Research ArticleExperimental Studies

Quantitative Structure–Cytotoxicity Relationship of 2-Arylazolylchromones and 2-Triazolylchromones

JUNKO NAGAI, HAIXIA SHI, NATSUKO SEZAKI, NAO YOSHIDA, KENJIRO BANDOW, YOSHIHIRO UESAWA, HIROSHI SAKAGAMI, MINEKO TOMOMURA, AKITO TOMOMURA, KOICHI TAKAO and YOSHIAKI SUGITA
Anticancer Research December 2019, 39 (12) 6479-6488; DOI: https://doi.org/10.21873/anticanres.13862

Abstract

Background/Aim: 4H-1-Benzopyran-4-one (chromone), present in various flavonoids as a backbone structure, has been used for the synthesis of anticancer drugs. The study aimed at investigating the cytotoxicity of eight 2-arylazolylchromones and twelve 2-triazolylchromones against four human oral squamous cell carcinoma (OSCC) cell lines and three human normal mesenchymal oral cells, and then performed a quantitative structure–activity relationship (QSAR) analysis. Materials and Methods: Cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. The distribution of cells to various phases of cell cycle was determined by cell cycle analysis. A total of 3,218 physicochemical, structural and quantum chemical features were calculated for QSAR analysis from the most stabilized structure optimized using CORINA. Results: 2-[4-(4-fluorophenyl)-1H-imidazol-1-yl]-4H-1-benzopyran-4-one [6] had the highest tumor-specificity (TS), comparable with that of 5-flurouracil (5-FU) and doxorubicin, inducing cytostatic growth inhibition, accumulation of G2+M phase cells with no cells in the G1 phase. All eight 2-triazolylchromones showed much lower tumor-specificity, confirming our previous finding. Tumor-specificity was also correlated with 3D shape, topological shape, size, ionization potential, and the presence of more than two aromatic rings in the molecule and imidazole ring in the nitrogen-containing heterocyclic ring. Conclusion: [6] can be a lead compound for designing anticancer drugs.

To develop new anticancer drugs, we have first established an in vitro screening system with four oral squamous cell carcinoma (OSCC) cell lines (Ca9-22, HSC-2, HSC-3, HSC-4) and three human oral normal mesenchymal cells (gingival fibroblast HGF, periodontal ligament fibroblast HPLF, pulp cell HPC) (1). Our large-scale in vitro screening of the antitumor activity of natural polyphenols such as tannins, flavonoids and antioxidants has demonstrated, surprisingly, lower tumor-specificity of most of these low molecular weight substances as compared with anticancer drugs (1). However, 4H-1-benzopyran-4-one (chromone), present in various flavonoids as a backbone structure, has been used for the synthesis of new types of anticancer drugs (2). Novel cytotoxic agents based on chromen-4-one and chromane-2,4-dione scaffolds (3), chrysin derivatives (4) and O-alkyl derivatives of naringenin and their oximes (5) have been synthesized, however, their tumor-specificity has not been described. We have synthesized 16 groups of chemically modified derivatives (239 compounds) (6, 7). We have found that 3-styrylchromones (8), 3-styryl-2H-chromenes (9) and 2-azolylchromones, especially, three sets of 4H-1-benzopyran-4-ones with indole ring (10) had comparable tumor-specificity and lower cytotoxicity against human oral keratinocytes (human oral mucosal keratinocyte HOK, primary human gingival epithelial cells HGEP), as compared with common anticancer drugs (11).

As far as we know, only two studies from our groups have reported the biological activity of azolylchromone (10, 12). In order to perform quantitative structure–activity relationship (QSAR) analysis, we investigated the tumor-specificity of eight newly synthesized 2-arylazolylchromones and twelve 2-triazolylchromones (Figure 1) using four malignant and three non-malignant human cells.

Figure 1.
Figure 1.

The structure of the eight 2-arylazolylchromones [1-8] and the twelve 2-triazolylchromones [9-20] investigated in this study.

