Challenges associated with the synthesis of unusual o-carboxamido stilbenes by the Heck protocol: Intriguing substituent effects, their toxicological and chemopreventive implications

Abstract

The syntheses of fourteen unusual o-carboxamido stilbenes by the Heck protocol revealed surprising complexity related to intriguing substituent effects with mechanistic implications. The unexpected cytotoxic and chemopreventive properties also seem to be substituent dependent. For example, although stilbene 15d (with a 4-methoxy substituent) showed cytotoxicity on HT29 colon cancer cells with an IC(50) of 4.9 μM, the 3,4-dimethoxy derivative (15c) is inactive. It is interesting to observe that the 3,5-dimethoxy derivative (15e) showed remarkable chemopreventive activity in WRL-68 fetal hepatocytes, surpassing the gold standard, resveratrol. The resveratrol concentration needed to be 5 times higher than that of 15e to produce comparable elevation of NQO1.

Design, Synthesis and Cytotoxic Evaluation of o-Carboxamido Stilbene Analogues

“…( E )- N -(2-(3,4-dimethoxystyryl)phenyl)furan-2-carboxamide, 6j [15]. Mp 142–144 °C; IR (NaCl): 3239, 1651, 1575, 1514, 1456, 1265, 1157, 1137, 1027, 751 cm −1 ; UV (MeOH) max nm: 210, 252, 326; 1 H NMR (CDCl 3 , 400 MHz) δ: 8.19 (br s, 1H, NH), 8.00 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.47 (dd, J = 1.8, 1.0 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 2.8 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.07 (d, J = 16.5 Hz, 1H), 7.05 (d, J = 8.9 Hz, 1H), 7.03 (s, 1H), 6.96 (d, J = 16.5 Hz, 1H), 6.85 (d, J = 8.2, 2.3 Hz, 1H), 6.54 (dd, J = 3.4, 1.8 Hz, 1H), 3.89 (s, 3H, OCH 3 ), 3.88 (s, 3H, OCH 3 ); 13 C NMR (CDCl 3 , 100 MHz): 156.4, 149.4, 149.2, 148.0, 144.5, 134.0, 132.7, 130.4, 130.2, 128.2, 127.1, 125.6, 123.7, 121.4, 120.1, 115.4, 112.7, 111.4, 109.3, 56.1 (OCH 3 ), 56.0 (OCH 3 ); HRMS (+ESI) [M + H] + : 320.1411, C 21 H 20 NO 4 requires 320.1392.…”

“…( E )- N -(2-(2-(biphenyl-4-yl)vinyl)phenyl)furan-2-carboxamide, 6l [15]. Mp 142–143 °C; IR (NaCl): 3283, 1671, 1585, 1521, 1487, 1452, 1304, 762 cm −1 ; UV (MeOH) max nm: 204, 267, 323; 1 H NMR (CDCl 3 , 400 MHz) δ: 8.19 (br s, 1H, NH), 8.04 (d, J = 7.8 Hz, 1H), 7.58–7.64 (m, 7H), 7.52 (t, J = 1.0 Hz, 1H), 7.44–7.48 (m, 2H), 7.32–7.38 (m, 2H), 7.21–7.30 (m, 3H), 7.10 (d, J = 16.5 Hz, 1H); 13 C NMR (CDCl 3 , 100 MHz): 156.4, 148.0, 144.5, 141.0, 140.6, 136.1, 134.2, 132.5, 130.2, 129.0, 128.6, 127.6, 127.5, 127.3, 127.0, 125.7, 123.7, 123.3, 115.6, 112.7; HRMS (+ESI) [M + Na] + : 388.1324, C 27 H 22 NO requires 388.1308.…”

“…( E )- N -(2-(3,4-dimethoxystyryl)phenyl)cyclohexanecarboxamide, 6p [15]. Mp 204–206 °C; IR (NaCl): 2930, 2853, 1682, 1515, 1449, 1269, 1137, 1026, 757 cm −1 ; UV (MeOH) max nm: 217, 300; 1 H NMR (CDCl 3 , 400 MHz) δ: 7.77 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.25 (td, J = 8.0, 1.4 Hz, 1H), 7.21 (br s, 1H, NH), 7.17 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.3 Hz, 1H), 7.02 (s, 1H), 6.97 (d, J = 16.5 Hz, 1H), 6.91 (d, J = 16.5 Hz, 1H), 3.91 (s, 3H, OCH 3 ), 3.90 (s, 3H, OCH 3 ), 2.31 (tt, J = 11.7, 3.4 Hz, 1H), 1.22–2.01 (m, 10H); 13 C NMR (CDCl 3 , 100 MHz): 174.5, 149.3, 149.2, 134.6, 132.2, 130.8, 130.2, 128.1, 126.8, 125.6, 124.4, 121.7, 120.1, 111.3, 108.9, 56.1 (OCH 3 ), 55.9 (OCH 3 ), 46.3, 29.9, 25.8; HRMS (+ESI) [M + H] + : 366.2069, C 23 H 28 NO 3 requires 366.2069.…”

“…( E )- N -(2-(3,4-dimethoxystyryl)phenyl)butyramide, 6s [15]. Mp 139–140 °C; IR (NaCl): 3280, 2963, 1510, 1267, 1025, 759 cm −1 ; UV (MeOH) max nm: 206, 323; 1 H NMR (CDCl 3 , 400 MHz) δ: 7.63 (d, J = 7.8 Hz, 1H), 7.56 (br s, 1H, NH), 7.46 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 7.0 Hz, 1H), 7.11 (t, J = 7.3 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.97 (s, 1H), 6.95 (d, J = 15.6 Hz, 1H), 6.85 (d, J = 16.2 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 3.86 (s, 3H, OCH 3 ), 3.85 (s, 3H, OCH 3 ), 2.31 (t, J = 7.3 Hz, 2H), 1.69–1.75 (m, 2H, CH 2 ), 0.97 (t, J = 7.3 Hz, 3H); 13 C NMR (CDCl 3 , 100 MHz): 172.0, 149.2, 149.1, 134.6, 131.6, 131.1, 130.3, 127.9, 126.5, 125.7, 124.9, 121.8, 120.1, 111.3, 109.1, 56.0 (OCH 3 ), 55.9 (OCH 3 ), 39.3, 19.4, 13.9 (CH 3 ); HRMS (+ESI) [M + H] + : 326.1755, C 20 H 24 NO 3 requires 326.1756.…”

“…Previously our group has synthesized a nine o -carboxamido stilbene, incorporating the amide moiety and exhibiting good biological activity against a colon cell line (HT-29), liver cell line (HEP-G2), Jurkat cell and murine leukemic cell line [15–17]. In continuation of this study, we have further synthesized more analogues and all these compounds were evaluated for their cytotoxicity against 6 human cell lines; colon cancer (HT-29), estrogen-sensitive breast cancer (MCF-7), estrogen-insensitive breast cancer (MDA-MB-231), prostate cancer (DU-145), pancreatic cancer (BxPC-3) and normal pancreatic cells (hTERT-HPNE).…”