growth compared to 15-LOX inhibition was a cyclic analog 7h with a framework similar to a natural product isolated from Larrea divaricata. The results for 7h are significant because while NDGA displays biological promiscuity, 7h exhibits greater specificity towards the breast cancer target IGF-1R with that added benefit of possessing a 10-fold weaker potency against 15-LOX, an enzyme which has a purported tumor suppressing role in breast cancer. With increased specificity and potency, 7h may serve as a new lead in developing novel therapeutic agents for breast cancer.Nordihydroguaiaretic acid (NDGA, Figure 1) is isolated from the resinous extract of the creosote bush Larrea divaricata. 1 It has also been reported that NDGA inhibits the growth of tumors, both in vitro and in vivo 2 but relatively high concentrations are required to achieve efficacy in most cases. Preliminary in vivo studies have revealed that NDGA inhibits tumor growth by inhibiting receptor tyrosine kinase (RTK) phosphorylation. 3 NDGA has been shown to inhibit several RTKs overexpressed in certain cancer cells. In a previous study, we noted that NDGA inhibits both the IGF-1R and HER2/neu with moderate potency and impairs subsequent signaling through the anti-apoptotic pathway in breast cancer cell. 3, 4 These and other RTKs such as the epidermal growth factor receptor (EGFR) are overexpressed in breast and other cancers and contribute to a poor prognosis 5-7 .Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal ...

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Structure−Activity Relationship Studies of Nordihydroguaiaretic Acid Inhibitors toward Soybean, 12-Human, and 15-Human Lipoxygenase

Cited by 101 publications

References 20 publications

Baicalein is a potent in vitro inhibitor against both reticulocyte 15-human and platelet 12-human lipoxygenases

Baicalein is a potent in vitro inhibitor against both reticulocyte 15-human and platelet 12-human lipoxygenases

In Vitro Propagation of "Jarilla" (Larrea divaricata CAV.) and Secondary Metabolite Production

Inhibition of IGF-1R and lipoxygenase by nordihydroguaiaretic acid (NDGA) analogs

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