Materials and Methods

Materials. Dulbecco's modified Eagle's medium (DMEM) was purchased from GIBCO BRL (Grand Island, NY, USA); fetal bovine serum (FBS), doxorubicin, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), ribonuclease (RNase) A from Sigma-Aldrich Inc. (St. Louis, MO, USA); propidium iodide (PI), dimethyl sulfoxide (DMSO), actinomycin D, 4% paraformaldehyde phosphate buffer solution from Wako Pure Chem. Ind. (Osaka, Japan); 5-fluorouracil (5-FU) from Kyowa (Tokyo, Japan); Nonidet-40 (NP-40) from Nakalai Tesque Inc. (Kyoto, Japan); and culture plastic dishes and 96-well plates from Techno Plastic Products AG (Trasadingen, Switzerland).

Synthesis of 2-arylazolylchromones and 2-triazolylchromones. 2-(3-Phenyl-1H-pyrazol-1-yl)-4H-1-benzopyran-4-one [1], 2-[3-(2-pyridinyl)-1H-pyrazol-1-yl]-4H-1-benzopyran-4-one [2], 6-methoxy-2-[3-(2-pyridinyl)-1H-pyrazol-1-yl]-4H-1-benzopyran-4-one [3], 7-methoxy-2-[3-(2-pyridinyl)-1H-pyrazol-1-yl]-4H-1-benzopyran-4-one [4], 2-(4-phenyl-1H-imidazol-1-yl)-4H-1-benzopyran-4-one [5], 2-[4-(4-fluorophenyl)-1H-imidazol-1-yl]-4H-1-benzopyran-4-one [6], 2-[4-(4-chlorophenyl)-1H-imidazol-1-yl]-4H-1-benzopyran-4-one [7], 2-(4,5-diphenyl-1H-imidazol-1-yl)-4H-1-benzopyran-4-one [8], 2-(1H-1,2,4-triazol-1-yl)-4H-1-benzopyran-4-one [9], 6-methoxy-2-(1H-1,2,4-triazol-1-yl)-4H-1-benzopyran-4-one [10], 7-methoxy-2-(1H-1,2,4-triazol-1-yl)-4H-1-benzopyran-4-one [11], 6-chloro-2-(1H-1,2,4-triazol-1-yl)-4H-1-benzopyran-4-one [12], 2-(3-methyl-1H-1,2,4-triazol-1-yl)-4H-1-benzopyran-4-one [13], 6-methoxy-2-(3-methyl-1H-1,2,4-triazol-1-yl)-4H-1-benzopyran-4-one [14], 7-methoxy-2-(3-methyl-1H-1,2,4-triazol-1-yl)-4H-1-benzopyran-4-one [15], 6-chloro-2-(3-methyl-1H-1,2,4-triazol-1-yl)-4H-1-benzopyran-4-one [16], 2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-4H-1-benzopyran-4-one [17], 2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methoxy-4H-1-benzopyran-4-one [18], 2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-7-methoxy-4H-1-benzopyran-4-one [19] and 6-chloro-2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-4H-1-benzopyran-4-one [20] (Figure 1) were synthesized by the conjugated addition reactions of 3-iodochromone derivatives with selected azoles, as described previously (12). All compounds were dissolved in DMSO at 40 mM and stored at −20°C before use.

View this table:
Table I.

Cytotoxic activity of the eight 2-arylazolylchromones and the twelve 2-triazolylchromones against oral malignant and non-malignant cells. Each value represents the mean of triplicate determinations. The tumor-specificity index (TS) and potency-selectivity expression (PSE) values were determined using human oral squamous cell carcinoma (OSCC) cell lines compared with human normal oral mesenchymal cells, and paired cells derived from the same (gingival) tissue.

