curcumin and pyrimidine

Topics: Antineoplastic Agents; Benzopyrans; Binding Sites; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HEK293 Cells; Humans; MCF-7 Cells; Molecular Docking Simulation; Molecular Structure; Piperazine; Piperazines; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Quinolines; Structure-Activity Relationship

Most of protein post-translational modifications occur in the Golgi and many human diseases are associated with abnormal Golgi function or improper post translational modifications of proteins in the Golgi. In this study, we designed and synthesized 4 × 6 series of novel isothiouronium-modified (E,E)-4,6-bis(styryl)-pyrimidine analogs and found that they localized at the Golgi as visualized by the intrinsic fluorescence of the analogs. The isothiouronium-modified analogs had potent cytotoxicity in both normal (Chinese Hamster Ovary or CHO) and cancer cells. Furthermore, permethylated isothiouronium-modified analogs showed cancer cell-selective cytotoxicity. The molecular mechanisms underlying Golgi localization of isothiouronium-modified compounds were investigated using 7 CHO and 4 human cancer cell lines and the results indicated that the compounds had binding partners in the Golgi. Thus, isothiouronium-modified analogs might be promising anticancer agents, novel Golgi staining reagents, and useful research tools for studying Golgi functions in normal or cancer cells and in Golgi-related human diseases.

Topics: Animals; Antineoplastic Agents; Biological Transport; Cell Line, Tumor; Cricetinae; Curcumin; Golgi Apparatus; Humans; Isothiuronium; Pyrimidines

Curcumin (bis-α,β-unsaturated β-diketone), the chief constituent of turmeric plant (Curcuma longa), plays significant role in prevention of various diseases including diabetes. The research objective in the current study was to synthesize novel anti-diabetic curcumin derivatives with inhibitory properties against α-amylase (α-Amy) and α-glucosidase (α-Gls), as these two carbohydrate-hydrolysing enzymes are known to be important molecular targets for attenuation of postprandial hyperglycemia. The curcumin-based pyrano[2,3-d]pyrimidine derivatives were synthesized in the presence of curcumin, barbituric acids and aldehydes, using a multi-component reaction (MCR). Also, their inhibitory properties against α-Amy and α-Gls were evaluated spectroscopically. The curcumin-derived compounds with two invariant substructures (curcumin-based subunit and barbituric acid moiety) and one variable aryl (Ar) group demonstrated inhibitory action against α-Amy and α-Gls. Moreover, the synthetic compounds revealed prominent antioxidant activities, when examined by a 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) decolorization assay system. Overall, these antioxidant inhibitors are potentially important anti-diabetic drugs, not only to restore euglysemic condition, but also to limit activity of the major reactive oxygen species (ROS) producing pathways in diabetic patients.

Topics: alpha-Amylases; alpha-Glucosidases; Animals; Antioxidants; Curcumin; Enzyme Activation; Enzyme Inhibitors; Humans; Hypoglycemic Agents; Inhibitory Concentration 50; Models, Molecular; Molecular Structure; Pyrimidines; Rats; Reactive Oxygen Species

Epidermal growth factor receptor (EGFR) is an effective molecular target of anti-cancer therapies. Curcumin inhibits cancer cell growth in vitro by suppressing gene expression of EGFR and reduces tumor growth in various animal models. To overcome instable and insoluble properties of curcumin as therapeutics, we designed and synthesized six novel pyrimidine-substituted curcumin analogues with or without a hydroxyl group originally present in curcumin. The cell viability tests indicated that IC50 of the analogues containing hydroxyl group were 3 to 8-fold lower than those of the analogues without hydroxyl group in two colon cancer cell lines tested. Western blot analysis indicates the analogues containing hydroxyl group inhibited expression and tyrosine phosphorylation of EGFR. Further protein analyses showed that the analogues had anti-cellular proliferation, pro-apoptosis, and cell cycle arrest properties associated with suppressed EGFR expression. These results indicate that the hydroxyl groups in curcumin and the analogues were critical for observed biological activities.

Topics: Apoptosis; Cell Cycle Checkpoints; Curcumin; Drug Design; ErbB Receptors; HCT116 Cells; HT29 Cells; Humans; Phosphorylation; Pyrimidines; Signal Transduction

In search of potential therapeutics for cancer, we described herein the synthesis, characterization, and in vitro anticancer activity of a novel series of curcumin analogues. The anticancer effects were evaluated on a panel of 60 cell lines, according to the National Cancer Institute (NCI) screening protocol. There were 10 tested compounds among 14 synthesized compounds, which showed potent anticancer activity in both one-dose and 5-dose assays. The most active compound of the series was 3,5-bis(4-hydroxy-3-methylstyryl)-1H-pyrazole-1-yl(phenyl)methanone which showed mean growth percent of -28.71 in one-dose assay and GI₅₀ values between 0.0079 and 1.86 µM in 5-dose assay.

Topics: Binding Sites; Cell Line, Tumor; Crystallography, X-Ray; Curcumin; ErbB Receptors; Humans; Molecular Docking Simulation; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines