Further Quantitative Structure–Cytotoxicity Relationship Analysis of 3-Styrylchromones

Abstract

Background/Aim: Very few studies are available about the biological activity of 3-styrylchromones. Our previous study demonstrated the importance of methoxy group at 6-position of the chromone ring and hydroxyl group at 4'position of phenyl group in styryl moiety. As a sequel of this study, we synthesized fourteen compounds that include eight 3-styrylchromones where methoxy group was introduced at 7position of chromone rings, and then evaluated their tumorspecificity. Materials and Methods: Tumor-specificity (TS) was calculated by relative cytotoxicity against human oral squamous cell carcinoma cell lines versus human normal oral cells. Apoptosis induction and growth arrest were monitored by cell-cycle analysis. Quantitative structure-activity relationship analysis of TS was performed with 3,167 chemical descriptors. Results and Discussion: Two compounds, 7methoxy-3-[(1E)-2-phenylethenyl]-4H-1-benzopyran-4-one [7] and 3-[(1E)-2-(4-hydroxyphenyl)ethenyl]-7-methoxy-4H-1benzopyran-4-one [14] showed higher tumor-specificity than doxorubicin and 5-FU, suggesting the importance of methoxy group in 7-position of the chromone ring. These compounds induced the apoptosis and mitotic arrest in HSC-2 cells. The tumor-specificity of 3-styrylchromone derivatives were most correlated with descriptors for molecule shape and electronic charge. The present study suggested that modification by introducing methoxy group at 7-position, instead at 6-position, further increased the tumor-specificity of 3-styrylchromone. Chromone is a two-ring backbone structure contained in many flavonoids. 3-Chromone is a compound that has a styryl group attached at 3-position of chromone. We previously reported that (E)-3-(4-hydroxystyryl)-6-methoxy-4H-chromen-4-one (compound A) showed approximately 69-fold higher cytotoxicity against human oral squamous cell carcinoma (OSCC) cell lines as compared with human normal oral cells (1). On the other hand, natural polyphenols such as tannins and flavonoids showed only marginal tumor-specificity (2, 3). As far as we are aware, only five studies of biological activities of 3-styrylchromone derivatives have been reported so far. This includes antimicrobial activity (4), antipicornavirus activity (5), free radical scavenging and αglucosidase inhibitory activity (6), apoptosis induction (7) and tumor-specificity (1). Quantitative structure-activity relationship (QSAR) analysis demonstrated the importance of methoxy group at 6-position of the chromone ring and hydroxyl group at 4'position of phenyl group in styryl moiety (1). As a sequel of this study, we synthesized fourteen compounds that include eight 3-styrylchromones where methoxy group was introduced at 7-position of chromone ring, and then evaluated the tumor-specificity. We first investigated their cytotoxicity against four human oral squamous cell carcinoma (OSCC) cells lines (Ca9-22, derived from gingival tissue; HSC-2, HSC-3. HSC-4, derived from tongue) and three human normal oral mesenchymal cells [human gingival fibroblast (HGF), human periodontal l...

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 ].…”

“…We found that highly tumor-specific 3-styrylchromone derivatives [7-methoxy-3-[(1 E )-2-phenylethenyl]-4 H -1-benzopyran-4-one (compound 22 ) and 3-[(1 E )-2-(4-hydroxyphenyl)ethenyl]-7-methoxy-4 H -1-benzopyran-4-one (compound 29 )] (TS M = 301 and 182, respectively) ( Supplementary Table S1 ) induced subG1 and G2 + M arrest [ 35 ]. We also have recently reported that several G2/M blockers such as taxanes paclitaxel (Taxol ® , the first microtubule stabilizing agent [ 57 ]) and docetaxel, show very high TS M values (>7267 and >86,122, respectively) [ 58 ].…”

A Unique Anti-Cancer 3-Styrylchromone Suppresses Inflammatory Response via HMGB1-RAGE Signaling

“…Opti-MEM ® and Mouse IL-6 Uncoated ELISA Kit were purchased from Thermo Fisher Scientific (Waltham, MA, USA). 2) were synthesized by Knoevenagel condensation of the appropriate 3-formylchromone with selected phenylacetic acid derivatives, as described previously [42,44]. All the compounds were characterized by 1 H NMR, MS spectra and elemental analyses after purification by silica gel column chromatography and recrystallization.…”

“…As stated, the HMGB1-RAGE axis in TME is closely associated with carcinogenesis; thus, anti-cancer compounds targeting this axis that possess further anti-inflammatory activity may have far-reaching therapeutic potential. In this study, four 6-methoxy-3-styrylchromone (6M3SC) derivatives, which have already identified as anti-cancer agents [41][42][43][44], were selected by a papaverine 3D pharmacophore similarity search and examined in terms of their anti-inflammatory activities by a cell-based inflammatory assay method driven by the HMGB1-RAGE-mediated system using macrophage-like RAW264.7 cells. This research is the first to demonstrate a unique 6-methoxy-3-hydroxy-styrylchromone (compound 3, 6M3HSC) that has both potent anti-cancer and anti-inflammatory activities.…”