Novel 2-(2-alkylthiobenzenesulfonyl)-3-(phenylprop-2-ynylideneamino)guanidine derivatives as potent anticancer agents – Synthesis, molecular structure, QSAR studies and metabolic stability
Abstract
A series of new 2-(2-alkylthiobenzenesulfonyl)-3-(phenylprop-2-ynylideneamino)guanidine derivatives have been synthesized and evaluated in vitro by MTT assays for their antiproliferative activity against cell lines of colon cancer HCT-116, cervical cancer HeLa and breast cancer MCF-7. The obtained results indicated that these compounds display prominent cytotoxic effect. The best anticancer properties have been observed for derivatives 44 (IC50 = 6-18 uM) and 45 (IC50 = 8-14 μM). Very good results of antiproliferative assays have been also shown for compounds 26, 36, and 46 and noticeable anticancer profile has been found for set of derivatives 34e39. Based on results of MTT assays the structure-activity relationships have been drawn. More in-depth biological research revealed that compounds 26, 33, 37, 39, 41 and 43 display cytotoxic effect only against cancer cells and do not inhibit the growth of nonmalignant HaCaT cells. Furthermore, the novel series of derivatives have shown good metabolic stability, especially among the pharmacologically active compounds. To obtain a deeper insight into the molecular description of compounds activity the QSAR studies have been applied. Support vector machines (SVM) have been used to developed QSAR models for predicting the anti-proliferative activity of novel derivatives. The obtained SVM models have shown prognostic ability for HCT-116 and HeLa cell lines and as a result these models may be useful for further development of structurally similar derivatives with better biological properties.
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
no. 138,
pages 357 - 370,
ISSN: 0223-5234 - Language:
- English
- Publication year:
- 2017
- Bibliographic description:
- Pogorzelska A., Sławiński J., Żołnowska B., Szafrański K., Kawiak A., Chojnacki J., Ulenberg S., Zielińska J., Bączek T.: Novel 2-(2-alkylthiobenzenesulfonyl)-3-(phenylprop-2-ynylideneamino)guanidine derivatives as potent anticancer agents – Synthesis, molecular structure, QSAR studies and metabolic stability// EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. -Vol. 138, (2017), s.357-370
- DOI:
- Digital Object Identifier (open in new tab) 10.1016/j.ejmech.2017.06.059
- Bibliography: test
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- 3H, arom.), 7.78 (brs, 1H, NH), 7.82 (s, 1H, H-6 arom.), 10.96 (s, 1H, NH) ppm; open in new tab
- HRMS (ESI-TOF) þ ] 579.0898, found 579.0922. Anal. (C 26 H 22 ClF 3 N 4 O 2 S 2 ) C, H, N.
- 1.3.13. 2-{4-Chloro-5-methyl-2-[(4-trifluoromethylbenzyl)thio] benzenesulfonyl}-3-(3-phenylprop-2-ynylideneamino)guanidine (38). Starting from 20 (0.226 g) and phenylpropiolaldehyde diethyl acetal with stirring for 2 h, the title compound 38 was obtained (0.218 g, 77%): m.p. 176e179 C; IR (KBr): 3398, 3292, 3248 (NH), 2190 (C≡C), 1637 (NH), 1560, 1514, 1489, 1446 (C¼N, C¼C), 1323, 1177 (SO 2 ) cm À1 ; 1 H NMR (200 MHz, DMSO-d 6 ): d 2.26 (s, 3H, CH 3 ), 4.47 (s, 2H, SCH 2 ), 7.17 (s, 1H, N¼CH), 7.47e7.54 (m, 3H, H-3, arom.), 7.58 (m, 5H, arom.), 7.70e7.74 (m, 2H, arom.), 7.84e7.89 (m, 3H, 2 Â NH, H-6 arom.), 11.35 (s, 1H, NH) ppm; open in new tab
- HRMS (ESI-TOF) open in new tab
- C, H, N.
