Synthesis and pharmacological evaluation of 2,3‐diphenyl acrylonitriles‐bearing halogen as selective anticancer agents

• Published in: Chemical biology & drug design Vol. 92; no. 2; pp. 1419 - 1428
• Main Authors: Li, Jia‐Jun, Ma, Jun, Xin, Ya‐Bing, Quan, Zhe‐Shan, Tian, Yu‐Shun
• Format: Journal Article
• Language: English
• Published: HOBOKEN Wiley 01.08.2018
• Subjects: 2,3‐diphenyl acrylonitrile; Acrylonitrile - chemical synthesis; Acrylonitrile - chemistry; Acrylonitrile - pharmacology; anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biochemistry & Molecular Biology; Cell Line, Tumor; Cell Movement - drug effects; Chemistry, Medicinal; cyano group; G2 Phase Cell Cycle Checkpoints - drug effects; halogen; Halogens - chemistry; Humans; Life Sciences & Biomedicine; M Phase Cell Cycle Checkpoints - drug effects; Pharmacology & Pharmacy; Science & Technology; selective inhibition; Structure-Activity Relationship; halogen; APOPTOSIS; ANALOGS; selective inhibition; COMBRETASTATIN A-4; 2,3-diphenyl acrylonitrile; cyano group; anticancer; BIOLOGICAL EVALUATION; CHEMISTRY; CURRENT CLINICAL STATUS; DERIVATIVES; VERAPAMIL
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13180

Eighteen novel 2,3‐diphenyl acrylonitrile derivatives bearing halogens were designed, synthesized, and evaluated for biological activity. Preliminary in vitro results indicated that the majority of the compounds with a para‐substituted halogen had considerable antiproliferative activity against five human cancer cell lines, including MGC‐803, AGS, and BEL‐7402, with IC50 values in the range of 0.46–100 μm. No significant toxic effects on the non‐cancerous human liver cell line L‐02 were observed. The selective inhibitory activities against cancer cells were significantly better than that of the control lead compound CA‐4 and CA‐4P. Particularly, potent activities were found for the derivatives of 3‐(4‐halogen phenyl)‐2‐(3,4,5‐trimethoxyphenyl)acrylonitrile, such as 5c (4‐fluoro), 5f (4‐bromo), 5h (4‐chloro), and 5k (4‐trifluoro‐ methyl), for AGS with IC50 values of 0.75 ± 0.24, 0.68 ± 0.21, 0.41 ± 0.05, and 1.49 ± 0.92 μm, respectively. The antiproliferative effects of 5f were attributed to cell‐cycle arrest in the G2/M phase, induction of cellular apoptosis, suppression of cell migration, and inhibition of cell colony formation in AGS cells. Eighteen novel 2,3‐diphenyl acrylonitrile derivatives‐bearing halogens were synthesized. The majority of the compounds with a para‐substituted halogen had considerable selective anticancer activity in vitro with no toxic effects on L‐02 normal liver cells. The selective inhibitory activities against cancer cells were significantly better than that of the control lead compound CA‐4 and CA‐4P. Among them, the antiproliferation effects of 3‐(4‐bromophenyl)‐2‐(3,4,5‐trimethoxyphenyl)acrylonitrile (5f) were attributed to cell‐cycle arrest in the G2/M phase, induction of cellular apoptosis, suppression of cell migration, and inhibition of cell colony formation in AGS cells.