Quantitative Structure–Cytotoxicity Relationship of 2-Styrylchromones

Abstract

Background/Aim: Studies of biological activity of 2styrylchromone derivatives focusing on antioxidant, antiinflammatory, antiviral and antitumor activity are limited. In this study, eighteen synthetic 2-styrylchromone derivatives were investigated for their cytotoxicity against human malignant and non-malignant cells, and then subjected to quantitative structure-activity relationship (QSAR) analysis. Materials and Methods: Tumor-specificity was calculated by the ratio of mean 50% cytotoxic concentration (CC 50) against four normal oral cells to that against oral squamous cell carcinoma cell lines. Induction of apoptosis and growth arrest were evaluated by cellcycle analysis. For QSAR analysis, 3,117 types of physicochemical, structural, and quantum chemical features were calculated from the most stabilized structure of 2styrylchromone derivatives. Results: Two 2-styrylchromone derivatives in which a methoxy group was introduced at the 4position of the benzene ring showed tumor-specificity equivalent to or higher than doxorubicin in TS value. These compounds accumulated the subG 1 and G 2 /M phase cells, suggesting the induction of apoptosis. Their tumor-specificity can be explained mainly by molecular shape and electronic state. Conclusion: These findings suggest the applicability of 2-styrylchromone to develop safe and effective anticancer agents as seed compounds. Our group recently found that low-molecular weight natural polyphenols, such as tannins and flavonoids showed very low anticancer activity (evaluated by tumor-specificity with human cultured malignant and none-malignant cells) (1). On the other hand, chemical modification of chromone, two ring backbone structure present in flavonoids, yielded derivatives with much higher tumor-specificity (2, 3). 2-Styrylchromone is a derivative having a styryl group bonded to the 2-position of the chromone skeleton. Synthetic 2styrylchromone derivatives have been reported to show radical scavenging (4, 5), anti-inflammatory (6), hepatoprotective (7), neuroprotective (8-10), anti-human immunodeficiency virus (11), anti-norovirus (12), anti-rhinovirus (13, 14), antitumor (15-18), and monoamine oxidase B inhibiting (19) activity. However, very few studies tested their cytotoxicity against normal cells (16). In the present study, we investigated the cytotoxicity of eighteen synthetic 2-styrylchromone derivatives (Figure 1) against four human oral squamous cell carcinoma (OSCC) cells lines (Ca9-22, HSC-2, HSC-3, HSC-4) and three human normal oral mesenchymal cells [human gingival fibroblast (HGF), human periodontal ligamental fibroblast (HPLF) and human pulp cell (HPC)], and performed quantitative structure-activity relationship (QSAR) analysis. Materials and Methods Materials.

Further Quantitative Structure–Cytotoxicity Relationship Analysis of 3-Styrylchromones

“…We found that TS value (D/B in Table I) of two 3styrylchromones [7,14] (TS=301.1, 182.0) is much higher than the maximum TS values of 3-(N-cyclicamino)chromones (TS=12.3) (17), pyrano [4,3-b]chromones (TS=47.8) (18), 2arylazolylchromones and 2-triazolylchromones (TS=21.2) (19) and 2-styrylchromones (TS=89.1) (20). This suggests that [7,14] can be lead compounds for designing new types of anticancer drugs.…”

[Retracted] Styrylchromones: Biological Activities and Structure‐Activity Relationship

“…Uesawa and co-workers [ 66 ] investigated the cytotoxic activity of 2-SC 1 , 30 , 56 , 58 , 88 , 92 , and 104 – 115 ( Figure 39 ) against four human oral squamous cell carcinoma (Ca9-22, derived from gingival tissue; HSC-2, HSC-3, and HSC-4, derived from tongue) and three human oral mesenchymal cells (HGF, HPLF, and HPC). Cytotoxic activity was assessed by the MTT assay, and the results were presented as CC 50 , for each cell line (without the associated error) and the mean values of the four tumor cell lines and the three normal cells (with the associated error), SI, and potency-selectivity expression (PSE).…”

“…The subG 1 population is a marker of apoptosis. Thus, these two 2-SC induced apoptosis of HSC-2 cell more potently than the positive control, actinomycin D (1 μ M) [ 66 ]. The results obtained for 2-SC 58 were in line with those obtained in the previous study [ 65 ], where this 2-SC demonstrated an antiproliferative and microtubule-stabilizing effect [ 65 ].…”

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

“…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.…”

“…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 ].…”