Synthesis and anticancer activity of γ-(triazolyl ethylidene)butenolides and polyfunctional pyrrolinones

• Published in: European journal of medicinal chemistry 2014-07, Vol.82, p.106-119
• Main Authors: Devender, N., Ramakrishna, K.K.G., Hamidullah, Shukla, Sanjeev K., Konwar, Rituraj, Tripathi, Rama P.
• Format: Article
• Language: English
• Subjects: 1,2,3-Triazole; 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - chemical synthesis; 4-Butyrolactone - chemistry; 4-Butyrolactone - pharmacology; 5-Hydroxy pyrrolinone; Anticancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HCT116 Cells; HEK293 Cells; Humans; MCF-7 Cells; Molecular Structure; Pyrrolidinones - chemical synthesis; Pyrrolidinones - chemistry; Pyrrolidinones - pharmacology; Reactive Oxygen Species - metabolism; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; γ-Ethylidenebutenolide; γ-Ethylidenepyrrolinone
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.05.042

A series of novel γ-(triazolyl ethylidene)butenolides (4–23) were prepared from commercially available l-ascorbic acid in good yields. These butenolides on reaction with ethanolic ammonia/amines led to formation of respective 5-hydroxy pyrrolinones (24–33). The two of these pyrrolinones on dehydration with p-toluenesulfonic acid, were transformed into γ-(triazolyl ethylidene)pyrrolinones (34, 35). Among all the newly synthesized hybrid molecules tested for anticancer activity in vitro, compounds 24, 25, 26, 27, 28, 30 and 32 showed significant activity against MCF-7, MDA-MB-231, PC-3 or U-937 cells. In particular compound 25 (IC50 = 11.3 μM) exhibited most potent activity against breast cancer cells and preliminary studies revealed that potency of this compound is due to ROS generation, subsequent activation of p38, leading to apoptosis and inhibition of cancer cells. Synthesis and bioevaluation of a novel γ-(triazolyl ethylidene)butenolides and consequent pyrrolinones is reported. In which, compound 25 showed potent activity (IC50 = 11.3 μM) against MDA-MB-231 cells in vitro. [Display omitted] •Access of novel polyfunctional butenolides and pyrrolinones of high therapeutic value.•One of the compounds with IC50 = 11.3 μM against MDA-MB-231 cancer cell lines.•Compounds act via ROS production and apoptosis induction.