Synthesis, biological evaluation and structure–activity relationship studies of isoflavene based Mannich bases with potent anti-cancer activity

Chen, Yilin; Cass, Shelley L.; Kutty, Samuel K.; Yee, Eugene; Chan, Daniel Shiu‐Hin; Gardner, Christopher R.; Vittorio, Orazio; Pasquier, Eddy; Black, David StC.; Kumar, Naresh

doi:10.1016/j.bmcl.2015.09.027

Cited by 30 publications

(12 citation statements)

References 18 publications

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“…Daidzein, the most widely studied soy phytoestrogen, shows promise as a potential antiosteoporosis agent. Many reports have shown that daidzein has an effect not only on osteogenic activity, but also has anticancer activity (Adjaklyet al, 2013;Strong et al, 2014;Chen et al, 2015). Daidzein-enhanced osteoblast growth might be mediated through the upregulation of BMP expression in primary osteoblast cells (Jia et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Daidzein promotes osteoblast proliferation and differentiation in OCT1 cells through stimulating the activation of BMP-2/Smads pathway

Tang

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Daidzein, the most widely studied soy phytoestrogen, is not only a potential antiosteoporosis agent owing to its possible osteogenic activity, but also shows anticancer activity. However, the mechanisms through which daidzein affects osteoblast function have not been investigated thoroughly. Here, we show that daidzein stimulated cell proliferation and differentiation of osteoblasts, demonstrated by upregulation of XTT activity, enhancement of alkaline phosphatase (ALP) activity, and upregulation of osteoblast-specific marker genes, including Runt-related transcription factor 2 (Runx2) and Smad1, as well as upregulation of Runx2 and Smad1 protein expression. To determine the mechanisms underlying daidzein's effects on osteoblast differentiation, we first tested the role of daidzein in bone morphogenetic protein (BMP)-2 gene expression in OCT1 cells, and found that it significantly upregulated the expression of BMP-2. Furthermore, it significantly enhanced the phosphorylated protein level of Smad1/5/8 and the protein level of Osterix and increased the activity of 12xSBE-OC-Luc. Finally, we demonstrated that daidzein stimulated Col I, Runx2, and ALP expression, while these effects were significantly blocked by the BMP signaling inhibitor noggin. Together, our data indicate that daidzein acts through stimulating the activation of BMP-2/Smads pathway to promote osteoblast proliferation and differentiation.

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Section: Introductionmentioning

confidence: 99%

Daidzein promotes osteoblast proliferation and differentiation in OCT1 cells through stimulating the activation of BMP-2/Smads pathway

Tang

et al. 2016

Genet. Mol. Res.

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“…Oxazine compounds contain oxygen and nitrogen double heteroatoms, which can introduce various active pharmacophores on the N atom and have a wide range of biological activities [ 23 ]. Oxazinyl isoflavonoid compounds were also synthesized by Wang et al [ 24 ] and Chen’s group [ 25 ], who exhibited potent anti-cancer activities.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Activity of Novel Oxazinyl Flavonoids as Antiviral and Anti-Phytopathogenic Fungus Agents

Wang

et al. 2022

Molecules

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A series of oxazinyl flavonoids were synthesized on the basis of flavone. The structures of all target compounds were characterized by 1H NMR, 13C NMR, and HRMS. The effect of the different substituent on the N-position of oxazinyl flavonoids against tobacco mosaic virus (TMV) activities and plant pathogen activities was systematically investigated. In vivo anti-TMV activity showed that most of the compounds showed moderate-to-excellent antiviral activities against TMV at 500 μg/mL. Compounds 6b, 6d, 6j–6k, and 6n–6q showed better antiviral activities than ribavirin (a commercially available antiviral agent) and apigenin. In particular, compounds 6n and 6p even displayed slightly higher activities than ningnanmycin, which were expected to become new antiviral candidates. Antiviral mechanism research by molecular docking exhibited that compounds 6n and 6p could interact with TMV CP and inhibit virus assembly. Then, the antifungal activities of these compounds against six kinds of plant pathogenic fungi were tested, and the results showed that these oxazinyl flavonoids had broad-spectrum fungicidal activities. Compounds 6h exhibited antifungal activity of up to 91% against Physalospora piricola and might become a candidate drug for new fungicides.

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“…To further enhance the anti-tumor property of phenoxodiol 1 , strategies consisting of molecular hybridization or the employment of a drug delivery vehicle have been carried out. The hybridization of phenoxodiol 1 with various moieties, such as a thiosemicarbazone (Yee et al, 2017a), a 1-amino-2-propanol side chain (Yee et al, 2013), and a Mannich base (Chen et al, 2015), and the encapsulation of phenoxodiol 1 into β-cyclodextrin (Yee et al, 2017c) have been reported to show superior anti-tumor activity than the free phenoxodiol 1 . In particular, the β-cyclodextrin–phenoxodiol complex showed a 5-fold improvement in specificity against the cancer cell types tested as compared to phenoxodiol 1 alone (Yee et al, 2017c).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Dextran–Phenoxodiol and Evaluation of Its Physical Stability and Biological Activity

Yee

Cirillo

Brandl

et al. 2019

Front. Bioeng. Biotechnol.

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Phenoxodiol, an isoflavene anti-tumor agent, was conjugated on the polysaccharide dextran using immobilized laccase as biocatalyst. The success of the enzymatic conjugation was determined by UV-vis spectrophotometry and its functionalization degree was assessed by 1 H NMR and was found to be 3.25 mg phenoxodiol/g of conjugate. An accelerated stability test showed that the resultant conjugate was nine times more stable than the free phenoxodiol when tested for its residual anti-oxidant activity with the Folin–Ciocalteu assay. The in vitro anti-proliferative activity of the conjugate was evaluated against neuroblastoma SKN-BE(2)C, triple-negative breast cancer MDA-MB-231, and glioblastoma U87 cancer cells. The conjugate was shown to be generally more potent than phenoxodiol against all three cell types tested. Additionally, the cytotoxicity and anti-angiogenic activity of the conjugate were also evaluated against non-malignant human lung fibroblast MRC-5 and human microvascular endothelial cells HMEC-1, respectively. The conjugate was found to be 1.5 times less toxic than phenoxodiol while mostly retaining 62% of its anti-angiogenic activity in the conjugate form. This study provides further evidence that the conjugation of natural product-derived drugs onto polysaccharide molecules such as dextran can lead to better stability and enhanced biological activity of the conjugate compared to the free drug alone.

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Synthesis, biological evaluation and structure–activity relationship studies of isoflavene based Mannich bases with potent anti-cancer activity

Cited by 30 publications

References 18 publications

Daidzein promotes osteoblast proliferation and differentiation in OCT1 cells through stimulating the activation of BMP-2/Smads pathway

Daidzein promotes osteoblast proliferation and differentiation in OCT1 cells through stimulating the activation of BMP-2/Smads pathway

Synthesis and Biological Activity of Novel Oxazinyl Flavonoids as Antiviral and Anti-Phytopathogenic Fungus Agents

Synthesis of Dextran–Phenoxodiol and Evaluation of Its Physical Stability and Biological Activity

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