tailieunhanh - Báo cáo khoa học: Structure–activity relation for synthetic phenoxazone drugs Evidence for a direct correlation between DNA binding and pro-apoptotic activity

The structure–activity relations of a series of synthetic phenoxazone drugs with aminoalkyl side chains of variable length and different terminal groups were investigated by examining their biological activity and DNA complexation affinity. Biological activitywas determined fromtheir ability to induce apoptosis and cell cycle perturbations (activation of cell cycle checkpoints) using the human malignant MOLT-3 cell line. The thermodynamic parameters of drug– DNA complexation were determined by differential scan-ning calorimetry | Eur. J. Biochem. 270 4200-4207 2003 FEBS 2003 doi Structure-activity relation for synthetic phenoxazone drugs Evidence for a direct correlation between DNA binding and pro-apoptotic activity Alexei N. Veselkov1 Vladimir Ya. Maleev2 Evgenie N. Glibin3 Leonid Karawajew4 and David B. Davies5 1 Department of Physics and Chemistry Sevastopol National Technical University Crimea Ukraine department of Biophysical and Medical Physics Kharkov National University Ukraine 3Department of Chemistry St Petersburg State Technological University Russia 4Department of Haematology Oncology and Tumour Immunology Robert-Rossle Clinic Charite Humboldt-University of Berlin Germany 5School of Biological and Chemical Sciences Birkbeck College University of London UK The structure-activity relations of a series of synthetic phenoxazone drugs with aminoalkyl side chains of variable length and different terminal groups were investigated by examining their biological activity and DNA complexation affinity. Biological activity was determined from their ability to induce apoptosis and cell cycle perturbations activation of cell cycle checkpoints using the human malignant MOLT-3 cell line. The thermodynamic parameters of drug-DNA complexation were determined by differential scanning calorimetry. By comparing the activities of compounds with different terminal groups amino dimethylamino and diethylamino we found that the existence of a terminal dimethylamino group in the alkylamino side chain is an important factor for anti-tumour activity. Minor modifications in the dimethylaminoalkyl side chain . elongation by one methylene group led to notable changes in both the anti-tumour activity and DNA-binding properties of the drug providing unambiguous evidence of a marked structure-activity relation. Keywords apoptotic activity differential scanning calorimetry DSC drug-DNA binding phenoxazone drugs structure-activity relationship. Many anti-tumour drugs are thought