- 1.3.14. 2-{4-Chloro-5-methyl-2-[(4-trifluoromethylbenzyl)thio] benzenesulfonyl}-3-(1-methyl-3-phenylprop-2-ynylideneamino)gua- nidine (39). Starting from 20 (0.226 g) and 4-phenylbut-3-yn-2- one with stirring for 4 h, the title compound 39 was obtained (0.270 g, 94%): m.p. 187e190 C; IR (KBr): 3455, 3280, 3249 (NH), 2921 (CH), 2184 (C≡C), 1636 (NH), 1558, 1513, 1492, 1441 (C¼N, C¼C), 1324, 1162 (SO 2 ) cm À1 ; 1 H NMR (200 MHz, DMSO-d 6 ): d 2.18 (s, 3H, CH 3 ), 2.25 (s, 3H, CH 3 ), 4.45 (s, 2H, SCH 2 ), 7.47e7.54 (m, 3H, H-3, arom.), 7.57e7.70 (m, 6H, NH, arom.), 7.71e7.74 (m, 2H, arom.), 7.83e7.85 (m, 2H, NH, H-6 arom.), 11.03 (s, 1H, NH) ppm; open in new tab
- HRMS (ESI-TOF) open in new tab
- C, H, N.
- 1. 3 . 1 5 . 2 -{ 4 -C h l o r o -2 -[ ( 2 -c h l o r o b e n z y l ) t h i o ] -5 - methylbenzenesulfonyl}-3-(3-phenylprop-2-ynylideneamino)guani- dine (40). Starting from 21 (0.210 g) and phenylpropiolaldehyde diethyl acetal with stirring for 3 h, the title compound 40 was ob- tained (0.231 g, 87%): m.p. 190e193 C; open in new tab
- IR (KBr): 3373, 3265 (NH), 2193 (C≡C), 1633 (NH), 1566, 1511, 1489, 1474 (C¼N, C¼C), 1330, 1168 (SO 2 ) cm À1 ; 1 H NMR (500 MHz, DMSO-d 6 ): d 2.27 (s, 3H, CH 3 ), 4.34 (s, 2H, SCH 2 ), 7.08 (s, 1H, N¼CH), 7.20e7.27 (m, 2H, arom.), 7.38e7.40 (m, 2H, arom.), 7.43e7.46 (m, 3H, NH, H-3, arom.), 7.48e7.51 (m, 1H, arom.), 7.67e7.68 (m, 3H, arom.), 7.80 (brs, 1H, NH), 7.87 (s, 1H, H-6 arom.), 11.23 (s, 1H, NH) ppm;
- HRMS (ESI-TOF) open in new tab
- C, H, N.
- 1. 3 . 1 6 . 2 -{ 4 -C h l o r o -2 -[ ( 2 -c h l o r o b e n z y l ) t h i o ] -5 - m e t h y l b e n z e n e s u l f o n y l } -3 -( 1 -m e t h y l -3 -p h e n y l p r o p -2 - ynylideneamino)guanidine (41). Starting from 21 (0.210 g) and 4- phenylbut-3-yn-2-one with stirring for 6 h, the title compound 41 was obtained (0.186 g, 68%): m.p. 177e179 C; IR (KBr): 3396, 3291, 3244 (NH), 2181 (C≡C), 1633 (NH), 1567, 1508, 1491, 1474 (C¼N, C¼C), 1340, 1169 (SO 2 ) cm À1 ; 1 H NMR (500 MHz, DMSO-d 6 ): open in new tab
- d 2.16 (s, 3H, CH 3 ), 2.25 (s, 3H, CH 3 ), 4.45 (s, 2H, SCH 2 ), 7.20e7.23 (m, 1H, arom.), 7.26e7.29 (m, 1H, arom.), 7.38e7.40 (m, 2H, arom.), 7.42e7.51 (m, 5H, NH, H-3, arom.), 7.67e7.69 (m, 2H, arom.), 7.73 (brs, 1H, NH), 7.85 (s, 1H, H-6 arom.), 10.93 (s, 1H, NH) ppm; HRMS (ESI-TOF) open in new tab
- C, H, N.
