oxadiazoles and Leukemia

We used the concept of bioisosteres to design and synthesize a novel series of dasatinib derivatives for the treatment of leukemia. Unfortunately, most of the dasatinib derivatives did not show appreciable inhibition against leukemia cell lines K562 and HL60. However, acrylamide compound 2c had comparable inhibitory activity with dasatinib against K562 cells (IC

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Dasatinib; Drug Design; Drug Screening Assays, Antitumor; Humans; Leukemia; Mice; Neoplastic Stem Cells; Oxadiazoles; Triazoles

Multi-target drug design, in which drugs are designed as single molecules to simultaneously modulate multiple physiological targets, is an important strategy in the field of drug discovery. QT-011, a tamibarotene-furoxan derivative, was here prepared and proposed to exert synergistic effects on antileukemia by releasing nitric oxide and tamibarotene. Compared with tamibarotene itself, QT-011 displayed stronger antiproliferative effects on U937 and HL-60 cells and was more effective evaluated in a nude mice U937 xenograft model in vivo. In addition, QT-011 could release nitric oxide which might contribute to the antiproliferative activity. Autodocking assays showed that QT-011 fits well with the hydrophobic pocket of retinoic acid receptors. Taken together, these results suggest that QT-011 might be a highly effective derivative of tamibarotene and a potential candidate compound as antileukemia agent.

Topics: Animals; Antineoplastic Agents; Benzoates; Blotting, Western; Cell Proliferation; Female; Humans; Leukemia; Mice; Mice, Nude; Models, Chemical; Nitric Oxide; Ovarian Neoplasms; Oxadiazoles; Receptors, Retinoic Acid; Tetrahydronaphthalenes; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

A novel small molecule inhibitor, 4-(3-methoxy-phenylsulfannyl)-7-nitro-benzofurazan-3-oxide (MNB), competes with the Bak BH3 peptide to bind Bcl-2 protein with a binding affinity of IC(50) = 0.70 microM, as assessed by a fluorescence polarization based binding assay. HL-60 cells express the highest levels of Bcl-2 among the cell lines examined. Treated with 5 microM of MNB only for 6 h, 85% of HL-60 cells were detected to undergo apoptosis. Pan-caspase inhibitor, Z-VAD-FMK, blocks MNB-induced apoptosis in HL-60 cells. Caspase-2, caspase-3, caspase-7, caspase-8, caspase-9, and PARP activation were observed at as early as 4 to 6 h of MNB treatment. In addition, it has been confirmed that the caspase-3 specific inhibitor, Z-DEVD-FMK, blocks the activation of caspase-8 in MNB-treated HL-60 cells. MNB treatment does not change Bcl-2 or Bax expression level in HL-60 cells, but causes Bid cleavage. Further experiments have illustrated that MNB inhibits the heterodimerization of Bcl-2 with Bax or Bid, reduces the mitochondrial membrane potential (DeltaPsimt), and induces cytochrome c release from mitochondria in HL-60 cells. These results suggest that MNB induces apoptosis in HL-60 by inhibiting the heterodimerization of Bcl-2 with pro-apoptosis Bcl-2 members, resulting in a decrease in the mitochondrial membrane potential and cytochrome c release, activation of caspases and PARP; it is a caspase-dependent process in which the activation of caspase-8 is dependent on the mitochondrial apoptosis signal transduction pathway. MNB prolongs the life spans of HL-60 bearing mice, potently kills fresh AML and ALL cells, indicating that it has the potential to be developed to treat leukemia.

Topics: Animals; Apoptosis; BH3 Interacting Domain Death Agonist Protein; Caspase 2; Cysteine Endopeptidases; Disease Models, Animal; HL-60 Cells; Humans; Leukemia; Mice; Mice, Nude; Oxadiazoles; Proto-Oncogene Proteins c-bcl-2

Topics: Adolescent; Anti-Inflammatory Agents; Bronchitis; Child; Child, Preschool; Citrates; Female; Gastrointestinal Diseases; Growth; Humans; Infant; Infant, Newborn; Leukemia; Lung Neoplasms; Muscles; Osteosarcoma; Oxadiazoles; Pyloric Stenosis; Sarcoma; Sarcoma, Ewing