The aims of this Project are design and synthesis of new COX-2 as well as dual COX-2 and 5-LOX inhibitors, investigation of their anticancer potential, identification of the most promising drug candidates and optimization of their structures in order to improve pharmacokinetic properties. Compounds will be designed (using structure-based and ligand-based in silico methods) and synthesized. Cytotoxicity towards 4 selected cancer cell lines will be evaluated using MTT assay. Analysis of wider anticancer potential of 5 selected compounds will be performed - synergism with conventional chemotherapy (using MTT assay) and radiotherapy (by clonogenic assay), inhibition of angiogenesis (on zebra fish embryos) and activity towards multidrug resistant cancer cells (direct cytotoxicity and sensitization to conventional chemotherapy using MTT assay). The most promising (lead) compounds will be underlined and for two of them, mechanisms of action will be proposed using bioinformatics analysis. Evaluation of selected pharmacokinetic properties will include estimation of passive gastrointestinal absorption using PAMPA and biopartitioning micellar chromatography, estimation of binding to human serum albumin using HPLC method and electrochemistry and investigation of metabolism using human liver microsomes. QSPR, QSRR and QSMARt models and analysis of metabolism will enable optimization of structures of lead compounds to improve their pharmacokinetic properties.