Cell culture. Human normal oral mesenchymal cells (HGF, HPLF, HPC) (13) at 10-18 population doublings were used in this study. Human oral squamous cell carcinoma (OSCC) cell lines (Ca9-22, derived from gingival tissue; HSC-2, HSC-3 and HSC-4 derived from tongue) were purchased from Riken Cell Bank (Tsukuba, Japan). All cells were cultured at 37°C in DMEM supplemented with 10% heat-inactivated FBS, 100 units/ml, penicillin G and 100 μg/ml streptomycin sulfate under a humidified 5% CO2 atmosphere. Cell morphology was examined periodically under a light microscope (EVOS FL; Thermo Fisher Scientific, Waltham, MA, USA).

Assay for cytotoxic activity. Cells were plated at 2×103 cells/0.1 ml in a 96-microwell plate. After 48 h, the medium was replaced with 0.1 ml of fresh medium containing different concentrations of single test compounds. Cells were incubated for 48 h and the relative viable cell number was then determined in triplicate by the MTT method, as described previously (7-11). Control cells were treated with the same percentage of DMSO and the cell death induced by DMSO was subtracted. The concentration of compound that reduced the viable cell number by 50% (CC50) was determined from the dose–response curve.

Calculation of tumor-specificity index (TS). TS was calculated by dividing the mean CC50 against normal oral cell types by the mean CC50 against OSCC cell lines (D/B in Table I). Since both Ca9-22 and HGF cells were derived from gingival tissue (14), TS was also calculated by dividing the CC50 against HGF by the mean CC50 against Ca9-22 (C/A in Table I).

Figure 2.
Figure 2.

Cytotoxicity of compound [6] against the four human OSCC cell lines, Ca9-22 (●), HSC-2 (▪), HSC-3 (▲) and HSC-4) (◆), and the three human normal mesenchymal oral cells, HGF (○), HPLF (□) and HPC (▵). Cells were incubated for 48 h without (control) or with the indicated concentrations of [6], and cell viability was determined by MTT method, and expressed as a percentage of the control. Each value represents the mean±S.D. of triplicate assays.

Figure 3.
Figure 3.

Effect of [6] on cell-cycle distribution in HSC-2 cells. HSC-2 cells were incubated for 24 h with the indicated concentrations of [6] or 1 μM actinomycin D (Act D) as positive control and then assessed for cell-cycle distribution by cell sorter.

Calculation of potency-selectivity expression (PSE). PSE was calculated by dividing the mean CC50 against normal oral cells by the (mean CC50 against OSCC cell lines)2 and then multiplied by 100 (in the case of HGF, HPLF, HPC vs. Ca9-22, HSC-2, HSC-3, HSC-4) [(D/B2) ×100 in Table I]; and by dividing the CC50 against HGF by (CC50 against Ca9-22)2, and then multiplied by 100 (in the case of HGF vs. Ca9-22) [(C/A2) ×100 in Table I].

Cell-cycle analysis. Treated and untreated cells (approximately 106 cells) were harvested, fixed with paraformaldehyde, treated with RNase A, stained with PI in the presence of 0.01% NP-40, filtered through Falcon® cell strainers and then subjected to cell sorting (SH800 Series; SONY Imaging Products and Solutions Inc., Kanagawa, Japan) and cell-cycle analysis was performed using Cell Sorter Software version 2.1.2. (SONY Imaging Products and Solution Inc.), as described previously (15).

Estimation of CC50 values for computational analysis. Since the CC50 values had a distribution pattern close to the logarithmically normal distribution, we used the negative log CC50 (pCC50) values for the comparison of cytotoxicity between compounds. The mean pCC50 values for normal cells and tumor cell lines were defined as N and T, respectively. The difference (T–N) was used as a tumor-specificity index in the following analyses (8-10).

Figure 4.
Figure 4.

Top six chemical descriptors that showed higher correlation with cytotoxicity of eight 2-arylazolylchromones [1-8] and twelve 2-triazolylchromones [9-20] against OSCC cells. The mean negative log CC50 values (T) against tumor cells were plotted. CC50: concentration of compound that reduced the viable cell number by 50%. Top six chemical descriptors were: SaaN (topological shape and electric state), P_VSA_e_3 (topological shape and electric state), SlogP_VSA1 (topological size and lipophilicity), BCUT_PEOE_1 (topological shape and partial charges), T(N..N) (topological shape and size) and nBnz (topological shape and size).

