3,5-Disubstituted-thiazolidine-2,4-dione analogs as anticancer agents: Design, synthesis and biological characterization

• Published in: European journal of medicinal chemistry Vol. 47; no. 1; pp. 125 - 137
• Main Authors: Liu, Kai, Rao, Wei, Parikh, Hardik, Li, Qianbin, Guo, Tai L., Grant, Steven, Kellogg, Glen E., Zhang, Shijun
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 2012; Elsevier
• Subjects: Anticancer; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Catalytic Domain; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; DNA - biosynthesis; Drug Design; General aspects; Humans; Life Sciences & Biomedicine; MAP Kinase Kinase 1 - chemistry; MAP Kinase Kinase 1 - metabolism; MAP Kinase Signaling System - drug effects; Medical sciences; Models, Molecular; Multitarget molecule; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - chemistry; Phosphatidylinositol 3-Kinases - metabolism; Science & Technology; Signaling pathways; Structure-Activity Relationship; Thiazolidine-2,4-dione; Thiazolidinediones - chemical synthesis; Thiazolidinediones - chemistry; Thiazolidinediones - metabolism; Thiazolidinediones - pharmacology; Signaling pathways; Anticancer; Multitarget molecule; Thiazolidine-2,4-dione; Apoptosis; MAMMALIAN TARGET; RAF/MEK/ERK; KINASE PATHWAY; ACTIVATION; INVOLVEMENT; CANCER; DISCOVERY; PI3K/AKT PATHWAY; INHIBITION; PROGRESSION; Antineoplastic agent; Human; Cyclohexane derivatives; Histiocytic lymphoma; Thiazolidinedione derivatives; In vitro; Modeling; Biological activity; Signal transduction; Cell line; Molecular model; Chemical synthesis; Prostate; Tumor cell; Thiazolidine derivatives
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.10.031

A series of 2,5-disubstituted-thiazolidine-2,4-dione analogs based on the newly identified lead 1, a potential anticancer agent via the inhibition of the Raf/MEK/extracellular signal regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascades, were synthesized and biologically characterized. A new lead structure, 15, was identified to have improved anti-proliferative activities in U937 cells, to induce apoptosis in U937, M12 and DU145 cancer cells, and to arrest U937 cells at the S-phase. Furthermore, Western blot analysis demonstrated a correlation of the anti-proliferative activity and blockade of the Raf/MEK/ERK and PI3K/Akt signaling pathways. Collectively, these results strongly encourage further optimization of 15 as a new lead with multi-target properties to develop more potent compounds as anticancer agents. [Display omitted] ► Thiazolidine-2,4-dione analogs have anticancer activity. ► We designed and synthesized a series of 3,5-disubstituted-thiazolidine-2,4-dione analogs as anticancer candidates. ► Synthesized compounds were tested in various human cancer cell lines. ► Compound 15 was identified as a new lead compound to develop more potent analogs.