- 1. 3 . 17 . 2 -{ 4 -C h l o r o -2 -[ ( 3 -c h l o r o b e n z y l ) t h i o ] -5 - methylbenzenesulfonyl}-3-(3-phenylprop-2-ynylideneamino)guani- dine (42). Starting from 22 (0.210 g) and phenylpropiolaldehyde diethyl acetal with stirring for 3 h, the title compound 42 was ob- tained (0.247 g, 93%): m.p. 195e197 C; open in new tab
- IR (KBr): 3373, 3306 (NH), 2192 (C≡C), 1643 (NH), 1568, 1511, 1451 (C¼N, C¼C), 1331, 1154 (SO 2 ) cm À1 ; 1 H NMR (500 MHz, DMSO-d 6 ): d 2.25 (s, 3H, CH 3 ), 4.33 (s, 2H, SCH 2 ), 7.13 (s, 1H, N¼CH), 7.26e7.29 (m, 3H, arom.), 7.39 (s, 1H, arom.), 7.44e7.51 (m, 4H, H-3, arom.), 7.69e7.70 (m, 2H, arom.), 7.72 (brs, 1H, NH), 7.83 (brs, 1H, NH), 7.85 (s, 1H, H-6 arom.), 11.26 (s, 1H, NH) ppm;
- HRMS (ESI-TOF) m/z calcd for C 24 H 20 Cl 2 N 4 O 2 S 2 [M þ H þ ] 531.0477, found 531.0506. Anal. (C 24 H 20 Cl 2 N 4 O 2 S 2 ) C, H, N. 4 . 1. 3 . 18 . 2 -{ 4 -C h l o r o -2 -[ ( 3 -c h l o r o b e n z y l ) t h i o ] -5 - m e t h yl b e n z e n e s u l f o n yl } -3 -( 1 -m e t h yl -3 -p h e n y l p r o p -2 - ynylideneamino)guanidine (43). Starting from 22 (0.210 g) and 4- phenylbut-3-yn-2-one with stirring for 10 h, the title compound 43 was obtained (0.202 g, 76%): m.p. 175e178 C; IR (KBr): 3447, 3257, 3200 (NH), 2182 (C≡C), 1631 (NH), 1555, 1511, 1491, 1477 (C¼N, C¼C), 1341, 1173 (SO 2 ) cm À1 ; 1 H NMR (500 MHz, DMSO-d 6 ): open in new tab
- d 2.18 (s, 3H, CH 3 ), 2.23 (s, 3H, CH 3 ), 4.32 (s, 2H, SCH 2 ), 7.25e7.31 (m, 3H, arom.), 7.39 (s, 1H, arom.), 7.44e7.46 (m, 2H, arom.), 7.49e7.51 (m, 2H, H-3, arom.), 7.55 (brs, 1H, NH), 7.70e7.72 (m, 2H, arom.), 7.79 (brs, 1H, NH), 7.83 (s, 1H, H-6 arom.), 10.98 (s, 1H, NH) ppm; 13 C NMR (125 MHz, DMSO-d 6 ): d 19.6, 22.9, 36.1, 80.9, 102.6, 120.6, 127.9, 128.4, 129.2, 129.5, 129.6, 130.8, 130.9, 131.3, 132.9, 133.2, 133.5, 133.6, 135.5, 137.4, 139.4, 140.6, 154.5 ppm; HRMS (ESI-TOF) open in new tab
- m/z calcd for C 25 H 22 Cl 2 N 4 O 2 S 2 [M þ H þ ] 545.0634, found 545.0620. Anal. (C 25 H 22 Cl 2 N 4 O 2 S 2 ) C, H, N. 4 . 1. 3 . 1 9 . 2 -{ 4 -C h l o r o -2 -[ ( 4 -c h l o r o b e n z y l ) t h i o ] -5 - methylbenzenesulfonyl}-3-(3-phenylprop-2-ynylideneamino)guani- dine (44). Starting from 23 (0.210 g) and phenylpropiolaldehyde diethyl acetal with stirring for 12 h, the title compound 44 was obtained (0.237 g, 89%): m.p. 175e177 C; IR (KBr): 3386, 3302, 3220 (NH), 2191 (C≡C), 1639 (NH), 1567, 