title: Interactions of Non-Phosphorous Glycerolipids with DNA: Energetics, Molecular Docking and Topoisomerase I Attenuation.
abstract: The phosphorus-containing glycerolipid based antitumor drugs (edelfosine as a prototype) are currently in clinical trials. To avoid the use of potentially harmful phosphoric reagents in the preparation of biologically active glycerolipids, and to obtain the compounds without the phosphoester bond cleavable inside the cells, we developed the synthesis of non-phosphorous glycerolipids (NPGLs) with neutral or cationic polar 'heads'. In this study, we analyzed the ability of novel NPGLs L1-L5 to interact with duplex DNA and interfere with the DNA modifying enzyme topoisomerase I (topo I). In cell-free systems, NPGLs formed highly affine complexes with DNA. Molecular docking revealed that NPGLs fitted very well into the DNA minor groove. Compounds L2 (with two long hydrophobic 'tails') and L4 (with ethylimidazolium cationic group), the most affine DNA binders, showed the best calculated energies of complex formation with DNA and topo I. The models demonstrated the binding of NPGLs to the topo I site known for interaction with conventional inhibitors. Each NPGL attenuated the topo I mediated unwinding of supercoiled DNA. Again, L2 and, to a lesser extent, L4 were the most potent topo I inhibitors. Thus, NPGLs with polar 'heads' emerge as a new class of DNA ligands and interfacial topo I antagonists.
authors.forename: Valery Y
authors.initials: VY
authors.lastname: Grinberg
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Tsvetkov
authors.forename: Alina A
authors.initials: AA
authors.lastname: Markova
authors.forename: Lyubov G
authors.initials: LG
authors.lastname: Dezhenkova
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Burova
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Grinberg
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Dubovik
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Plyavnik
authors.affiliation: Laboratory of Tumor Cell Death Blokhin Cancer Center, 24 Kashirskoye shosse, Moscow 115478, Russian Federation. shtilaa@yahoo.com.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Shtil
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D053758:Nanoparticles / Q000737:chemistry; D010742:Phospholipid Ethers / Q000737:chemistry*; D059004:Topoisomerase I Inhibitors / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D010742:Phospholipid Ethers; D059004:Topoisomerase I Inhibitors; C026659:edelfosine; D004247:DNA; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human