ABSTRACT
Side population (SP) cells mediate chemoresistance in leukemia. However, chemical inhibition approach to target SP cells has been poorly studied. Herein, we report the discovery of isatin derivatives of nicotinic acid amide as potent side population cell inhibitors. The selected derivatives showed superior potency over the reference drug verapamil. Furthermore, the treatment increased chemosensitivity and inhibited the cell proliferation on three different leukemic cell lines, K562, THP-1 and U937, suggesting that both SP and the bulk of leukemic cells are affected. Moreover, treatment with the most potent compound Nic9 reduced the expression of ABCG2, demonstrating that side population inhibition effect of the target derivatives is at least via ABCG2 inhibition. Importantly, the target derivatives induced erythrocyte/dendritic differentiation to leukemic cells mainly through Musashi/Numb pathway modulation.
Subject(s)
Isatin/pharmacology , Leukemia/drug therapy , Niacinamide/pharmacology , Side-Population Cells/drug effects , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/antagonists & inhibitors , ATP-Binding Cassette Transporters/physiology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Resistance, Neoplasm , Humans , Leukemia/pathology , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/physiology , Neoplastic Stem Cells/drug effects , Nerve Tissue Proteins/analysis , Receptors, Nerve Growth Factor/analysisABSTRACT
Four new complexes of Hg (II), Pb (II), Sn (II) and Bi (III) with indomethacin drug ligand (IMC) were synthesized and characterized by using infrared, electronic, 1H-NMR spectral, thermogravimetric and conductivity measurements. The IMC was found to act as bidentate chelating agent. IMC complexes coordinate through the oxygen of the carboxyl group. The molar ratio chelation is 1:2 (M2+:IMC) with general formula [M (IMC) 2], nH2O for Hg (II), Pb(II) and Sn(II), but 1:3 for Bi(III) ions. Antibacterial screening of these heavy metal complexes against Escherichia coli (Gram-ve), Bacillus subtilis (Gram +ve) and anti-fungi (Asperagillus oryzae, Asperagillus niger, Asperagillus Flavus) were investigated. In the present study, we found evidence suggesting that Bi+3/IMC possesses the capacity to protect the stomach, sperm, testes, cellular ATP, cellular NAD, INSL3, PGD2, PGE2 and antioxidant enzymes from deleterious actions of IMC.
Subject(s)
Anti-Bacterial Agents , Bacteria/growth & development , Gastric Mucosa/metabolism , Indomethacin , Metals, Heavy , Oxidative Stress/drug effects , Reproduction/drug effects , Testis/metabolism , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Indomethacin/analogs & derivatives , Indomethacin/chemical synthesis , Indomethacin/chemistry , Indomethacin/pharmacology , Male , Metals, Heavy/chemistry , Metals, Heavy/pharmacology , Rats , Rats, WistarABSTRACT
A novel poly (vinyl chloride) PVC membrane sensor for Fe(2+) ions is described. The sensor is based on the use of newly synthesized chiral 2,6-bis-(carboxamide methyl ester)pyridine derivative as neutral ionophore in plasticized PVC membrane. The sensor display a fast, stable and near-Nernstian response over a relative wide ferrous concentration range (1 × 10(-3) to 6 × 10(-6) M), with cationic slope of 31.5 ± 0.5, mV per concentration decade over a pH range of 5.0-9.0. The direct determination of 0.25-56.0 µg/ml of ferrous in aqueous solution shows an average recovery of 98.5% and a mean relative standard deviation of 1.5% at 20.0 µg/ml. The sensor displays long life-span, long-term stability, high reproducibility, and short response time. Selectivity coefficients for Fe(II) relative to a number of interfering substances were investigated. The sensor shows high significantly for Fe(2+) over Fe,(3+) Cu,(2+) Zn,(2+) Cd,(2+) Hg,(2+) Pb,(2+) Ni,(2+) Co,(2+) Mn,(2+) Al,(3+) alkaline earth and alkali metal ions. The sensor is successfully applied for measurement of ferrous in drug formulations. The results obtained for the determination of ferrous using the proposed sensor are comparable favourably with those obtained using the spectrophotometric method. Copyright © 2010 John Wiley & Sons, Ltd.
Subject(s)
Ferrous Compounds/analysis , Ion-Selective Electrodes , Ionophores/chemistry , Membranes, Artificial , Pharmaceutical Preparations/chemistry , Polyvinyl Chloride/chemistry , Calibration , Cations/chemistry , Dicarboxylic Acids/chemistry , Hydrogen-Ion Concentration , Ionophores/chemical synthesis , Molecular Structure , Plasticizers/chemistry , Potentiometry/methods , Pyridines/chemical synthesis , Pyridines/chemistry , Reproducibility of Results , Tablets/chemistryABSTRACT
Chlordane, is one of many environmental pollutants that reach human or animal body through food and water consumption, its presence may frequently be associated with other metals such as lead. In this work, the toxicity of chlordane and lead to reproductive tissues in Swiss mice was studied. Oral daily doses of 75 and 275 mg/kg b.w. were administered to male mice, for 35 days, animals were sacrificed at the 2nd, 3rd, 4th, and 5th week. The results show that chloradane had a damaging effect on testicular tissues, the effect was obvious through reduction in diameter of the seminiferous tubules, number of spermatogonia, and primary and secondary spermatocytes and spermatids. The effect was remarkably increased by the presence of lead, which needs more investigation in order to determine whether it's a synergistic or additive effect.