1507, 1491 (C¼N, C¼C), 1330, 1162 (SO 2 ) cm À1 ; 1 H NMR (500 MHz, DMSO-d 6 ): d 2.23 (s, 3H, CH 3 ), 4.31 (s, 2H, SCH 2 ), 7.14 (s, 1H, N¼CH), 7.25 (d, J ¼ 8.8 Hz, 2H, arom.), 7.34 (d, J ¼ 8.3 Hz, 2H, arom.), 7.43e7.49 (m, 2H, arom.), 7.50e7.52 (m, 1H, arom.), 7.53 (s, 1H, H-3 arom.), 7.68e7.70 (m, 2H, arom.), 7.77 (brs, 1H, NH), 7.82e7.83 (m, 2H, NH, H-6 arom.), 11.29 (s, 1H, NH) ppm;
- HRMS (ESI-TOF) m/z calcd for C 24 H 20 Cl 2 N 4 O 2 S 2 [M þ H þ ] 531.0477, found 531.0508. Anal. (C 24 H 20 Cl 2 N 4 O 2 S 2 ) C, H, N. 4 . 1. 3 . 2 0 . 2 -{ 4 -C h l o r o -2 -[ ( 4 -c h l o r o b e n z y l ) t h i o ] -5 - m e t h yl b e n z e n e s u l f o n yl } -3 -( 1 -m e t h yl -3 -p h e n y l p r o p -2 - ynylideneamino)guanidine (45). Starting from 23 (0.210 g) and 4- phenylbut-3-yn-2-one with stirring for 5 h, the title compound 45 was obtained (0.223 g, 84%): m.p. 202e205 C; IR (KBr): 3451, 3261 (NH), 2179 (C≡C), 1632 (NH), 1564, 1491, 1444 (C¼N, C¼C), 1342, 1175 (SO 2 ) cm À1 ; 1 H NMR (500 MHz, DMSO-d 6 ): d 2.17 (s, 3H, CH 3 ), 2.22 (s, 3H, CH 3 ), 4.30 (s, 2H, SCH 2 ), 7.27 (d, J ¼ 8.8 Hz, 2H, arom.), 7.33 (d, J ¼ 8.3 Hz, 2H, arom.), 7.43e7.46 (m, 2H, H-3, arom.), 7.48e7.51 (m, 2H, arom.), 7.55 (brs, 1H, NH), 7.69e7.70 (m, 2H, arom.), 7.77 (brs, 1H, NH), 7.81 (s, 1H, H-6 arom.), 10.97 (s, 1H, NH) ppm;
- HRMS (ESI-TOF) m/z calcd for C 25 H 22 Cl 2 N 4 O 2 S 2 [M þ H þ ] 545.0634, found 545.0637. Anal. (C 25 H 22 Cl 2 N 4 O 2 S 2 ) C, H, N. 4.1.3.21. 2-[4-Chloro-5-methyl-2-(naphthalene-1-ylmethylthio)ben- zenesulfonyl}-3-(3-phenylprop-2-ynylideneamino)guanidine (46). open in new tab
- Starting from 24 (0.218 g) and phenylpropiolaldehyde diethyl acetal with stirring for 20 h, the title compound 46 was obtained (0.213 g, 78%): m.p. 191e194 C; open in new tab
- IR (KBr): 3446, 3274 (NH), 3060, 2913, 2856 (CH), 2188 (C≡C), 1636 (NH), 1563, 1510, 1490, 1443 (C¼N, C¼C), 1343, 1168 (SO 2 ) cm À1 ; 1 H NMR (500 MHz, DMSO-d 6 ): d 2.27 (s, 3H, CH 3 ), 4.76 (s, 2H, SCH 2 ), 6.97 (s, 1H, N¼CH), 7.37e7.42 (m, 3H, arom.), 7.46e7.51 (m, 4H, NH, arom.), 7.58 (s, 1H, H-3 arom.), 7.61e7.63 (m, 3H, arom.), 7.78 (brs, 1H, NH), 7.83e7.84 (d, J ¼ 8.0 Hz, 1H, arom.), 7.88 (s, 1H, H-6 arom.), 7.91e7.92 (m, 1H, arom.), 8.16e8.18 (m, 1H, arom.), 11.18 (s, 1H, NH) ppm;
- HRMS (ESI-TOF) m/z calcd for C 28 H 23 ClN 4 O 2 S 2 [M þ H þ ] 547.1024, found 545.1029. Anal. open in new tab
- C, H, N.
