Quantitative Structure–Cytotoxicity Relationship of 2-Azolylchromones

Sakagami, Hiroshi; Okudaira, Noriyuki; Uesawa, Yoshihiro; Takao, Koichi; Kagaya, Hajime; Sugita, Yoshiaki

doi:10.21873/anticanres.12282

Cited by 6 publications

(17 citation statements)

References 7 publications

(9 reference statements)

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“…We investigated a total 291 compounds from 17 different groups ( A~Q ) of their cytotoxicity (assessed by CC 50 ) against four human OSCC (Ca9-22, HSC-2, HSC-3, and HSC-4) and three human normal mesenchymal cells (HGF, HPLF, and HPC), and then their tumor specificity (assessed by TS M , calculated as describe in Figure 2 , and potency-selectivity expression (PSE)) [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. PSE, that reflects both tumor specificity and cytotoxicity against tumor cells, was calculated by dividing the TS M by CC 50 for tumor cells, and then multiplying by 100.…”

Section: Development Of Newly Synthesized Chromone Derivatives Witmentioning

confidence: 99%

“…This demonstrated that only limited numbers of compounds show higher tumor specificity, although their structures are very similar with each other. It is possible that such highly tumor-specific compounds show the optimal 3D structure, since the tumor specificity of chromone compounds shows the tight correlation with chemical descriptors that reflect the 3-D structure ( Table 4 ) [ 33 , 35 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ].…”

Section: Development Of Newly Synthesized Chromone Derivatives Witmentioning

confidence: 99%

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Development of Newly Synthesized Chromone Derivatives with High Tumor Specificity against Human Oral Squamous Cell Carcinoma

et al. 2020

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Since many anticancer drugs show severe adverse effects such as mucositis, peripheral neurotoxicity, and extravasation, it was crucial to explore new compounds with much reduced adverse effects. Comprehensive investigation with human malignant and nonmalignant cells demonstrated that derivatives of chromone, back-bone structure of flavonoid, showed much higher tumor specificity as compared with three major polyphenols in the natural kingdom, such as lignin-carbohydrate complex, tannin, and flavonoid. A total 291 newly synthesized compounds of 17 groups (consisting of 12 chromones, 2 esters, and 3 amides) gave a wide range of the intensity of tumor specificity, possibly reflecting the fitness for the optimal 3D structure and electric state. Among them, 7-methoxy-3-[(1E)-2-phenylethenyl]-4H-1-benzopyran-4-one (compound 22), which belongs to 3-styrylchromones, showed the highest tumor specificity. 22 induced subG1 and G2 + M cell population in human oral squamous cell carcinoma cell line, with much less keratinocyte toxicity as compared with doxorubicin and 5-FU. However, 12 active compounds selected did not necessarily induce apoptosis and mitotic arrest. This compound can be used as a lead compound to manufacture more active compound.

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Section: Development Of Newly Synthesized Chromone Derivatives Witmentioning

confidence: 99%

Section: Development Of Newly Synthesized Chromone Derivatives Witmentioning

confidence: 99%

Development of Newly Synthesized Chromone Derivatives with High Tumor Specificity against Human Oral Squamous Cell Carcinoma

et al. 2020

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“…Chromone (4 H -1-benzopyran-4-one) is a backbone structure of flavonols, flavones, flavanones and isoflavones [29] (Figure 1B). We synthesized eight classes of chromones derivatives (total 134 compounds): 3-styrylchromones (15 compounds) [30,31] (containing compound A), 3-benzylidenechromanones (17 compounds) [32] (containing compound B), 3-styryl-2 H -chromenes (16 compounds) [33] (containing compound C), 2-azolylchromones (24 compounds) [34] (containing compound D), 3-( N -cyclicamino)chromones (15 compounds) [35] (containing compound E), 2-( N -cyclicamino)chromones (15 compounds) [36] (containing compound F), furo[2,3- b ]chromones (12 compounds) [37] (containing compound G) and pyrano[4,3- b ]chromones (20 compounds) [38] (containing compound H). The eight compounds that produced the highest TS value in each group are listed in Figure 4.…”

