New derivative of 2-(2,4-dihydroxyphenyl)thieno-1,3-thiazin-4-one (BChTT) elicits antiproliferative effect via p38-mediated cell cycle arrest in cancer cells

• Published in: Bioorganic & medicinal chemistry 2016-03, Vol.24 (6), p.1356-1361
• Main Authors: Juszczak, Małgorzata, Walczak, Katarzyna, Matysiak, Joanna, Lemieszek, Marta K., Langner, Ewa, Karpińska, Monika M., Pożarowski, Piotr, Niewiadomy, Andrzej, Rzeski, Wojciech
• Format: Article
• Language: English
• Subjects: 2-(2,4-Dihydroxyphenyl)thieno-1,3-thiazin-4-one; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative action; Cell cycle arrest; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclin D1; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HT29 Cells; Humans; Molecular Structure; Neoplasms - enzymology; Neoplasms - pathology; p38 kinase; p38 Mitogen-Activated Protein Kinases - metabolism; Rats; Structure-Activity Relationship; Thiazines - chemical synthesis; Thiazines - chemistry; Thiazines - pharmacology; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.02.009

[Display omitted] 2-(2,4-Dihydroxyphenyl)thieno-1,3-thiazin-4-ones are a group of new compounds with potential anticancer activity. This type of derivatives was poorly investigated in the area of synthesis and biological activities. In the present study the antiproliferative action of the most active derivative BChTT was described. The aim of biological evaluation was to investigate the ability of the compound to inhibit cancer cell proliferation and identify mechanism involved in its action on the molecular level. BChTT inhibited the proliferation of lung cancer A549, colon cancer HT-29 and glioma C6 cells in the concentration-dependent manner. It was not toxic to normal cells including skin fibroblasts, hepatocytes and oligodendrocytes in the antiproliferative concentrations. BChTT decreased the DNA synthesis in the treated cancer cells and induced cell cycle arrest in the G0/G1 phase. Moreover, the ability of the compound to activate p38 kinase and decrease cyclin D1 expression was estimated. Participation of p38 kinase in the antiproliferative action of the compound was confirmed by the analysis of BChTT activity in the cells with the p38 silenced gene. The obtained results may suggest the ability of the tested derivative to inhibit cancer cells proliferation by induction of p38-mediated cyclin D1 downregulation.