2-(4-fluorophenylamino)-5-(2-4-dihydroxyphenyl)-1-3-4-thiadiazole and 2-amino-1-3-4-thiadiazole

The anticancer potential of 2-amino-1,3,4-thiadiazole compounds has been documented by in vitro and in vivo studies. In our previous research, we described the synthesis as well as the antiproliferative and neuroprotective activities of 2-(4-fluorophenyloamino)-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole (FABT). The aim of the present study was to investigate the molecular mechanisms involved in FABT-induced growth inhibition in A549 lung carcinoma cells. Western blotting analysis revealed that FABT inhibited the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, and Real-time PCR analysis showed no changes in the expression of P44ERK1 and CREB1 genes. Furthermore, FABT induced cell cycle arrest in the GO/G1 phase and enhanced p27/Kip1 expression. Our results suggest that FABT acts by inhibiting ERK1/2 pathway and cell cycle progression through G1 into S phase in A549 cells. Further studies are needed to completely explain the molecular mechanisms of anticancer action of this 2-aminothiadiazole derivative.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p27; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; MAP Kinase Signaling System; Models, Molecular; Thiadiazoles

Anticancer activity studies of 2-(4-fluorophenylamino)-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole (FABT), as one of the most promising derivatives from the N-substituted 2-amino-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole set, have been continued. The tested compound inhibited proliferation of tumor cells derived from cancers of nervous system (medulloblastoma/rhabdosarcoma, neuroblastoma, and glioma) and peripheral cancers including colon adenocarcinoma and lung carcinoma. The anticancer effect of FABT was attributed to decreased cell division and inhibited cell migration. Furthermore, in anticancer concentrations it exerted a trophic effect in neuronal cell culture and had no influence on viability of normal cells including astrocytes, hepatocytes, and skin fibroblasts. Moreover, a prominent neuroprotective activity of FABT was observed in the neuronal cultures exposed to neurotoxic agents like serum deprivation and glutamate. To determine probability of tautomeric transition and indicate potential sites of interactions of FABT molecule with the receptor, quantum-chemical calculations with the ab initio Hartree-Fock model were made.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Computer Simulation; Drug Screening Assays, Antitumor; Hepatocytes; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Neurons; Neuroprotective Agents; Rats; Rats, Wistar; Sensitivity and Specificity; Structure-Activity Relationship; Thiadiazoles; Thiazoles