- 1.3.22. 2-[4-Chloro-5-methyl-2-(naphthalene-1-ylmethylthio)ben- zenesulfonyl}-3-(1-methyl-3-phenylprop-2-ynylideneamino)guani- dine (47). Starting from 24 (0.218 g) and 4-phenylbut-3-yn-2-one with stirring for 8 h, the title compound 47 was obtained (0.199 g, 71%): m.p. 177e180 C; IR (KBr): 3448, 3265 (NH), 2182 (C≡C), 1633 (NH), 1566, 1491, 1444 (C¼N, C¼C), 1342, 1171 (SO 2 ) cm À1 ; 1 H NMR (500 MHz, DMSO-d 6 ): d 2.05 (s, 3H, CH 3 ), 2.26 (s, 3H, CH 3 ), 4.75 (s, 2H, SCH 2 ), 7.37e7.41 (m, 4H, arom.), 7.45e7.51 (m, 4H, arom.), 7.59e7.63 (m, 3H, NH, H-3, arom.), 7.71 (brs, 1H, NH), 7.84e7.86 (m, 2H, H-6, arom.), 7.91e7.93 (m, 1H, arom.), 8.16 (d, J ¼ 8.3 Hz, 1H, arom.), 10.87 (s, 1H, NH) ppm; open in new tab
- HRMS (ESI-TOF) m/z calcd for C 29 H 25 ClN 4 O 2 S 2 [M þ H þ ] 561.1180, found 561.1193. Anal. open in new tab
- , 35%): m.p. 192e195 C; IR (KBr): 3430, 3329, 3236 (NH), 3062, 2902 (CH), 2190 (C≡C), 1633 (NH), 1567, 1502, 1487 (C¼N, C¼C), 1346, 1171 (SO 2 ) cm À1 ; 1 H NMR (500 MHz, DMSO-d 6 ): d 2.27 (s, 3H, CH 3 ), 4.23 (s, 2H, SCH 2 ), 6.02 (s, 2H, O-CH 2 -O), 6.91 (s, 1H, N¼CH), 6.97 (s, 1H, arom.), 7.09 (s, 1H, arom.), 7.42e7.50 (m, 4H, H-3, arom.), 7.66e7.68 (m, 3H, NH, arom.), 7.79 (brs, 1H, NH), 7.86 (s, 1H, H-6 arom.), 11.21 (s, 1H, NH) ppm; open in new tab
- HRMS (ESI-TOF) open in new tab
- C, H, N.
- 1. 3 . 24 . 2 -[ 4 -C h l o ro -2 -( 6 -ch l o ro b e n z o [ d ] [ 1, 3 ] d i o x o l -5 - ylmethylthio)-5-methylbenzenesulfonyl]-3-(1-methyl-3-phenylprop- 2-ynylideneamino)guanidine (49). Starting from 25 (0.232 g) and 4- phenylbut-3-yn-2-one with stirring for 14 h, the title compound 49 was obtained (0.092 g, 31%): m.p. 178e181 C; IR (KBr): 3454, 3258 (NH), 2180 (C≡C), 1639 (NH), 1552, 1471 (C¼N, C¼C), 1342, 1176 open in new tab
- (SO 2 ) cm À1 ; 1 H NMR (200 MHz, DMSO-d 6 ): d 2.18 (s, 3H, CH 3 ), 2.27 (s, 3H, CH 3 ), 4.23 (s, 2H, SCH 2 ), 6.04 (s, 2H, O-CH 2 -O), 6.92 (s, 1H, arom.), 7.01 (s, 1H, arom.), 7.44e7.50 (m, 5H, NH, H-3, arom.), 7.66e7.71 (m, 3H, NH, arom.), 7.85 (s, 1H, H-6 arom.), 10.94 (s, 1H, NH) ppm; open in new tab
- HRMS (ESI-TOF) m/z calcd for C 26 H 22 Cl 2 N 4 O 4 S 2 [M þ H þ ] 589.0532, found 589.0554. Anal. (C 26 H 22 Cl 2 N 4 O 4 S 2 ) C, H, N. open in new tab
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