Purpose-To evaluate the effectiveness of mitigation of acute ionizing radiation damage by mitochondria-targeted small molecules.Materials and Methods-We evaluated the nitroxide-linked alkene peptide isostere JP4-039, the nitric oxide synthase inhibitor-linked alkene peptide esostere MCF201-89, and the p53/mdm2/ mdm4 inhibitor BEB55 in radiation mitigation by clonogenic survival curves with the murine hematopoietic progenitor cell line 32D cl 3, human bone marrow stromal (KM101) and pulmonary epithelial (IB3) cell line. The p53 dependent mechanism of action was tested with p53 +/+ and p53 −/− murine bone marrow stromal cell lines. C57BL/6 NHsd female mice were injected I.P. after 9.5 Gy total body irradiation (TBI) with JP4-039, MCF201-89, or BEB55 individually or in combination.Results-Each drug, JP4-039, MCF201-89, or BEB55, individually or as a mixture of all 3 compounds, increased the survival of 32D cl 3 cells and IB3 cells significantly over control irradiated cells (p=0.0021, p=0.0011, p=0.0038, and p=0.0073, respectively), and (p=0.0193, p=0.0452, p=0.0017, and p=0.0019 respectively). KM101 cells were protected by individual drugs (p=0.0007, p=0.0235, p=0.0044, respectively). JP4-039 and MCF201-89 increased irradiation survival of both p53+/+ (p=0.0396 and p=0.0071, respectively) and p53−/− cells (p=0.0007 and p=0.0188 respectively), while BEB55 was ineffective with (p53−/−) cells. Drugs administered individually or as a mixtures of all 3 after TBI significantly increased mouse survival (p=0.0234, 0.0009, 0.0052 and 0.0167 respectively).Corresponding Author: Joel S. Greenberger M.D., Department of Radiation Oncology, University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Rm. 533, Pittsburgh, PA 15232, Tel: 412-647-3602, Fax: 412-647-1161, greenbergerjs@upmc

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Organic chemistryOrganic chemistry Z 0200The Chemistry of Isocyanides, Their Multicomponent Reactions and Their Libraries -[120 refs.]. -(UGI, L.; WERNER, B.; DOEMLING, A.; Molecules 8 (2003) 1, 53-66; Inst. Org. Chem.

Membrane proteins pose problems for the application of NMR-based ligand-screening methods because of the need to maintain the proteins in a membrane mimetic environment such as detergent micelles: they add to the molecular weight of the protein, increase the viscosity of the solution, interact with ligands non-specifically, overlap with protein signals, modulate protein dynamics and conformational exchange and compromise sensitivity by adding highly intense background signals. In this article, we discuss the special considerations arising from these problems when conducting NMR-based ligand-binding studies with membrane proteins. While the use of (13)C and (15)N isotopes is becoming increasingly feasible, (19)F and (1)H NMR-based approaches are currently the most widely explored. By using suitable NMR parameter selection schemes independent of or exploiting the presence of detergent, (1)H-based approaches require least effort in sample preparation because of the high sensitivity and natural abundance of (1)H in both, ligand and protein. On the other hand, the (19)F nucleus provides an ideal NMR probe because of its similarly high sensitivity to that of (1)H and the lack of natural (19)F background in biologic systems. Despite its potential, the use of NMR spectroscopy is highly underdeveloped in the area of drug discovery for membrane proteins.