Section: Chromone Derivatives As New Type Of Anticancer Candidatementioning

confidence: 99%

“…2, Table 1). We reported that 3-styrylchromones [30] and azolylchromones [34] induced apoptosis (caspase-3 activation) in human OSCC cell line. On the contrary, 7-methoxy-2-(4-morpholinyl)-4 H -1-benzopyran-4-one, the most active compound among fifteen 2-( N -cyclicamino)chromone derivatives (structure depicted in Figure 4F) showed an excellent tumor-specificity (TS = 63.4) (Figure 5A), low keratinocyte toxicity (Table 1, Exp.…”

Section: Chromone Derivatives As New Type Of Anticancer Candidatementioning

confidence: 99%

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Recent Progress of Basic Studies of Natural Products and Their Dental Application

et al. 2018

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The present article reviews the research progress of three major polyphenols (tannins, flavonoids and lignin carbohydrate complexes), chromone (backbone structure of flavonoids) and herbal extracts. Chemical modified chromone derivatives showed highly specific toxicity against human oral squamous cell carcinoma cell lines, with much lower toxicity against human oral keratinocytes, as compared with various anticancer drugs. QSAR analysis suggests the possible correlation between their tumor-specificity and three-dimensional molecular shape. Condensed tannins in the tea extracts inactivated the glucosyltransferase enzymes, involved in the biofilm formation. Lignin-carbohydrate complexes (prepared by alkaline extraction and acid-precipitation) and crude alkaline extract of the leaves of Sasa species (SE, available as an over-the-counter drug) showed much higher anti-HIV activity, than tannins, flavonoids and Japanese traditional medicine (Kampo). Long-term treatment with SE and several Kampo medicines showed an anti-inflammatory and anti-oxidant effects in small size of clinical trials. Although the anti-periodontitis activity of synthetic angiotensin II blockers has been suggested in many papers, natural angiotensin II blockers has not yet been tested for their possible anti-periodontitis activity. There should be still many unknown substances that are useful for treating the oral diseases in the natural kingdom.

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A Comparative Study of Tumor-Specificity and Neurotoxicity Between 3-Styrylchromones and Anticancer Drugs

Abe¹,

Sakagami²,

Amano³

et al. 2023

Preprint

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Background. Many anticancer drugs used in clinical practice cause adverse events such as oral mucositis, neurotoxicity, and extravascular leakage. We have reported that two 3-styrylchromone derivatives, 7-methoxy-3-[(1E)-2-phenylethenyl]-4H-1-benzopyran-4-one (compound A) and 3-[(1E)-2-(4-hydroxyphenyl)ethenyl]-7-methoxy-4H-1-benzopyran-4-one (compound B) showed the highest tumor-specificity against human oral squamous cell carcinoma (OSCC) cell lines among 291 related compounds. After confirming their superiority by comparing their tumor specificity with newly synthesized 65 derivatives, we investigated the neurotoxicity of these compounds, in comparison with 4 popular anticancer drugs. Methods: Tumor-specificity (TSM, TSE, TSN) was evaluated as the ratio of mean CC50 for human normal oral mesenchymal (gingival fibroblast, pulp cell), oral epithelial cells (gingival epithelial progenitor), and neuronal cells (PC-12, SH-SY5Y, LY-PPB6, differentiated PC-12) to OSCC cells (Ca9-22, HSC-2), respectively. Results: Compounds A and B showed one-order of magnitude higher TSM as compared with newly synthesized derivatives, confirming its prominent tumor-specificity. Docetaxel showed one order of magnitude higher TSM, but two order of magnitude lower TSE than compounds A and B. Compounds A and B showed higher TSM, TSE and TSN values than doxorubicin, 5-FU and cisplatin, damaging OSCC cells at concentrations that do not affect the viability of normal epithelial and neuronal cells. QSAR prediction based on the Tox21 database suggested that compounds A and B may inhibit the signaling pathway of estrogen-related receptors.

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Quantitative Structure–Cytotoxicity Relationship of 2-Azolylchromones

Abstract: Chemical modification of the lead compound may be a potential choice for designing a new type of anticancer drug.

Cited by 6 publications

References 7 publications

Development of Newly Synthesized Chromone Derivatives with High Tumor Specificity against Human Oral Squamous Cell Carcinoma

Development of Newly Synthesized Chromone Derivatives with High Tumor Specificity against Human Oral Squamous Cell Carcinoma

Recent Progress of Basic Studies of Natural Products and Their Dental Application

A Comparative Study of Tumor-Specificity and Neurotoxicity Between 3-Styrylchromones and Anticancer Drugs

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