title: Synthetic prodiginine obatoclax (GX15-070) and related analogues: anion binding, transmembrane transport, and cytotoxicity properties.
abstract: Synthetic prodiginine obatoclax shows promise as a potential anticancer drug. This compound promotes apoptosis of cancer cells, although the mechanism of action is unclear. To date, only the inhibition of BCL-2 proteins has been proposed as a mechanism of action. To gain insight into other possible modes of action, we have studied the anion-binding properties of obatoclax and related analogues in solution, in the solid state, and by means of density functional theory calculations. These compounds are well suited to interact with anions such as chloride and bicarbonate. The anion-transport properties of the compounds synthesized were assayed in model phospholipid liposomes by using a chloride-selective-electrode technique and (13)C NMR spectroscopy. The results demonstrated that these compounds are efficient anion exchangers that promote chloride, bicarbonate, and nitrate transport through lipid bilayers at very low concentrations. In vitro studies on small-cell lung carcinoma cell line GLC4 showed that active ionophores are able to discharge pH gradients in living cells and the cytotoxicity of these compounds correlates well with ionophoric activity.
authors: Departamento de Química, Facultad de Ciencias, Universidad de Burgos, 09001 Burgos, Spain.
authors: Borja
authors: B
authors: Díaz de Greñu
authors: Paulina
authors: P
authors: Iglesias Hernández
authors: Margarita
authors: M
authors: Espona
authors: David
authors: D
authors: Quiñonero
authors: Mark E
authors: ME
authors: Light
authors: Tomás
authors: T
authors: Torroba
authors: Ricardo
authors: R
authors: Pérez-Tomás
authors: Roberto
authors: R
authors: Quesada
mesh_terms: D000818:Animals; D000838:Anions / Q000737:chemistry* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001692:Biological Transport; D002417:Cattle; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D007211:Indoles; D017136:Ion Transport; D007476:Ionophores / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism; D008175:Lung Neoplasms / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D011353:Prodigiosin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D014407:Tumor Cells, Cultured
chemical_list: D000838:Anions; D000970:Antineoplastic Agents; D007211:Indoles; D007476:Ionophores; D008081:Liposomes; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; C010307:prodiginine; D011353:Prodigiosin; C520962:obatoclax