Figure 5.
Figure 5.

Top six chemical descriptors that showed higher correlation with cytotoxicity of eight 2-arylazolylchromones [1-8] and twelve 2-triazolylchromones [9-20] against normal oral cells. The mean negative log CC50 values (N) against normal cells were plotted. Top six chemical descriptors were: T(N..N) (topological shape and size), P_VSA_i_4 (topological shape and ionization potential), R1v+ (3D shape and size), RTv+ (3D shape and size), SM1_Dz(i) (topological shape, size and ionization potential), PEOE_VSA-0 (topological shape and electric state).

Figure 6.
Figure 6.

Top six chemical descriptors that showed higher correlation with tumor specificity of eight 2-arylazolylchromones [1-8] and twelve 2-triazolylchromones [9-20]. The mean negative log TS values (T-N) were plotted. Top six chemical descriptors were: CATS3D_03_AA (3D shape and size), ATSC4s (topological shape and size), E1s (3D shape and size), L2i (3D shape, size and ionization potential), std_dim2 (3D shape) and L2u (3D shape and size).

Calculation of chemical descriptors. The 3D structure of each chemical structure (Marvin Sketch ver 16; ChemAxon, Budapest, Hungary) (16), was optimized by CORINA Classic (Molecular Networks GmbH, Nürnberg, Germany) (17) with forcefield calculations (amber-10: EHT) in Molecular Operating Environment (MOE) version 2019.0101 (Chemical Computing Group Inc., Quebec, Canada) (18). The number of structural descriptors calculated from MOE and Dragon 7.0 (Dragon 7 version 7.0.2 (Kode srl., Pisa, Italy) (19) were 354 and 5,255, respectively. Among them, the number of descriptors used for analysis were 314 and 2,904 (total 3,218), respectively.

Statistical analysis. The CC50 values were expressed as mean±S.D. of triplicate assays. The relation among cytotoxicity, tumor-specificity index and chemical descriptors was investigated using simple regression analyses by JMP®Pro version 14.3.0 (SAS Institute Inc., Cary, NC, USA) (20). Statistical comparison between the means of two or three groups was performed by Wilcoxon exact test and Steel-Dwass test, respectively. The significance level was set at p<0.05.

Results

Cytotoxicity and tumor-specificity. Among eight 2-arylazolylchromones, [5] showed the highest cytotoxicity against four OSCC cell lines (mean CC50=6.5 μM) (B in Table I), followed by [1] (14.8 μM) > [8] (18.0 μM) > [6] (18.4 μM) > [7] (186.1 μM) > [4] (261.8 μM) > [2, 3] (>400 μM). On the other hand, [5] showed the highest cytotoxicity against three normal oral mesenchymal cells (mean CC50=22.3 μM) (D in Table I), followed by [1] (31.8 μM) > [8] (168.2 μM) > [2] (348.7 μM) > [6] (388.9 μM) > [3, 4, 7] (>400 μM) (Table I). When tumor-specificity (TS) was calculated by the ratio of the mean CC50 for normal oral cells to that of OSCC cells (D/B in Table I), [6] showed the highest TS value (21.2), followed by [8] (9.3) > [5] (3.4) > [1] (2.2) > [7] (2.1) > [4] (1.5) > [3] (1.0) > [2] (0.9). [6] also showed the highest PSE value [(D/B2) ×100 in Table I] (115.0), followed by [5] (52.1) > [8] (51.7) > [1] (14.5) > [7] (1.2) > [4] (0.6) > [3] (0.3) > [2] (0.2). The prominent TS and PSE values of [6] were not changed when the target cells were changed into Ca9-22 and HGF (both derived from gingival tissue): 22.8 (C/A) and 142. [(C/A2) ×100 in Table I], respectively. The dose-response curve (Figure 2) demonstrated that [6] exerted cytostatic growth inhibition against all seven cells. It is apparent that all OSCC cells (Ca9-22, HSC-2, HSC-3, HSC-4) were more sensitive to [6] than the normal oral cells (HGF, HPLF, HPC). Cell-cycle analysis demonstrated that [6] did not affect the distribution of cells to subG1 phase but induced accumulation of cells in the G2+M phase cells (Figure 3).

The twelve 2-triazolylchromones [9-20] showed much lower TS [0.6~2.6 (D/B), 0.1~2.4 (C/A)] and PSE values {0.2~4.0 [(D/B2) ×100], 0.02~4.0 [(C/A2) ×100]} (Table I).

View this table:
Table II.

Properties of descriptors that significantly correlated with cytotoxicity against tumor cells (T) and normal cells (N), and tumor-specificity (T-N).

Computational analysis. QSAR analysis of cytotoxicity and tumor-specificity of eight 2-arylazolylchromones and twelve 2-triazolylchromones were next performed. Since significant correlation (p<0.05) was found between cytotoxicity against tumor and normal cells and TS with 629, 59 and 481 chemical descriptors (data not shown), the top six chemical descriptors were chosen for QSAR analysis (Figures 4, 5 and 6, and Table II).

The cytotoxicity of 20 compounds against OSCC cells was negatively correlated with descriptors SaaN (topological shape and electric state) (r2=0.709, p<0.0001), P_VSA_e_3 (topological shape and electric state) (r2=0.667, p<0.0001), SlogP_VSA1 (topological size and lipophilicity) (r2=0.667, p<0.0001), BCUT_PEOE_1 (topological shape and partial charges) (r2=0.635, p<0.0001) and T(N..N) (topological shape and size) (r2=0.608, p=0.0001), but positively with nBnz (topological shape and size) (r2=0.597, p=0.0001) (Figure 4).

The cytotoxicity of 20 compounds against human normal oral mesenchymal cells was negatively correlated with T(N..N) (topological shape and size) (r2=0.338, p=0.0072), P_VSA_i_4 (topological shape and ionization potential) (r2=0.337, p=0.0072), SM1_Dz(i) (topological shape, size and ionization potential) (r2=0.330, p=0.0080) and PEOE_VSA-0 (topological shape and electric state) (r2=0.325, p=0.0087), but positively with R1v+ (3D shape and size) (r2=0.335, p=0.0075) and RTv+ (3D shape and size) (r2=0.335, p=0.0075), (Figure 5).

Figure 7.
Figure 7.

Correlation between T and the presence of benzene, pyridine, pyrazole and imidazole rings. Statistical comparison between the means of two or three groups was performed by Wilcoxon exact test and Steel-Dwass test, respectively. The significance level was set at p<0.05.

The TS of 20 compounds was correlated with CATS3D_03_AA (3D shape and size) (r2=0.608, p<0.0001), ATSC4s (topological shape and size) (r2=0.589, p=0.0001), E1s (3D shape and size) (r2=0.564, p=0.0001), L2i (3D shape, size and ionization potential) (r2=0.555, p=0.0002), std_dim2 (3D shape) (r2=0.555, p=0.0002) and L2u (3D shape, size) (r2=0.550, p=0.0002) (Figure 6).

Functional group analysis. The cytotoxicity of 20 compounds against OSCC cell lines was increased when a phenyl group was at the R3 position (p=0.0018) but was reduced when it was replaced with pyridine (p=0.0175). When the nitrogen-containing heterocyclic ring had imidazole rather than pyrazole or triazole, cytotoxicity was increased (p=0.0047) (Figure 7).

Figure 8.
Figure 8.

Correlation between N and benzene ring. Statistical comparison between the means of two groups was performed by Wilcoxon exact test. The significance level was set at p<0.05.

Figure 9.
Figure 9.

Correlation between T-N and benzene and imidazole ring. Statistical comparison between the means of two or three groups was performed by Wilcoxon exact test and Steel-Dwass test, respectively. The significance level was set at p<0.05.

The cytotoxicity of 20 compounds against normal oral cells was higher when a phenyl group was present at R3 (p=0.0018) (Figure 8). The type of substituted groups and the presence or absence of halogen (F or Cl) did not significantly affect cytotoxicity (not shown).

Tumor-specificity of 20 compounds was significantly increased by having more than two benzene rings and imidazole in the nitrogen-containing heterocyclic ring (Figure 9).

Discussion

The present study demonstrated that cytotoxicity of eight 2-arylazolylchromones and twelve 2-triazolylchromones against tumor cell lines was significantly (p<0.0001) correlated with topological shape, size, partial charge and lipophilicity (Figures 4). Whenw at position R3, higher cytotoxicity was produced (Figures 7 and 8).

Their tumor-specificity was also significantly correlated (p<0.0002) with 3D shape, topological shape, size, ionization potential (Figure 6). When there were more than two aromatic rings in the molecule and imidazole ring in the nitrogen-containing heterocyclic ring, higher tumor-specificity was observed (Figure 9).

All eight 2-triazolylchromones showed much lower tumor-specificity (TS=0.6~2.6) (Table I), confirming our previous finding of low tumor-specificity of six 2-triazolylchromones 2-(1H-1,2,4-triazol-1-yl)-4H-1-benzopyran-4-one [4a], 7-methoxy-2-(1H-1,2,4-triazol-1-yl)-4H-1-benzopyran-4-one [4b], 6-methoxy-2-(1H-1,2,4-triazol-1-yl)-4H-1-benzopyran-4-one [4c], 2-(1H-1,2,3-triazol-1-yl)-4H-1-benzopyran-4-one [5a], 7-methoxy-2-(1H-1,2,3-triazol-1-yl)-4H-1-benzopyran-4-one [5b], 6-methoxy-2-(1H-1,2,3-triazol-1-yl)-4H-1-benzopyran-4-one [5c] TS=0.9-5)(15).

The present study also demonstrated that among the twenty compounds, [6] showed the highest tumor specificity (as shown by TS and PSE values) (Table I). Furthermore, the tumor-specificity of [6] (TS=21.2, PSE =115.0) was comparable with that of 5-FU (TS=56.4, PSE=318.0) and doxorubicin (TS=12.4; PSE=11689.5) (Table I). It should be noted that the TS value of [6] was higher than that of doxorubicin (TS=12.4). In contrast to positive control of actinomycin D, [6] did not increase the subG1 cell population (a marker of apoptosis), but rather induced cytostatic growth inhibition, accumulation of cells in the G2+M phase (Figure 3). The possibility of inhibition of microtubule formation by [6] should be investigated. Further studies are needed to test the possibility that non-apoptotic cell death is related to the cytostatic growth inhibition rather than cell killing. [6] can be a lead compound for designing a new type of anticancer drugs.

Acknowledgements

This work was partially supported by KAKENHI from the Japan Society for the Promotion of Science (JSPS) (15K08111, 16K11519).

Footnotes

  • ↵Authors' Contributions

    J.N. and Y.U. performed the QSAR analysis. HX.S. and H.S. performed the cytotoxicity assay. N.S., N.Y., K.T. and Y.S. synthesized 20 test compounds. K.B., M.T. and A. T. performed the cell cycle analysis. Y.U., H.S. and Y.S. authored or reviewed drafts of the article.

  • This article is freely accessible online.

  • Conflicts of Interest

    The Authors confirm that there are no conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

  • Received October 19, 2019.
  • Revision received November 5, 2019.
  • Accepted November 6, 2019.

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Quantitative Structure–Cytotoxicity Relationship of 2-Arylazolylchromones and 2-Triazolylchromones
JUNKO NAGAI, HAIXIA SHI, NATSUKO SEZAKI, NAO YOSHIDA, KENJIRO BANDOW, YOSHIHIRO UESAWA, HIROSHI SAKAGAMI, MINEKO TOMOMURA, AKITO TOMOMURA, KOICHI TAKAO, YOSHIAKI SUGITA
Anticancer Research Dec 2019, 39 (12) 6479-6488; DOI: 10.21873/anticanres.13862
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